Long lasting effects of chronic heavy cannabis abuse.

PubMed

Nestoros, Joannis N; Vakonaki, Elena; Tzatzarakis, Manolis N; Alegakis, Athanasios; Skondras, Markos D; Tsatsakis, Aristidis M

2017-06-01

The purpose of this study was to evaluate the extent of short-term memory impairment and schizophrenia-like symptoms in heavy and systematic cannabis users and the association between the severity of abuse and the longevity of its persistent symptoms after refraining from such use. A complete psychiatric examination and a psychometric evaluation were performed in 48 solely cannabis users. Additionally, head hair samples were analyzed and the detected cannabinoids levels were correlated with the psychometric findings. A total of 33.3% (n = 16) of the total examined cannabis users were currently imprisoned. The years of abuse ranged from 1 to 35 years and the median daily dose was 5.84.4 gr and 4.84.0 gr for prisoners (n = 16) and non prisoners (n = 32), respectively. A total of 39.6% of the users experienced hallucinations (mostly auditory), 54.2% experienced delusions (mostly ideas of reference and persecution), 85.4% had organic brain dysfunction in a test addressing visual-motor functioning and visual perception skills, and all users (100%) were found to have organic brain dysfunction in a test of visual memory immediate recall. The cannabinoid metabolite levels in the hair samples were consistent with the reported history of substance abuse and total grams of consumption for the participants below 35 years old (p < .001). Statistically elevated cannabinoids levels were observed in users with auditory hallucinations compared to users without any hallucinations (p = .019). The existence of hallucinations, delusions, and organic brain dysfunction in heavy cannabis users seems to be associated with cannabinoid levels in hair. The continuation of persistent symptoms 3 months after the discontinuation of cannabis abuse, was a remarkable finding. We provide evidence that chronic and heavy cannabis abuse results in long-lasting brain dysfunction in all users and in long-lasting schizophrenia-like psychotic symptoms in more than half of all users. These findings suggest a reevaluation of the current classification of cannabis as a "soft narcotic" which erroneously, therefore, is typically considered harmless. (Am J Addict 2017;26:335-342). © 2017 American Academy of Addiction Psychiatry.

Post-operative cognitive dysfunction after knee arthroplasty: a diagnostic dilemma

PubMed Central

Yap, Kiryu K.; Joyner, Peter

2014-01-01

Post-operative cognitive dysfunction (POCD) is common in the elderly, and significantly impacts their recovery. We present an unusual diagnostic challenge where a 65-year-old male presented 4-week post-total knee arthroplasty with acute cognitive dysfunction lasting 19 days. Curiously, there were no findings uncovering a specific cause, but during investigation underlying predisposing factors such as depression, mild memory deficits and generalized brain volume loss were identified. The impression after psychogeriatric review was that of an organic brain syndrome with overlay of depression, with a complex presentation as POCD. After escalation of behavioural disturbance, he was commenced on anti-psychotic/depressant, with immediate response. We emphasize the importance of pre-operative evaluation of cognitive function and risk factors in all geriatric patients undergoing elective surgery, and the need for further characterization of POCD, as well as experimental research elucidating the underlying mechanisms to better identify and treat this important post-surgical phenomenon. PMID:25988029

Blood-brain barrier dysfunction in brain diseases: clinical experience.

PubMed

Schoknecht, Karl; Shalev, Hadar

2012-11-01

The blood-brain barrier, a unique feature of the cerebral vasculature, is gaining attention as a feature in common neurologic disorders including stroke, traumatic brain injury, epilepsy, and schizophrenia. Although acute blood-brain barrier dysfunction can induce cerebral edema, seizures, or neuropsychiatric symptoms, epileptogenesis and cognitive decline are among the chronic effects. The mechanisms underlying blood-brain barrier dysfunction are diverse and may range from physical endothelial damage in traumatic brain injury to degradation of extracellular matrix proteins via matrix metalloproteinases as part of an inflammatory response. Clinically, blood-brain barrier dysfunction is often detected using contrast-enhanced imaging. However, these techniques do not give any insights into the underlying mechanism. Elucidating the specific pathways of blood-brain barrier dysfunction at different time points and in different brain diseases using novel imaging techniques promises a more accurate blood-brain barrier terminology as well as new treatment options and personalized treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Wound Trauma Mediated Inflammatory Signaling Attenuates a Tissue Regenerative Response in MRL/MpJ Mice

DTIC Science & Technology

2010-01-01

multi-system organ failure, and remote organ injury at sites such as the lung, liver , small intestines, and brain, representing major causes of...inflammatory components. The development of systemic inflammation following severe thermal injury has been implicated in immune dysfunction, delayed wound...healing, multi-system organ failure and increased mortality. Methods: In this study, we examined the impact of thermal injury -induced systemic

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

PubMed Central

Ten, Vadim S.

2017-01-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units—alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise. PMID:27901512

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants.

PubMed

Ten, Vadim S

2017-02-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

Early Effects of Prolonged Cardiac Arrest and Ischemic Postconditioning during Cardiopulmonary Resuscitation on Cardiac and Brain Mitochondrial Function in Pigs.

PubMed

Matsuura, Timothy R; Bartos, Jason A; Tsangaris, Adamantios; Shekar, Kadambari Chandra; Olson, Matthew D; Riess, Matthias L; Bienengraeber, Martin; Aufderheide, Tom P; Neumar, Robert W; Rees, Jennifer N; McKnite, Scott H; Dikalova, Anna E; Dikalov, Sergey I; Douglas, Hunter F; Yannopoulos, Demetris

2017-07-01

Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR). A total of 63 swine were randomized to no ischemia (Naïve), 19min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15min of CA with 4min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue. Compared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain. Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs. Copyright © 2017 Elsevier B.V. All rights reserved.

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment ofmore » learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in As induced VaD.« less

Dorsal brain stem syndrome: MR imaging location of brain stem tegmental lesions in neonates with oral motor dysfunction.

PubMed

Quattrocchi, C C; Longo, D; Delfino, L N; Cilio, M R; Piersigilli, F; Capua, M D; Seganti, G; Danhaive, O; Fariello, G

2010-09-01

The anatomic extent of brain stem damage may provide information about clinical outcome and prognosis in children with hypoxic-ischemic encephalopathy and oral motor dysfunction. The aim of this study was to retrospectively characterize the location and extent of brain stem lesions in children with oral motor dysfunction. From January 2005 to August 2009, 43 infants hospitalized at our institution were included in the study because of a history of hypoxic-ischemic events. Of this group, 14 patients showed oral motor dysfunction and brain stem tegmental lesions detected at MR imaging. MR imaging showed hypoxic-ischemic lesions in supra- and infratentorial areas. Six of 14 patients revealed only infratentorial lesions. Focal symmetric lesions of the tegmental brain stem were always present. The lesions appeared hyperintense on T2-weighted images and hypointense on IR images. We found a strong association (P < .0001) between oral motor dysfunction and infratentorial lesions on MR imaging. Oral motor dysfunction was associated with brain stem tegmental lesions in posthypoxic-ischemic infants. The MR imaging examination should be directed to the brain stem, especially when a condition of prolonged gavage feeding is necessary in infants.

Why Autism Must Be Taken Apart

ERIC Educational Resources Information Center

Waterhouse, Lynn; Gillberg, Christopher

2014-01-01

Although accumulated evidence has demonstrated that autism is found with many varied brain dysfunctions, researchers have tried to find a single brain dysfunction that would provide neurobiological validity for autism. However, unitary models of autism brain dysfunction have not adequately addressed conflicting evidence, and efforts to find a…

The contribution of single case studies to the neuroscience of vision.

PubMed

Zihl, Josef; Heywood, Charles A

2016-03-01

Visual neuroscience is concerned with the neurobiological foundations of visual perception, that is, the morphological, physiological, and functional organization of the visual brain and its co-operative partners. One important approach for understanding the functional organization of the visual brain is the study of visual perception from the pathological perspective. The study of patients with focal injury to the visual brain allows conclusions about the representation of visual perceptual functions in the framework of association and dissociation of functions. Selective disorders have been reported for more "elementary" visual capabilities, for example, color and movement vision, but also for visuo-cognitive capacities, such as visual agnosia or the visual field of attention. Because these visual disorders occur rather seldom as selective and specific dysfunctions, single cases have always played, and still play, a significant role in gaining insights into the functional organization of the visual brain. © 2016 The Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

The Influence of Adipose Tissue on Brain Development, Cognition, and Risk of Neurodegenerative Disorders.

PubMed

Letra, Liliana; Santana, Isabel

2017-01-01

The brain is a highly metabolic organ and thus especially vulnerable to changes in peripheral metabolism, including those induced by obesity-associated adipose tissue dysfunction. In this context, it is likely that the development and maturation of neurocognitive circuits may also be affected and modulated by metabolic environmental factors, beginning in utero. It is currently recognized that maternal obesity, either pre-gestational or gestational, negatively influences fetal brain development and elevates the risk of cognitive impairment and neuropsychiatric disorders in the offspring. During infancy and adolescence, obesity remains a limiting factor for healthy neurodevelopment, especially affecting executive functions but also attention, visuospatial ability, and motor skills. In middle age, obesity seems to induce an accelerated brain aging and thus may increase the risk of age-related neurodegenerative diseases such as Alzheimer's disease. In this chapter we review and discuss experimental and clinical evidence focusing on the influence of adipose tissue dysfunction on neurodevelopment and cognition across lifespan, as well as some possible mechanistic links, namely the role of the most well studied adipokines.

Traumatic Brain Injury: At the Crossroads of Neuropathology and Common Metabolic Endocrinopathies

PubMed Central

Li, Melanie

2018-01-01

Building on the seminal work by Geoffrey Harris in the 1970s, the neuroendocrinology field, having undergone spectacular growth, has endeavored to understand the mechanisms of hormonal connectivity between the brain and the rest of the body. Given the fundamental role of the brain in the orchestration of endocrine processes through interactions among neurohormones, it is thus not surprising that the structural and/or functional alterations following traumatic brain injury (TBI) can lead to endocrine changes affecting the whole organism. Taking into account that systemic hormones also act on the brain, modifying its structure and biochemistry, and can acutely and chronically affect several neurophysiological endpoints, the question is to what extent preexisting endocrine dysfunction may set the stage for an adverse outcome after TBI. In this review, we provide an overview of some aspects of three common metabolic endocrinopathies, e.g., diabetes mellitus, obesity, and thyroid dysfunction, and how these could be triggered by TBI. In addition, we discuss how the complex endocrine networks are woven into the responses to sudden changes after TBI, as well as some of the potential mechanisms that, separately or synergistically, can influence outcomes after TBI. PMID:29538298

Novel clinical features of nonconvulsive status epilepticus

PubMed Central

Nagayama, Masao; Yang, Sunghoon; Geocadin, Romergryko G.; Kaplan, Peter W.; Hoshiyama, Eisei; Shiromaru-Sugimoto, Azusa; Kawamura, Mitsuru

2017-01-01

Nonconvulsive status epilepticus (NCSE) has rapidly expanded from classical features such as staring, repetitive blinking, chewing, swallowing, and automatism to include coma, prolonged apnea, cardiac arrest, dementia, and higher brain dysfunction, which were demonstrated mainly after the 2000s by us and other groups. This review details novel clinical features of NCSE as a manifestation of epilepsy, but one that is underdiagnosed, with the best available evidence. Also, we describe the new concept of epilepsy-related organ dysfunction (Epi-ROD) and a novel electrode and headset which enables prompt electroencephalography. PMID:28979770

Pituitary disorders as a predictor of apathy and executive dysfunction in adult survivors of childhood brain tumors.

PubMed

Fox, Michelle E; King, Tricia Z

2016-11-01

The relationship between apathy and endocrine dysfunction, both frequent outcomes of neurological insult, has not yet been investigated in brain tumor survivors. The present study aimed to assess the relationship between pituitary disorders and apathy and other facets of executive function in long-term adult survivors of childhood brain tumors and to differentiate between apathy and depression in this population. Seventy-six adult survivors of childhood brain tumors at least 5 years past diagnosis participated. An informant completed the Frontal Systems Behavior Scale (FrSBe), and 75 of the 76 participants completed a Structured Clinical Interview for the DSM-IV-TR (SCID). Information on neuroendocrine dysfunction was obtained through medical chart review. Clinically significant levels of apathy on the FrSBe were identified in 41% of survivors. Pituitary dysfunction significantly explained 9% of the variance in apathy scores and affected whether an individual presented with clinical levels of apathy. Pituitary dysfunction predicted higher levels of executive dysfunction but did not impact whether a participant reached clinical levels of executive dysfunction. A past major depressive episode (MDE) significantly predicted current apathy but showed no relationship with pituitary disorders. Radiation treatment predicted pituitary dysfunction but not the differences in apathy or executive functions. Apathy and executive dysfunction in survivors of childhood brain tumors are strongly predicted by pituitary dysfunction, and individuals with pituitary dysfunction are more likely to present with clinical levels of apathy as adults. Clinical levels of apathy may present absent of current depression, and pituitary dysfunction impacts apathy uniquely. © 2016 Wiley Periodicals, Inc.

Adolescent TBI-induced hypopituitarism causes sexual dysfunction in adult male rats.

PubMed

Greco, Tiffany; Hovda, David A; Prins, Mayumi L

2015-02-01

Adolescents are at greatest risk for traumatic brain injury (TBI) and repeat TBI (RTBI). TBI-induced hypopituitarism has been documented in both adults and juveniles and despite the necessity of pituitary function for normal physical and brain development, it is still unrecognized and untreated in adolescents following TBI. TBI induced hormonal dysfunction during a critical developmental window has the potential to cause long-term cognitive and behavioral deficits and the topic currently remains unaddressed. The purpose of this study was to determine if four mild TBIs delivered to adolescent male rats disrupts testosterone production and adult behavioral outcomes. Plasma testosterone was quantified from 72 hrs preinjury to 3 months postinjury and pubertal onset, reproductive organ growth, erectile function and reproductive behaviors were assessed at 1 and 2 months postinjury. RTBI resulted in both acute and chronic decreases in testosterone production and delayed onset of puberty. Significant deficits were observed in reproductive organ growth, erectile function and reproductive behaviors in adult rats at both 1 and 2 months postinjury. These data suggest adolescent RTBI-induced hypopituitarism underlies abnormal behavioral changes observed during adulthood. The impact of undiagnosed hypopituitarism following RTBI in adolescence has significance not only for growth and puberty, but also for brain development and neurobehavioral function as adults. © 2014 Wiley Periodicals, Inc.

Dysfunction of mitochondrial dynamics in the brains of scrapie-infected mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Hong-Seok; Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang, Gyeonggi-do 431-060; Choi, Yeong-Gon

Highlights: • Mfn1 and Fis1 are significantly increased in the hippocampal region of the ME7 prion-infected brain, whereas Dlp1 is significantly decreased in the infected brain. • Dlp1 is significantly decreased in the cytosolic fraction of the hippocampus in the infected brain. • Neuronal mitochondria in the prion-infected brains are enlarged and swollen compared to those of control brains. • There are significantly fewer mitochondria in the ME7-infected brain compared to the number in control brain. - Abstract: Mitochondrial dysfunction is a common and prominent feature of many neurodegenerative diseases, including prion diseases; it is induced by oxidative stress inmore » scrapie-infected animal models. In previous studies, we found swelling and dysfunction of mitochondria in the brains of scrapie-infected mice compared to brains of controls, but the mechanisms underlying mitochondrial dysfunction remain unclear. To examine whether the dysregulation of mitochondrial proteins is related to the mitochondrial dysfunction associated with prion disease, we investigated the expression patterns of mitochondrial fusion and fission proteins in the brains of ME7 prion-infected mice. Immunoblot analysis revealed that Mfn1 was up-regulated in both whole brain and specific brain regions, including the cerebral cortex and hippocampus, of ME7-infected mice compared to controls. Additionally, expression levels of Fis1 and Mfn2 were elevated in the hippocampus and the striatum, respectively, of the ME7-infected brain. In contrast, Dlp1 expression was significantly reduced in the hippocampus in the ME7-infected brain, particularly in the cytosolic fraction. Finally, we observed abnormal mitochondrial enlargement and histopathological change in the hippocampus of the ME7-infected brain. These observations suggest that the mitochondrial dysfunction, which is presumably caused by the dysregulation of mitochondrial fusion and fission proteins, may contribute to the neuropathological changes associated with prion disease.« less

Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy.

PubMed

Rempe, Ralf G; Hartz, Anika M S; Soldner, Emma L B; Sokola, Brent S; Alluri, Satya R; Abner, Erin L; Kryscio, Richard J; Pekcec, Anton; Schlichtiger, Juli; Bauer, Björn

2018-05-02

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo / ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A 2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage. SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A 2 , which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden. Copyright © 2018 the authors 0270-6474/18/384301-15$15.00/0.

Proton Magnetic Resonance Spectroscopy and MRI Reveal No Evidence for Brain Mitochondrial Dysfunction in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Corrigan, Neva M.; Shaw, Dennis. W. W.; Richards, Todd L.; Estes, Annette M.; Friedman, Seth D.; Petropoulos, Helen; Artru, Alan A.; Dager, Stephen R.

2012-01-01

Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ([superscript 1]HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally…

Model Centers Program for Learning Disabled Children: Historical Perspective.

ERIC Educational Resources Information Center

Senf, Gerald M.

This document describes the present federal effort on behalf of learning disabled children, beginning with its recent history. It traces the field of learning disabilities as a subspecialty within education from 1963, when a steering committee was appointed to organize a symposium on "The Child with Minimal Brain Dysfunction," through the Learning…

Rehabilitation of Visual and Perceptual Dysfunction after Severe Traumatic Brain Injury

DTIC Science & Technology

2013-03-01

Alexandra Bowers CONTRACTING ORGANIZATION: Schepens Eye Research Institute...Boston, MA 02114 REPORT DATE: March 2013 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command...should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. REPORT

[Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.

Beta-Adrenergic Receptor Polymorphisms and Cardiac Graft Function in Potential Organ Donors

PubMed Central

Khush, K.K.; Pawlikowska, L.; Menza, R.L.; Goldstein, B.A.; Hayden, V.; Nguyen, J.; Kim, H.; Poon, A.; Sapru, A.; Matthay, M.A.; Kwok, P.Y.; Young, W.L.; Baxter-Lowe, L.A.; Zaroff, J.G.

2012-01-01

Prior studies have demonstrated associations between β-adrenergic receptor polymorphisms and left ventricular dysfunction—an important cause of allograft non-utilization for transplantation. We hypothesized that βAR polymorphisms predispose donor hearts to LV dysfunction after brain death. 1,043 organ donors managed from 2001-2006 were initially studied. The following βAR single nucleotide polymorphisms were genotyped: β1AR 1165C/G (Arg389Gly), β1AR 145A/G (Ser49Gly), β2AR 46G/A (Gly16Arg), and β2AR 79C/G (Gln27Glu). In multivariable regression analyses, the β2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fraction<50%. The β1AR1165 and β2AR46 SNPs were associated with higher dopamine requirement during the donor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 mcg/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between βAR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. βAR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts. PMID:22994654

Lateralized Resting-State Functional Brain Network Organization Changes in Heart Failure

PubMed Central

Park, Bumhee; Roy, Bhaswati; Woo, Mary A.; Palomares, Jose A.; Fonarow, Gregg C.; Harper, Ronald M.; Kumar, Rajesh

2016-01-01

Heart failure (HF) patients show brain injury in autonomic, affective, and cognitive sites, which can change resting-state functional connectivity (FC), potentially altering overall functional brain network organization. However, the status of such connectivity or functional organization is unknown in HF. Determination of that status was the aim here, and we examined region-to-region FC and brain network topological properties across the whole-brain in 27 HF patients compared to 53 controls with resting-state functional MRI procedures. Decreased FC in HF appeared between the caudate and cerebellar regions, olfactory and cerebellar sites, vermis and medial frontal regions, and precentral gyri and cerebellar areas. However, increased FC emerged between the middle frontal gyrus and sensorimotor areas, superior parietal gyrus and orbito/medial frontal regions, inferior temporal gyrus and lingual gyrus/cerebellar lobe/pallidum, fusiform gyrus and superior orbitofrontal gyrus and cerebellar sites, and within vermis and cerebellar areas; these connections were largely in the right hemisphere (p<0.005; 10,000 permutations). The topology of functional integration and specialized characteristics in HF are significantly changed in regions showing altered FC, an outcome which would interfere with brain network organization (p<0.05; 10,000 permutations). Brain dysfunction in HF extends to resting conditions, and autonomic, cognitive, and affective deficits may stem from altered FC and brain network organization that may contribute to higher morbidity and mortality in the condition. Our findings likely result from the prominent axonal and nuclear structural changes reported earlier in HF; protecting neural tissue may improve FC integrity, and thus, increase quality of life and reduce morbidity and mortality. PMID:27203600

Compound mechanism hypothesis on +Gz induced brain injury and dysfunction of learning and memory

NASA Astrophysics Data System (ADS)

Sun, Xi-Qing; Li, Jin-Sheng; Cao, Xin-Sheng; Wu, Xing-Yu

2005-08-01

We systematically studied the effect of high- sustained +Gz on the brain and its mechanism in past ten years by animal centrifuge experiments. On the basis of the facts we observed and the more recent advances in acceleration physiology, we put forward a compound mechanism hypothesis to offer a possible explanation for +Gz-induced brain injury and dysfunction of learning and memory. It states that, ischemia during high G exposure might be the main factor accounting for +Gz-induced brain injury and dysfunction of learning and memory, including transient depression of brain energy metabolism, disturbance of ion homeostasis, increased blood-brain barrier permeability, increased brain nitric oxide synthase expression, and the protective effect of heat shock protein 70. In addition, the large rapid change of intracranial pressure and increased stress during +Gz exposure, and the hemorrheologic change after +Gz exposure might be one of the important factors accounting for +Gz-induced brain injury and dysfunction of learning and memory.

[Effects of diabetes and obesity on the higher brain functions in rodents].

PubMed

Asato, Megumi; Ikeda, Hiroko; Kamei, Junzo

2012-11-01

Metabolic disorders, such as diabetes and obesity, have been indicated to disturb the function of the central nervous system (CNS) as well as several peripheral organs. Clinically, it is well recognized that the prevalence of anxiety and depression is higher in diabetic and obesity patients than in the general population. We have recently indicated that streptozotocin-induced diabetic and diet-induced obesity mice have enhanced fear memory and higher anxiety-like behavior in several tests such as the conditioned fear, tail-suspension, hole-board and elevated open-platform tests. The changes in fear memory and anxiety-like behavior of diabetic and obese mice are due to the dysfunction of central glutamatergic and monoaminergic systems, which is mediated by the changes of intracellular signaling. These results suggest that metabolic disorders strongly affect the function of the CNS and disturb the higher brain functions. These dysfunctions of the CNS in diabetes and obesity are involved in the increased prevalence of anxiety disorders and depression. Normalization of these dysfunctions in the CNS will be a new attractive target to treat the metabolic disorders and their complications.

Structural and synaptic plasticity in stress-related disorders

PubMed Central

Christoffel, Daniel J.; Golden, Sam A.; Russo, Scott J.

2011-01-01

Stress can have a lasting impact on the structure and function of brain circuitry that results in long-lasting changes in the behavior of an organism. Synaptic plasticity is the mechanism by which information is stored and maintained within individual synapses, neurons, and neuronal circuits to guide the behavior of an organism. Although these mechanisms allow the organism to adapt to its constantly evolving environment, not all of these adaptations are beneficial. Under prolonged bouts of physical or psychological stress, these mechanisms become dysregulated, and the connectivity between brain regions becomes unbalanced, resulting in pathological behaviors. In this review, we highlight the effects of stress on the structure and function of neurons within the mesocorticolimbic brain systems known to regulate mood and motivation. We then discuss the implications of these spine adaptations on neuronal activity and pathological behaviors implicated in mood disorders. Finally, we end by discussing recent brain imaging studies in human depression within the context of these basic findings to provide insight into the underlying mechanisms leading to neural dysfunction in depression. PMID:21967517

Viral infection leading to brain dysfunction: more prevalent than appreciated?

PubMed Central

van den Pol, Anthony N.

2009-01-01

Virus infections of the brain can lead to transient or permanent neurologic or psychiatric dysfunction. Some of the complexities in establishing the causal role of viruses in brain disease are explored here. PMID:19840542

Vascular impairment as a pathological mechanism underlying long-lasting cognitive dysfunction after pediatric traumatic brain injury.

PubMed

Ichkova, Aleksandra; Rodriguez-Grande, Beatriz; Bar, Claire; Villega, Frederic; Konsman, Jan Pieter; Badaut, Jerome

2017-12-01

Traumatic brain injury (TBI) is the leading cause of death and disability in children. Indeed, the acute mechanical injury often evolves to a chronic brain disorder with long-term cognitive, emotional and social dysfunction even in the case of mild TBI. Contrary to the commonly held idea that children show better recovery from injuries than adults, pediatric TBI patients actually have worse outcome than adults for the same injury severity. Acute trauma to the young brain likely interferes with the fine-tuned developmental processes and may give rise to long-lasting consequences on brain's function. This review will focus on cerebrovascular dysfunction as an important early event that may lead to long-term phenotypic changes in the brain after pediatric TBI. These, in turn may be associated with accelerated brain aging and cognitive dysfunction. Finally, since no effective treatments are currently available, understanding the unique pathophysiological mechanisms of pediatric TBI is crucial for the development of new therapeutic options. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dynamin-Related Protein 1 as a therapeutic target in cardiac arrest

PubMed Central

Sharp, Willard W.

2015-01-01

Despite improvements in cardiopulmonary resuscitation (CPR) quality, defibrillation technologies, and implementation of therapeutic hypothermia, less than 10% of out-of-hospital cardiac arrest (OHCA) victims survive to hospital discharge. New resuscitation therapies have been slow to develop, in part, because the pathophysiologic mechanisms critical for resuscitation are not understood. During cardiac arrest, systemic cessation of blood flow results in whole body ischemia. CPR, and the restoration of spontaneous circulation (ROSC), both result in immediate reperfusion injury of the heart that is characterized by severe contractile dysfunction. Unlike diseases of localized ischemia/reperfusion (IR) injury (myocardial infarction and stroke), global IR injury of organs results in profound organ dysfunction with far shorter ischemic times. The two most commonly injured organs following cardiac arrest resuscitation, the heart and brain, are critically dependent on mitochondrial function. New insights into mitochondrial dynamics and the role of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) in apoptosis have made targeting these mechanisms attractive for IR therapy. In animal models, inhibiting Drp1 following IR injury or cardiac arrest confers protection to both the heart and brain. In this review, the relationship of the major mitochondrial fission protein Drp1 to ischemic changes in the heart and its targeting as a new therapeutic target following cardiac arrest are discussed. PMID:25659608

Sickle Cell Disease as a Neurodevelopmental Disorder

ERIC Educational Resources Information Center

Schatz, Jeffrey; McClellan, Catherine B.

2006-01-01

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which…

Emergency management of fat embolism syndrome

PubMed Central

Shaikh, Nissar

2009-01-01

Fat emboli occur in all patients with long-bone fractures, but only few patients develop systemic dysfunction, particularly the triad of skin, brain, and lung dysfunction known as the fat embolism syndrome (FES). Here we review the FES literature under different subheadings. The incidence of FES varies from 1–29%. The etiology may be traumatic or, rarely, nontraumatic. Various factors increase the incidence of FES. Mechanical and biochemical theories have been proposed for the pathophysiology of FES. The clinical manifestations include respiratory and cerebral dysfunction and a petechial rash. Diagnosis of FES is difficult. The other causes for the above-mentioned organ dysfunction have to be excluded. The clinical criteria along with imaging studies help in diagnosis. FES can be detected early by continuous pulse oximetry in high-risk patients. Treatment of FES is essentially supportive. Medications, including steroids, heparin, alcohol, and dextran, have been found to be ineffective. PMID:19561953

Endocrine dysfunction in sepsis: a beneficial or deleterious host response?

PubMed Central

Gheorghiţă, Valeriu; Barbu, Alina Elena; Gheorghiu, Monica Livia; Căruntu, Florin Alexandru

2015-01-01

Sepsis is a systemic, deleterious inflammatory host response triggered by an infective agent leading to severe sepsis, septic shock and multi-organ failure. The host response to infection involves a complex, organized and coherent interaction between immune, autonomic, neuroendocrine and behavioral systems. Recent data have confirmed that disturbances of the autonomic nervous and neuroendocrine systems could contribute to sepsis-induced organ dysfunction. Through this review, we aimed to summarize the current knowledge about the endocrine dysfunction as response to sepsis, specifically addressed to vasopressin, copeptin, cortisol, insulin and leptin. We searched the following readily accessible, clinically relevant databases: PubMed, UpToDate, BioMed Central. The immune system could be regarded as a “diffuse sensory organ” that signals the presence of pathogens to the brain through different pathways, such as the vagus nerve, endothelial activation/dysfunction, cytokines and neurotoxic mediators and the circumventricular organs, especially the neurohypophysis. The hormonal profile changes substantially as a consequence of inflammatory mediators and microorganism products leading to inappropriately low levels of vasopressin, sick euthyroid syndrome, reduced adrenal responsiveness to ACTH, insulin resistance, hyperglycemia as well as hyperleptinemia. In conclusion, clinical diagnosis of this “pan-endocrine illness” is frequently challenging due to the many limiting factors. The most important benefits of endocrine markers in the management of sepsis may be reflected by their potential to be used as biomarkers in different scoring systems to estimate the severity of the disease and the risk of death. PMID:25763364

CD40-CD40 Ligand Pathway is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis.

PubMed

Michels, Monique; Danieslki, Lucinéia Gainski; Vieira, Andriele; Florentino, Drielly; Dall'Igna, Dhébora; Galant, Letícia; Sonai, Beatriz; Vuolo, Francieli; Mina, Franciele; Pescador, Bruna; Dominguini, Diogo; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Petronilho, Fabrícia

2015-03-26

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.

CD40–CD40 Ligand Pathway Is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis

PubMed Central

Michels, Monique; Danieslki, Lucinéia Gainski; Vieira, Andriele; Florentino, Drielly; Dall’Igna, Dhébora; Galant, Letícia; Sonai, Beatriz; Vuolo, Francieli; Mina, Franciele; Pescador, Bruna; Dominguini, Diogo; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Petronilho, Fabrícia

2015-01-01

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40–CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40–CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40–CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40–CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis. PMID:25822797

Is magnetite a universal memory molecule?

PubMed

Størmer, Fredrik C

2014-11-01

Human stem cells possess memory, and consequently all living human cells must have a memory system. How memory is stored in cells and organisms is an open question. Magnetite is perhaps the best candidate to be a universal memory molecule. Magnetite may give us a clue, because it is the Earth's most distributed and important magnetic material. It is found in living organisms with no known functions except for involvement in navigation in some organisms. In humans magnetite is found in the brain, heart, liver and spleen. Humans suffer from memory dysfunctions in many cases when iron is out of balance. Anomalous concentrations of magnetite is known to be associated with a neurodegenerative disorder like Alzheimer's disease. Due to the rapid speed and accuracy of our brain, memory and its functions must be governed by quantum mechanics. Copyright © 2014 Elsevier Ltd. All rights reserved.

Development of the Korean Academy of Medical Sciences Guideline for Rating the Impairment in the Brain Injured and Brain Diseased Persons with Motor Dysfunction

PubMed Central

Baik, Jong Sam; Jang, Seong Ho; Park, Dong Sik

2009-01-01

To develop an objective and scientific method to evaluate the brain injured and brain diseased persons with motor dysfunction, American Medical Association's Guides to the Evaluation of Permanent Impairment was used as an exemplar. After the motor dysfunction due to brain injury or brain disease was confirmed, active range of motion and muscle strength of affected extremities were measured. Also, the total function of extremities was evaluated through the assessment of activities of daily living, fine coordination of hand, balance and gait. Then, the total score of manual muscle test and functional assessment of impaired upper and lower extremity were added, respectively. Spasticity of upper and lower extremity was used as minus factors. Patients with movement disorder such as Parkinson's disease were assessed based on the degree of dysfunction in response to medication. We develop a new rating system based on the concept of total score. PMID:19503680

Iron assessment to protect the developing brain.

PubMed

Georgieff, Michael K

2017-12-01

Iron deficiency (ID) before the age of 3 y can lead to long-term neurological deficits despite prompt diagnosis of ID anemia (IDA) by screening of hemoglobin concentrations followed by iron treatment. Furthermore, pre- or nonanemic ID alters neurobehavioral function and is 3 times more common than IDA in toddlers. Given the global prevalence of ID and the enormous societal cost of developmental disabilities across the life span, better methods are needed to detect the risk of inadequate concentrations of iron for brain development (i.e., brain tissue ID) before dysfunction occurs and to monitor its amelioration after diagnosis and treatment. The current screening and treatment strategy for IDA fails to achieve this goal for 3 reasons. First, anemia is the final state in iron depletion. Thus, the developing brain is already iron deficient when IDA is diagnosed owing to the prioritization of available iron to red blood cells over all other tissues during negative iron balance in development. Second, brain ID, independently of IDA, is responsible for long-term neurological deficits. Thus, starting iron treatment after the onset of IDA is less effective than prevention. Multiple studies in humans and animal models show that post hoc treatment strategies do not reliably prevent ID-induced neurological deficits. Third, most currently used indexes of ID are population statistical cutoffs for either hematologic or iron status but are not bioindicators of brain ID and brain dysfunction in children. Furthermore, their relation to brain iron status is not known. To protect the developing brain, there is a need to generate serum measures that index brain dysfunction in the preanemic stage of ID, assess the ability of standard iron indicators to detect ID-induced brain dysfunction, and evaluate the efficacy of early iron treatment in preventing ID-induced brain dysfunction. © 2017 American Society for Nutrition.

Reconceptualizing mental disorders: From symptoms to organs.

PubMed

Bunge, Mario

2017-06-01

Most mental pathologies are diagnosed on the sole basis of the symptoms reported by patients, such as "I'm feeling low." The thrust of this paper is the proposal to reconceptualize mental disorders as dysfunctions of brain subsystems. This shift from symptom to organ would bring psychiatry in line with the rest of medicine, and is analogous to the change in status of venereal infections from skin pathologies, such as chancres, to bacterial infections. The proposal in question is part of the reconceptualization of mental processes as brain processes, in line with the materialist conception of the mind as neural. A practical advantage of this conceptual change is that it suggests approaching mental disorders as brain dysfunctions treatable by biological and chemical means, in addition to social measures, such as accommodating mental patients in ordinary hospitals rather than in isolated "madhouses" at the mercy of amateurs or even charlatans. An additional advantage of the "embodiment" of mental diseases is that it suggests reframing some new research projects, such as explaining why the common cold causes mental fogginess, why hypertension can cause irritability, and why nicotine dependence can be even stronger than cocaine addiction. In other words, the present proposal is to complete the so-called "mapping of the mind onto the brain" by including the abnormal mental processes, which used to be treated by shamans at a time when the mind was conceived of as an immaterial entity detachable from the body. © 2017 The Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

Effect of Insulin Therapy using Hyper-insulinemic Normoglycemic Clamp on Inflammatory Response in Brain Dead Organ Donors.

PubMed

Aljiffry, M; Hassanain, M; Schricker, T; Shaheen, M; Nouh, T; Lattermann, R; Salman, A; Wykes, L; Metrakos, P

2016-05-01

Brain death is a major stress that is associated with a massive inflammatory response and systemic hyperglycemia. Severe inflammation leads to increased graft immunogenicity and risk of graft dysfunction; while acute hyperglycemia aggravates the inflammatory response and increases the risk of morbidity and mortality. Insulin therapy not only controls hyperglycemia but also suppresses inflammation. The present study is to investigate the anti-inflammatory properties and the normoglycemia maintenance of high dose insulin on brain dead organ donors. 15 brain dead organ donors were divided into 2 groups, insulin treated (n=6) and controls (n=9). Insulin was provided for a minimum of 6 h using the hyperinsulinemic normoglycemic clamp technique. The changes of serum cytokines, including IL-6, IL-10, IL-1β, IL-8, TNFα, TGFα and MCP-1, were measured by suspension bead array immunoassay and glucose by a glucose monitor. Compared to controls, insulin treated donors had a significant lower blood glucose 4.8 (4-6.9) vs. 9 (5.6-11.7) mmol/L, p<0.01); the net decreases of pro-inflammatory cytokines, such as IL-6 and MCP-1, and the net increase of anti-inflammatory cytokine, such as IL-10, reached significant level in insulin treated donors compared with those in controls. High dose insulin therapy decreases the concentrations of inflammatory cytokines in brain dead donors and preserves normoglycemia. High dose of insulin may have anti-inflammatory effects in brain dead organ donors and therefore, improve the quality of donor organs and potentially improve outcomes. © Georg Thieme Verlag KG Stuttgart · New York.

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

PubMed Central

Haldar, Swati; Tripathi, Ajai K.; Horback, Katharine; Wong, Joseph; Sharma, Deepak; Beserra, Amber; Suda, Srinivas; Anbalagan, Charumathi; Dev, Som; Mukhopadhyay, Chinmay K.; Singh, Ajay

2014-01-01

Abstract Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324–1363. PMID:23815406

Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities.

PubMed

Singh, Neena; Haldar, Swati; Tripathi, Ajai K; Horback, Katharine; Wong, Joseph; Sharma, Deepak; Beserra, Amber; Suda, Srinivas; Anbalagan, Charumathi; Dev, Som; Mukhopadhyay, Chinmay K; Singh, Ajay

2014-03-10

Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders.

Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution.

PubMed

Calderón-Garcidueñas, Lilian; Reed, William; Maronpot, Robert R; Henríquez-Roldán, Carlos; Delgado-Chavez, Ricardo; Calderón-Garcidueñas, Ana; Dragustinovis, Irma; Franco-Lira, Maricela; Aragón-Flores, Mariana; Solt, Anna C; Altenburg, Michael; Torres-Jardón, Ricardo; Swenberg, James A

2004-01-01

Air pollution is a complex mixture of gases (e.g., ozone), particulate matter, and organic compounds present in outdoor and indoor air. Dogs exposed to severe air pollution exhibit chronic inflammation and acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by pollutants. We investigated whether residency in cities with high levels of air pollution is associated with human brain inflammation. Expression of cyclooxygenase-2 (COX2), an inflammatory mediator, and accumulation of the 42-amino acid form of beta-amyloid (Abeta42), a cause of neuronal dysfunction, were measured in autopsy brain tissues of cognitively and neurologically intact lifelong residents of cities having low (n:9) or high (n:10) levels of air pollution. Genomic DNA apurinic/apyrimidinic sites, nuclear factor-kappaB activation and apolipoprotein E genotype were also evaluated. Residents of cities with severe air pollution had significantly higher COX2 expression in frontal cortex and hippocampus and greater neuronal and astrocytic accumulation of Abeta42 compared to residents in low air pollution cities. Increased COX2 expression and Abeta42 accumulation were also observed in the olfactory bulb. These findings suggest that exposure to severe air pollution is associated with brain inflammation and Abeta42 accumulation, two causes of neuronal dysfunction that precede the appearance of neuritic plaques and neurofibrillary tangles, hallmarks of Alzheimer's disease.

Social dysfunction after pediatric traumatic brain injury: a translational perspective

PubMed Central

Ryan, Nicholas P.; Catroppa, Cathy; Godfrey, Celia; Noble-Haeusslein, Linda J.; Shultz, Sandy R.; O'Brien, Terence J.; Anderson, Vicki; Semple, Bridgette D.

2016-01-01

Social dysfunction is common after traumatic brain injury (TBI), contributing to reduced quality of life for survivors. Factors which influence the emergence, development or persistence of social deficits after injury remain poorly understood, particularly in the context of ongoing brain maturation during childhood. Aberrant social interactions have recently been modeled in adult and juvenile rodents after experimental TBI, providing an opportunity to gain new insights into the underlying neurobiology of these behaviors. Here, we review our current understanding of social dysfunction in both humans and rodent models of TBI, with a focus on brain injuries acquired during early development. Modulators of social outcomes are discussed, including injury-related and environmental risk and resilience factors. Disruption of social brain network connectivity and aberrant neuroendocrine function are identified as potential mechanisms of social impairments after pediatric TBI. Throughout, we highlight the overlap and disparities between outcome measures and findings from clinical and experimental approaches, and explore the translational potential of future research to prevent or ameliorate social dysfunction after childhood TBI. PMID:26949224

Contemporary Patterns of Multiple Organ Dysfunction in Trauma.

PubMed

Shepherd, Joanna M; Cole, Elaine; Brohi, Karim

2017-04-01

Multiple organ dysfunction syndrome (MODS) is associated with poor outcomes for trauma patients. Different forms of MODS may exist and have different consequences. The ability to distinguish them clinically may have implications for prognosis and treatment. We wished to study whether prolonged MODS (PRMODS) could be observed as a distinct clinical entity to early resolving MODS (ERMODS) in critically injured patients. Adult major trauma patients recruited to a prospective observational study at a single major trauma center were eligible for inclusion. MODS was defined as Sequential Organ Failure Assessment (SOFA) score >5; and PRMODS as lasting >7 days. Time to recovery (TTR) was calculated as the number of days before the SOFA fell below the MODS threshold (≤5). Five hundred ninety-five patients were enrolled of whom 285 developed ERMODS (48%) and 184 (31%) PRMODS. Organ dysfunction was more severe and protracted in PRMODS, especially in patients without brain injury (mean SOFA 11 vs. 6, Day 2, P < 0.001; TTR 17 vs. 3 days, P < 0.001). PRMODS exhibited higher rates of hepatic and renal dysfunction (84% vs. 56%; and 78% vs. 47%, P≤0.001). Patterns of recovery were distinct in hepatic, renal, and neurological systems (TTR 15 vs. 4; 20 vs. 3; and 28 vs. 7 days, P < 0.01). PRMODS was associated with higher infection and mortality rates (91% vs. 41%; and 22% vs. 7%, P < 0.001). PRMODS appears common, a distinct clinical entity, and associated with worse patient outcomes. PRMODS may represent an important endpoint for studies evaluating outcomes following trauma.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

PubMed

Skelly, Donal T; Griffin, Éadaoin W; Murray, Carol L; Harney, Sarah; O'Boyle, Conor; Hennessy, Edel; Dansereau, Marc-Andre; Nazmi, Arshed; Tortorelli, Lucas; Rawlins, J Nicholas; Bannerman, David M; Cunningham, Colm

2018-06-06

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consoliodation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI -/- -dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Early detection of nonneurologic organ failure in patients with severe traumatic brain injury: Multiple organ dysfunction score or sequential organ failure assessment?

PubMed

Ramtinfar, Sara; Chabok, Shahrokh Yousefzadeh; Chari, Aliakbar Jafari; Reihanian, Zoheir; Leili, Ehsan Kazemnezhad; Alizadeh, Arsalan

2016-10-01

The aim of this study is to compare the discriminant function of multiple organ dysfunction score (MODS) and sequential organ failure assessment (SOFA) components in predicting the Intensive Care Unit (ICU) mortality and neurologic outcome. A descriptive-analytic study was conducted at a level I trauma center. Data were collected from patients with severe traumatic brain injury admitted to the neurosurgical ICU. Basic demographic data, SOFA and MOD scores were recorded daily for all patients. Odd's ratios (ORs) were calculated to determine the relationship of each component score to mortality, and area under receiver operating characteristic (AUROC) curve was used to compare the discriminative ability of two tools with respect to ICU mortality. The most common organ failure observed was respiratory detected by SOFA of 26% and MODS of 13%, and the second common was cardiovascular detected by SOFA of 18% and MODS of 13%. No hepatic or renal failure occurred, and coagulation failure reported as 2.5% by SOFA and MODS. Cardiovascular failure defined by both tools had a correlation to ICU mortality and it was more significant for SOFA (OR = 6.9, CI = 3.6-13.3, P < 0.05 for SOFA; OR = 5, CI = 3-8.3, P < 0.05 for MODS; AUROC = 0.82 for SOFA; AUROC = 0.73 for MODS). The relationship of cardiovascular failure to dichotomized neurologic outcome was not significant statistically. ICU mortality was not associated with respiratory or coagulation failure. Cardiovascular failure defined by either tool significantly related to ICU mortality. Compared to MODS, SOFA-defined cardiovascular failure was a stronger predictor of death. ICU mortality was not affected by respiratory or coagulation failures.

[Retinal vasculopathy with cerebral leukoencephalopathy carrying TREX1 mutation diagnosed by the intracranial calcification: a case report].

PubMed

Komaki, Ryouhei; Ueda, Takehiro; Tsuji, Yukio; Miyawaki, Toko; Kusuhara, Sentaro; Hara, Shigeo; Toda, Tatsushi

2018-02-28

A 40-year-old woman with renal dysfunction for 2 years was admitted to our hospital suffering from a headache. Family history revealed that her mother had a headache, renal dysfunction, and brain infarction in younger age. She had a retinal hemorrhage, a retinal atrophy, pitting edema in her lower extremities. Her neurological findings were unremarkable. Brain imaging showed multiple white matter lesions accompanied with calcifications and slightly enhancement. Kidney biopsy showed the thrombotic microangiopathy, Gene analysis demonstrated a causative mutation in three-prime repair exonuclease-1 (TREX1) gene, c.703_704insG (p.Val235GlyfsX6), thereby we diagnosed her as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). RVCL is an autosomal dominant condition caused by C-terminal frame-shift mutation in TREX1. TREX1 protein is a major 3' to 5' DNA exonuclease, which are important in DNA repair. While TREX1 mutations identified in Aicardi-Goutieres syndrome patients lead to a reduction of enzyme activity, it is suggested that mutations in RVCL alter an intracellular location of TREX1 protein. There are no treatments based evidences in RVCL. We administered cilostazol to protect endothelial function, and her brain lesions and renal function have not become worse for 10 months after. It is necessary to consider RVCL associated with TREX1 mutation if a patient has retinal lesions, white matter lesions accompanied with calcifications, and multiple organ dysfunction.

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice.

PubMed

Paul, Rajib; Borah, Anupom

2017-12-20

There exists an intricate relationship between hypercholesterolemia (elevated plasma cholesterol) and brain functions. The present study aims to understand the impact of hypercholesterolemia on pathological consequences in mouse brain. A chronic mouse model of hypercholesterolemia was induced by giving high-cholesterol diet for 12 weeks. The hypercholesterolemic mice developed cognitive impairment as evident from object recognition memory test. Cholesterol accumulation was observed in four discrete brain regions, such as cortex, striatum, hippocampus and substantia nigra along with significantly damaged blood-brain barrier by hypercholesterolemia. The crucial finding is the loss of acetylcholinesterase activity with mitochondrial dysfunction globally in the brain of hypercholesterolemic mice, which is related to the levels of cholesterol. Moreover, the levels of hydroxyl radical were elevated in the regions of brain where the activity of mitochondrial complexes was found to be reduced. Intriguingly, elevations of inflammatory stress markers in the cholesterol-rich brain regions were observed. As cognitive impairment, diminished brain acetylcholinesterase activity, mitochondrial dysfunctions, and inflammation are the prima facie pathologies of neurodegenerative diseases, the findings impose hypercholesterolemia as potential risk factor towards brain dysfunction.

White matter and cognition: making the connection

PubMed Central

Fields, R. Douglas

2016-01-01

Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society. PMID:27512019

[Brainstem auditory evoked potentials in neurophysiological assessment of brain stem dysfunction in patients with atherostenosis of vertebral arteries].

PubMed

Maksimova, M Yu; Sermagambetova, Zh N; Skrylev, S I; Fedin, P A; Koshcheev, A Yu; Shchipakin, V L; Sinicyn, I A

To assess brain stem dysfunction in patients with hemodynamically significant stenosis of vertebral arteries (VA) using short latency brainstem auditory evoked potentials (BAEP). The study group included 50 patients (mean age 64±6 years) with hemodynamically significant extracranial VA stenosis. Patients with hemodynamically significant extracranial VA stenosis had BAEP abnormalities including the elongation of interpeak intervals I-V and peak V latency as well as the reduction of peak I amplitude. After transluminal balloon angioplasty with stenting of VA stenoses, there was a shortening of peak V latency compared to the preoperative period that reflected the improvement of brain stem conductive functions. Atherostenosis of vertebral arteries is characterized by the signs of brain stem dysfunction, predominantly in the pontomesencephal brain stem. After transluminal balloon angioplasty with stenting of VA, the improvement of brain stem conductive functions was observed.

Learning Disability Assessed through Audiologic and Physiologic Measures: A Case Study.

ERIC Educational Resources Information Center

Greenblatt, Edward R.; And Others

1983-01-01

The report describes a child with central auditory dysfunction, the first reported case where brain-stem dysfunction on audiologic tests were associated with specific electrophysiologic changes in the brain-stem auditory-evoked responses. (Author/CL)

Neuroscience Literacy: "Brain Tells" as Signals of Brain Dysfunction Affecting Daily Life.

PubMed

Royeen, Charlotte B; Brašić, James R; Dvorak, Leah; Provoziak-O'Brien, Casey; Sethi, Chetna; Ahmad, S Omar

2016-01-01

The structures and circuits of the central and the peripheral nervous systems provide the basis for thinking, speaking, experiencing sensations, and performing perceptual and motor activities in daily life. Healthy people experience normal functioning without giving brain functions a second thought, while dysfunction of the neural circuits may lead to marked impairments in cognition, communication, sensory awareness, and performing perceptual and motor tasks. Neuroscience literacy provides the knowledge to associate the deficits observed in patients with the underlying deficits in the structures and circuits of the nervous system. The purpose of this paper is to begin the conversation in this area via a neuroscience literacy model of "Brain Tells," defined as stereotypical or observable behaviors often associated with brain dysfunction. Occupational therapists and other allied health professionals should be alert for the signs of "Brain Tells" that may be early warning signs of brain pathology. We also suggest that neuroscience literacy be emphasized in training provided to public safety workers, teachers, caregivers, and health care professionals at all levels.

Association of Blood Pressure Control Level With Left Ventricular Morphology and Function and With Subclinical Cerebrovascular Disease.

PubMed

Nakanishi, Koki; Jin, Zhezhen; Homma, Shunichi; Elkind, Mitchell S V; Rundek, Tatjana; Tugcu, Aylin; Sacco, Ralph L; Di Tullio, Marco R

2017-07-30

Left ventricular (LV) hypertrophy and subclinical cerebrovascular disease are early manifestations of cardiac and brain target organ damage caused by hypertension. This study aimed to investigate whether intensive office systolic blood pressure (SBP) control has beneficial effects on LV morphology and function and subclinical cerebrovascular disease in elderly patients with hypertension. We examined 420 patients treated for hypertension without history of heart failure and stroke from the CABL (Cardiovascular Abnormalities and Brain Lesions) study. All patients underwent 2-dimensional echocardiographic examination and brain magnetic resonance imaging. Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume. Patients were divided into 3 groups: SBP <120 mm Hg (intensive control); SBP 120 to 139 mm Hg (less intensive control); and SBP ≥140 mm Hg (uncontrolled). Prevalence of LV hypertrophy and diastolic dysfunction were lowest in the intensive control, intermediate in the less intensive control, and highest in the uncontrolled groups (12.8%, 31.8%, and 44.7%, respectively [ P <0.001], for LV hypertrophy; 46.8%, 61.7%, and 72.6%, respectively [ P =0.003], for diastolic dysfunction). Patients with less intensive SBP control had greater risk of LV hypertrophy than those with intensive control (adjusted odds ratio, 3.26; P =0.013). A similar trend was observed for LV diastolic dysfunction but did not reach statistical significance (adjusted odds ratio, 1.65; P =0.144). Conversely, intensive SBP control was not significantly associated with reduced risk of silent brain infarcts and white matter hyperintensity volume compared with less intensive control. Compared with less intensive control, intensive SBP control may have a stronger beneficial effect on cardiac than cerebral subclinical disease. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

PubMed

Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

2012-12-21

The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality.

PubMed

Lin, John C; Spinella, Philip C; Fitzgerald, Julie C; Tucci, Marisa; Bush, Jenny L; Nadkarni, Vinay M; Thomas, Neal J; Weiss, Scott L

2017-01-01

To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. Secondary analysis of a prospective, cross-sectional, point prevalence study. International, multicenter PICUs. Pediatric patients with severe sepsis identified on five separate days over a 1-year period. None. Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints.

New Diagnostic Terminology for Minimal Brain Dysfunction.

ERIC Educational Resources Information Center

Shaywitz, Bennett A.; And Others

1979-01-01

Minimal brain dysfunction has been redefined by the American Psychological Association as attention deficit disorder (ADD) and subdivided into categories with and without hyperactivity. The revised 'Diagnostic and Statistical Manual' (DSM III) is now undergoing field trials. Journal Availability: C. V. Mosby Company, 11830 Westline Industrial…

Brain Basics: Know Your Brain

MedlinePlus

... free mailed brochure Table of Contents Introduction The Architecture of the Brain The Geography of Thought The ... brain is diseased or dysfunctional. Image 1 The Architecture of the Brain The brain is like a ...

Adolescent Executive Dysfunction in Daily Life: Relationships to Risks, Brain Structure and Substance Use

PubMed Central

Clark, Duncan B.; Chung, Tammy; Martin, Christopher S.; Hasler, Brant P.; Fitzgerald, Douglas H.; Luna, Beatriz; Brown, Sandra A.; Tapert, Susan F.; Brumback, Ty; Cummins, Kevin; Pfefferbaum, Adolf; Sullivan, Edith V.; Pohl, Kilian M.; Colrain, Ian M.; Baker, Fiona C.; De Bellis, Michael D.; Nooner, Kate B.; Nagel, Bonnie J.

2017-01-01

During adolescence, problems reflecting cognitive, behavioral and affective dysregulation, such as inattention and emotional dyscontrol, have been observed to be associated with substance use disorder (SUD) risks and outcomes. Prior studies have typically been with small samples, and have typically not included comprehensive measurement of executive dysfunction domains. The relationships of executive dysfunction in daily life with performance based testing of cognitive skills and structural brain characteristics, thought to be the basis for executive functioning, have not been definitively determined. The aims of this study were to determine the relationships between executive dysfunction in daily life, measured by the Behavior Rating Inventory of Executive Function (BRIEF), cognitive skills and structural brain characteristics, and SUD risks, including a global SUD risk indicator, sleep quality, and risky alcohol and cannabis use. In addition to bivariate relationships, multivariate models were tested. The subjects (n = 817; ages 12 through 21) were participants in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. The results indicated that executive dysfunction was significantly related to SUD risks, poor sleep quality, risky alcohol use and cannabis use, and was not significantly related to cognitive skills or structural brain characteristics. In multivariate models, the relationship between poor sleep quality and risky substance use was mediated by executive dysfunction. While these cross-sectional relationships need to be further examined in longitudinal analyses, the results suggest that poor sleep quality and executive dysfunction may be viable preventive intervention targets to reduce adolescent substance use. PMID:29180956

Minimal Brain Dysfunction: Associations with Perinatal Complications.

ERIC Educational Resources Information Center

Nichols, Paul L.

Examined with over 28,000 7-year-old children whose mothers registered for prenatal care was the relationship between perinatal complications and such characteristics as poor school achievement, hyperactivity, and neurological soft signs associated with the diagnosis of minimal brain dysfunction (MBD). Ten perinatal antecedents were studied:…

Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection.

PubMed

Williamson, Lauren L; McKenney, Erin A; Holzknecht, Zoie E; Belliveau, Christine; Rawls, John F; Poulton, Susan; Parker, William; Bilbo, Staci D

2016-01-01

The incidence of autoimmune and inflammatory diseases has risen dramatically in post-industrial societies. "Biome depletion" - loss of commensal microbial and multicellular organisms such as helminths (intestinal worms) that profoundly modulate the immune system - may contribute to these increases. Hyperimmune-associated disorders also affect the brain, especially neurodevelopment, and increasing evidence links early-life infection to cognitive and neurodevelopmental disorders. We have demonstrated previously that rats infected with bacteria as newborns display life-long vulnerabilities to cognitive dysfunction, a vulnerability that is specifically linked to long-term hypersensitivity of microglial cell function, the resident immune cells of the brain. Here, we demonstrate that helminth colonization of pregnant dams attenuated the exaggerated brain cytokine response of their offspring to bacterial infection, and that combined with post-weaning colonization of offspring with helminths (consistent with their mothers treatment) completely prevented enduring microglial sensitization and cognitive dysfunction in adulthood. Importantly, helminths had no overt impact on adaptive immune cell subsets, whereas exaggerated innate inflammatory responses in splenic macrophages were prevented. Finally, helminths altered the effect of neonatal infection on the gut microbiome; neonatal infection with Escherichia coli caused a shift from genera within the Actinobacteria and Tenericutes phyla to genera in the Bacteroidetes phylum in rats not colonized with helminths, but helminths attenuated this effect. In sum, these data point toward an inter-relatedness of various components of the biome, and suggest potential mechanisms by which this helminth might exert therapeutic benefits in the treatment of neuroinflammatory and cognitive disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Occurrence of oculomotor dysfunctions in acquired brain injury: a retrospective analysis.

PubMed

Ciuffreda, Kenneth J; Kapoor, Neera; Rutner, Daniella; Suchoff, Irwin B; Han, M E; Craig, Shoshana

2007-04-01

The purpose of this retrospective study was to determine the frequency of occurrence of oculomotor dysfunctions in a sample of ambulatory outpatients who have acquired brain injury (ABI), either traumatic brain injury (TBI) or cerebrovascular accident (CVA), with associated vision symptoms. Medical records of 220 individuals with either TBI (n = 160) or CVA (n = 60) were reviewed retrospectively. This was determined by a computer-based query spanning the years 2000 through 2003, for the frequency of occurrence of oculomotor dysfunctions including accommodation, version, vergence, strabismus, and cranial nerve (CN) palsy. The majority of individuals with either TBI (90%) or CVA (86.7%) manifested an oculomotor dysfunction. Accommodative and vergence deficits were most common in the TBI subgroup, whereas strabismus and CN palsy were most common in the CVA subgroup. The frequency of occurrence of versional deficits was similar in each diagnostic subgroup. These new findings should alert the clinician to the higher frequency of occurrence of oculomotor dysfunctions in these populations and the associated therapeutic, rehabilitative, and quality-of-life implications.

Incorporating virtual reality graphics with brain imaging for assessment of sport-related concussions.

PubMed

Slobounov, Semyon; Sebastianelli, Wayne; Newell, Karl M

2011-01-01

There is a growing concern that traditional neuropsychological (NP) testing tools are not sensitive to detecting residual brain dysfunctions in subjects suffering from mild traumatic brain injuries (MTBI). Moreover, most MTBI patients are asymptomatic based on anatomical brain imaging (CT, MRI), neurological examinations and patients' subjective reports within 10 days post-injury. Our ongoing research has documented that residual balance and visual-kinesthetic dysfunctions along with its underlying alterations of neural substrates may be detected in "asymptomatic subjects" by means of Virtual Reality (VR) graphics incorporated with brain imaging (EEG) techniques.

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

PubMed

Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

2017-11-01

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Pupillary and Heart Rate Reactivity in Children with Minimal Brain Dysfunction

ERIC Educational Resources Information Center

Zahn, Theodore P.; And Others

1978-01-01

In an attempt to replicate and extend previous findings on autonomic arousal and responsivity in children with minimal brain dysfunction (MBD), pupil size, heart rate, skin conductance, and skin temperature were recorded from 32 MBD and 45 control children (6-13 years old). (Author/CL)

Anterior Temporal Lobe Connectivity Correlates with Functional Outcome after Aphasic Stroke

ERIC Educational Resources Information Center

Warren, Jane E.; Crinion, Jennifer T.; Ralph, Matthew A. Lambon; Wise, Richard J. S.

2009-01-01

Focal brain lesions are assumed to produce language deficits by two basic mechanisms: local cortical dysfunction at the lesion site, and remote cortical dysfunction due to disruption of the transfer and integration of information between connected brain regions. However, functional imaging studies investigating language outcome after aphasic…

Relations between Neurological Aberrations and Psychological Dysfunctions in Children with Serious Language Problems.

ERIC Educational Resources Information Center

Bo, Ola O.; And Others

1992-01-01

Relationships between neuropsychological aberrations and psychological dysfunction were studied for 20 Swedish children (average age around 10 years at first testing) with serious language problems through (1) electroencephalography; (2) brain stem response audiometry; (3) magnetic resonance imaging; and (4) brain electric activity mapping by…

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions.

PubMed

Zhang, Dong-Mei; Jiao, Rui-Qing; Kong, Ling-Dong

2017-03-29

High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption.

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

PubMed Central

Zhang, Dong-Mei; Jiao, Rui-Qing; Kong, Ling-Dong

2017-01-01

High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption. PMID:28353649

Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

PubMed

Wardill, Hannah R; Mander, Kimberley A; Van Sebille, Ysabella Z A; Gibson, Rachel J; Logan, Richard M; Bowen, Joanne M; Sonis, Stephen T

2016-12-15

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity. © 2016 UICC.

Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice

PubMed Central

Gauba, Esha; Guo, Lan; Du, Heng

2017-01-01

Brain aging is the known strongest risk factor for Alzheimer’s disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD. PMID:27834780

Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice.

PubMed

Gauba, Esha; Guo, Lan; Du, Heng

2017-01-01

Brain aging is the known strongest risk factor for Alzheimer's disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD.

[Time-organization of EEG patterns' structure in anxiety and phobic disorders].

PubMed

Sviatogor, I A; Mokhovikova, I A

2005-01-01

Thirty-five patients, aged 19-48 years (mean age 38 years) with anxiety and phobic disorders were examined. According to ICD-10 criteria--social phobia (F40.1), panic disorder (F41.0), somatoform autonomic dysfunction (F45.3) were diagnosed. Using electroencephalography data, qualitative and quantitative characteristics of the time- and spatial-organization of brain EEG activity in anxiety and phobic disorders of different severity were established. It were determined 4 types of wave interactions between EEG components, which reflected a different extent of the regulatory mechanisms lesions: 2 structures with one core component (alpha or beta), a structure with two core components and a non-organized structure.

Neural Systems Approaches to Understanding Major Depressive Disorder: An Intrinsic Functional Organization Perspective

PubMed Central

Hamilton, J. Paul; Chen, Michael C.; Gotlib, Ian H.

2012-01-01

Recent research detailing the intrinsic functional organization of the brain provides a unique and useful framework to gain a better understanding of the neural bases of Major Depressive Disorder (MDD). In this review, we first present a brief history of neuroimaging research that has increased our understanding of the functional macro-architecture of the brain. From this macro-architectural perspective, we examine the extant body of functional neuroimaging research assessing MDD with a specific emphasis on the contributions of default-mode, executive, and salience networks in this debilitating disorder. Next, we describe recent investigations conducted in our laboratory in which we explicitly adopt a neural-systems perspective in examining the relations among these networks in MDD. Finally, we offer directions for future research that we believe will facilitate the development of more detailed and integrative models of neural dysfunction in depression. PMID:23477309

Chlorella diet alters mitochondrial cardiolipin contents differentially in organs of Danio rerio analyzed by a lipidomics approach

PubMed Central

Chao, Yu-Jen; Wu, Wen-Hsin; Balazova, Maria; Wu, Ting-Yuan; Lin, Jamie; Liu, Yi-Wen

2018-01-01

The zebrafish (Danio rerio) is an important and widely used vertebrate model organism for the study of human diseases which include disorders caused by dysfunctional mitochondria. Mitochondria play an essential role in both energy metabolism and apoptosis, which are mediated through a mitochondrial phospholipid cardiolipin (CL). In order to examine the cardiolipin profile in the zebrafish model, we developed a CL analysis platform by using liquid chromatography-mass spectrometry (LC-MS). Meanwhile, we tested whether chlorella diet would alter the CL profile in the larval fish, and in various organs of the adult fish. The results showed that chlorella diet increased the chain length of CL in larval fish. In the adult zebrafish, the distribution patterns of CL species were similar between the adult brain and eye tissues, and between the heart and muscles. Interestingly, monolyso-cardiolipin (MLCL) was not detected in brain and eyes but found in other examined tissues, indicating a different remodeling mechanism to maintain the CL integrity. While the adult zebrafish were fed with chlorella for four weeks, the CL distribution showed an increase of the species of saturated acyl chains in the brain and eyes, but a decrease in the other organs. Moreover, chlorella diet led to a decrease of MLCL percentage in organs except the non-MLCL-containing brain and eyes. The CL analysis in the zebrafish provides an important tool for studying the mechanism of mitochondria diseases, and may also be useful for testing medical regimens targeting against the Barth Syndrome. PMID:29494608

Neuroanatomy and Physiology of Brain Dysfunction in Sepsis.

PubMed

Mazeraud, Aurelien; Pascal, Quentin; Verdonk, Franck; Heming, Nicholas; Chrétien, Fabrice; Sharshar, Tarek

2016-06-01

Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels. Copyright © 2016 Elsevier Inc. All rights reserved.

[The aggressive child (author's transl)].

PubMed

Harbauer, H

1978-08-01

In children a "normal" aggressiveness should be distinguished from "hostile" and "inhibited" aggression; the latter usually become apparent as heteroaggressive or autoaggressive behaviour. Autoaggression is more common with younger children. Different hypotheses about the origin of aggressiveness are discussed. In the younger child nail biting, trichotillomania, rocking, an intensified phase of contrariness and enkopresis may have components of aggressiveness. In older children and adolescents dissocial forms of development, drug taking, attempted suicid, and anorexia nervosa may be parts of aggressive behaviour. Minimal brain dysfunction, autism, and postencephalitic syndromes predominate amongst organic alterations of the brain as causes for aggressive behaviour. Particularly the Lesch-Nyhan-syndrome, but equally the Cornelia de Lange-syndrome show autoaggressive tendencies.

Public Education for Children with Brain Dysfunction.

ERIC Educational Resources Information Center

Rappaport, Sheldon R.

A foreword by William M. Cruickshank introduces a book designed to provide information on the problems of children with brain dysfunction and to furnish guidelines to habilitation. Subjects discussed are the status of education for these children, preparing the community for a school program, selection of school and preparation of the principal,…

Disrupted subject-specific gray matter network properties and cognitive dysfunction in type 1 diabetes patients with and without proliferative retinopathy.

PubMed

van Duinkerken, Eelco; Ijzerman, Richard G; Klein, Martin; Moll, Annette C; Snoek, Frank J; Scheltens, Philip; Pouwels, Petra J W; Barkhof, Frederik; Diamant, Michaela; Tijms, Betty M

2016-03-01

Type 1 diabetes mellitus (T1DM) patients, especially with concomitant microvascular disease, such as proliferative retinopathy, have an increased risk of cognitive deficits. Local cortical gray matter volume reductions only partially explain these cognitive dysfunctions, possibly because volume reductions do not take into account the complex connectivity structure of the brain. This study aimed to identify gray matter network alterations in relation to cognition in T1DM. We investigated if subject-specific structural gray matter network properties, constructed from T1-weighted MRI scans, were different between T1DM patients with (n = 51) and without (n = 53) proliferative retinopathy versus controls (n = 49), and were associated to cognitive decrements and fractional anisotropy, as measured by voxel-based TBSS. Global normalized and local (45 bilateral anatomical regions) clustering coefficient and path length were assessed. These network properties measure how the organization of connections in a network differs from that of randomly connected networks. Global gray matter network topology was more randomly organized in both T1DM patient groups versus controls, with the largest effects seen in patients with proliferative retinopathy. Lower local path length values were widely distributed throughout the brain. Lower local clustering was observed in the middle frontal, postcentral, and occipital areas. Complex network topology explained up to 20% of the variance of cognitive decrements, beyond other predictors. Exploratory analyses showed that lower fractional anisotropy was associated with a more random gray matter network organization. T1DM and proliferative retinopathy affect cortical network organization that may consequently contribute to clinically relevant changes in cognitive functioning in these patients. © 2015 Wiley Periodicals, Inc.

Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia.

PubMed

Besnard, Marianne; Eyrolle-Guignot, Dominique; Guillemette-Artur, Prisca; Lastère, Stéphane; Bost-Bezeaud, Frédérique; Marcelis, Ludivine; Abadie, Véronique; Garel, Catherine; Moutard, Marie-Laure; Jouannic, Jean-Marie; Rozenberg, Flore; Leparc-Goffart, Isabelle; Mallet, Henri-Pierre

2016-01-01

We detected an unusual increase in congenital cerebral malformations and dysfunction in fetuses and newborns in French Polynesia, following an epidemic of Zika virus (ZIKV), from October 2013 to March 2014. A retrospective review identified 19 cases, including eight with major brain lesions and severe microcephaly, six with severe cerebral lesions without microcephaly and five with brainstem dysfunction without visible malformations. Imaging revealed profound neurological lesions (septal and callosal disruption, ventriculomegaly, abnormal neuronal migration, cerebellar hypoplasia, occipital pseudocysts, brain calcifications). Amniotic fluid was drawn from seven cases at gestation weeks 20 to 29. ZIKV RNA was detected by RT-PCR and infectious ZIKV isolates were obtained in four of five microcephalic, but not in two non-microcephalic cases with severe brain lesions. Medical termination of pregnancy was performed in eleven cases; two cases with brainstem dysfunction died in the first months of life; six cases are alive, with severe neurological impairment. The results show that four of seven tested fetuses with major neurological injuries were infected with ZIKV in utero. For other non-microcephalic, congenital abnormalities we were not able to prove or exclude ZIKV infection retrospectively. The unusual occurrence of brain malformations or dysfunction without microcephaly following a ZIKV outbreak needs further studies.

40 plus or minus 10, a new magical number: reply to Russell.

PubMed

Larrabee, Glenn J; Millis, Scott R; Meyers, John E

2009-07-01

Russell (2009 this issue) has criticized our recently published investigation (Larrabee, Millis, & Meyers, 2008) comparing the diagnostic discrimination of an ability-focused neuropsychological battery (AFB) to that of the Halstead Reitan Battery (HRB). He contended that our symptom validity test (SVT) screening excluding 43% of brain dysfunction and 15% of control patients using computations based on Digit Span inappropriately excluded patients with brain damage, due to the correlation of Digit Span with the Average Index Score (AIS). Our exclusion of 43% of brain dysfunction participants matches the frequency of invalid neuropsychological data of 40-50% or more reported by numerous studies for a wide range of settings with external incentive. Moreover, our study was not an investigation of malingering; rather, we screened our data to insure that only valid data remained, for the most meaningful comparison of the AFB to the HRB. Russell's argument that Digit Span is correlated with brain damage confounds the criterion, AIS (a composite cognitive score), with the predictor, Digit Span (another cognitive score), rather than employing a truly independent neurologic criterion. The fact that Digit Span is notoriously insensitive to brain dysfunction underscores the robustness of our findings, for if we inappropriately excluded brain-damaged patients for low Digit Span, as Russell claimed, this resulted in our sample reflecting more subtle degree of brain dysfunction, and the superiority of the AFB over the HRB was demonstrated under the most challenging of discriminative conditions.

Zebrafish: a model animal for analyzing the impact of environmental pollutants on muscle and brain mitochondrial bioenergetics.

PubMed

Bourdineaud, Jean-Paul; Rossignol, R; Brèthes, D

2013-01-01

Mercury, anthropogenic release of uranium (U), and nanoparticles constitute hazardous environmental pollutants able to accumulate along the aquatic food chain with severe risk for animal and human health. The impact of such pollutants on living organisms has been up to now approached by classical toxicology in which huge doses of toxic compounds, environmentally irrelevant, are displayed through routes that never occur in the lifespan of organisms (for instance injecting a bolus of mercury to an animal although the main route is through prey and fish eating). We wanted to address the effect of such pollutants on the muscle and brain mitochondrial bioenergetics under realistic conditions, at unprecedented low doses, using an aquatic model animal, the zebrafish Danio rerio. We developed an original method to measure brain mitochondrial respiration: a single brain was put in 1.5 mL conical tube containing a respiratory buffer. Brains were gently homogenized by 13 strokes with a conical plastic pestle, and the homogenates were immediately used for respiration measurements. Skinned muscle fibers were prepared by saponin permeabilization. Zebrafish were contaminated with food containing 13 μg of methylmercury (MeHg)/g, an environmentally relevant dose. In permeabilized muscle fibers, we observed a strong inhibition of both state 3 mitochondrial respiration and cytochrome c oxidase activity after 49 days of MeHg exposure. We measured a dramatic decrease in the rate of ATP release by skinned muscle fibers. Contrarily to muscles, brain mitochondrial respiration was not modified by MeHg exposure although brain accumulated twice as much MeHg than muscles. When zebrafish were exposed to 30 μg/L of waterborne U, the basal mitochondrial respiratory control ratio was decreased in muscles after 28 days of exposure. This was due to an increase of the inner mitochondrial membrane permeability. The impact of a daily ration of food containing gold nanoparticles of two sizes (12 and 50 nm) was investigated at a very low dose for 60 days (40 ng gold/fish/day). Mitochondrial dysfunctions appeared in brain and muscle for both tested sizes. In conclusion, at low environmental doses, dietary or waterborne heavy metals impinged on zebrafish tissue mitochondrial respiration. Due to its incredible simplicity avoiding tedious and time-consuming mitochondria isolation, our one-pot method allowing brain respiratory analysis should give colleagues the incentive to use zebrafish brain as a model in bioenergetics. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

What can spontaneous fluctuations of the blood oxygenation-level-dependent signal tell us about psychiatric disorders?

PubMed

Fornito, Alex; Bullmore, Edward T

2010-05-01

Resting-state functional MRI (rs-fMRI) is an increasingly popular technique for studying brain dysfunction in psychiatric patients, and is widely assumed to measure intrinsic properties of functional brain organization. Here, we review rs-fMRI studies of psychiatric populations and consider how recent evidence concerning the neuronal basis, behavioural relevance, and the stability of rs-fMRI measures can inform and constrain interpretation of findings obtained using case-control designs. A range of rs-fMRI measures have been applied to different patient groups, although the findings have not always been consistent. The large-scale organization of rs-fMRI networks is robust and reproducible, and rs-fMRI measures show correlations with behavioural phenotypes relevant to psychiatry. However, evidence that such measures are also influenced by preceding psychological states and contexts, as well as individual variations in physiological arousal, may help to explain inconsistent findings in case-control comparisons. rs-fMRI measures show both stable and dynamic properties, the nature of which are only beginning to be uncovered. As such, interpreting significant differences between patients and controls on rs-fMRI measures as evidence for alterations in intrinsic functional brain organization should be done cautiously. Better understanding of the relationship between stable and transient aspects of spontaneous brain dynamics will be necessary to constrain interpretation of case-control studies and inform pathophysiological models.

Systemic Inflammatory Response Syndrome, Quick Sequential Organ Function Assessment, and Organ Dysfunction: Insights From a Prospective Database of ED Patients With Infection.

PubMed

Williams, Julian M; Greenslade, Jaimi H; McKenzie, Juliet V; Chu, Kevin; Brown, Anthony F T; Lipman, Jeffrey

2017-03-01

A proposed revision of sepsis definitions has abandoned the systemic inflammatory response syndrome (SIRS), defined organ dysfunction as an increase in total Sequential Organ Function Assessment (SOFA) score of ≥ 2, and conceived "qSOFA" (quick SOFA) as a bedside indicator of organ dysfunction. We aimed to (1) determine the prognostic impact of SIRS, (2) compare the diagnostic accuracy of SIRS and qSOFA for organ dysfunction, and (3) compare standard (Sepsis-2) and revised (Sepsis-3) definitions for organ dysfunction in ED patients with infection. Consecutive ED patients admitted with presumed infection were prospectively enrolled over 3 years. Sufficient observational data were collected to calculate SIRS, qSOFA, SOFA, comorbidity, and mortality. We enrolled 8,871 patients, with SIRS present in 4,176 (47.1%). SIRS was associated with increased risk of organ dysfunction (relative risk [RR] 3.5) and mortality in patients without organ dysfunction (OR 3.2). SIRS and qSOFA showed similar discrimination for organ dysfunction (area under the receiver operating characteristic curve, 0.72 vs 0.73). qSOFA was specific but poorly sensitive for organ dysfunction (96.1% and 29.7%, respectively). Mortality for patients with organ dysfunction was similar for Sepsis-2 and Sepsis-3 (12.5% and 11.4%, respectively), although 29% of patients with Sepsis-3 organ dysfunction did not meet Sepsis-2 criteria. Increasing numbers of Sepsis-2 organ system dysfunctions were associated with greater mortality. SIRS was associated with organ dysfunction and mortality, and abandoning the concept appears premature. A qSOFA score ≥ 2 showed high specificity, but poor sensitivity may limit utility as a bedside screening method. Although mortality for organ dysfunction was comparable between Sepsis-2 and Sepsis-3, more prognostic and clinical information is conveyed using Sepsis-2 regarding number and type of organ dysfunctions. The SOFA score may require recalibration. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Brain-Heart Interaction: Cardiac Complications After Stroke.

PubMed

Chen, Zhili; Venkat, Poornima; Seyfried, Don; Chopp, Michael; Yan, Tao; Chen, Jieli

2017-08-04

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed. © 2017 American Heart Association, Inc.

Cardiocerebral protection by emulsified isoflurane during cardiopulmonary resuscitation.

PubMed

Zhang, Ya-Jie; Wu, Meng-Jun; Li, Yi; Yu, Hai

2015-01-01

Although improvement in cardiopulmonary resuscitation (CPR) performance and the increasing success at achieving return of spontaneous circulation (ROSC) have been possible in recent years, the survival and discharge rates of post-cardiac arrest (CA) patients remain disappointing. The high mortality rate is attributed to whole-body ischemia/reperfusion (I/R) induced multi-organ dysfunction that is well known as post-cardiac arrest syndrome. Post-cardiac arrest myocardial dysfunction and brain injury are the main clinical features of this complex pathophysiological process. Previous evidences have shown that volatile anesthetics, such as isoflurane, trigger a powerful and highly integrated cell survival response during I/R period in multiple organs, including heart and brain, which reduces I/R injury. This effect that called anesthetic-induced postconditioning can be shown when volatile anesthetics are administered after the onset of ischemia and at the time of reperfusion. Emulsified isoflurane (EIso) is a new anesthetic for intravenous administration, which is conveniently feasible outside operating room. Therefore, we hypothesize that EIso postconditioning could provide the cardiocerebral protection, and combined with therapeutic hypothermia as sedative agent could produce enhanced cardiocerebral protection, which can result in significant improvement of neurologically intact post-cardiac arrest survival. We consider that it would become a feasible, safe and efficient cardiocerebral protective intervention in the prevention and alleviation of post-cardiac arrest syndrome, which would also improve the outcomes after CA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Implications of Circadian Rhythm in Dopamine and Mood Regulation.

PubMed

Kim, Jeongah; Jang, Sangwon; Choe, Han Kyoung; Chung, Sooyoung; Son, Gi Hoon; Kim, Kyungjin

2017-07-31

Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-erbα induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson's disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.

Disrupted insula-based neural circuit organization and conflict interference in trauma-exposed youth.

PubMed

Marusak, Hilary A; Etkin, Amit; Thomason, Moriah E

2015-01-01

Childhood trauma exposure is a potent risk factor for psychopathology. Emerging research suggests that aberrant saliency processing underlies the link between early trauma exposure and later cognitive and socioemotional deficits that are hallmark of several psychiatric disorders. Here, we examine brain and behavioral responses during a face categorization conflict task, and relate these to intrinsic connectivity of the salience network (SN). The results demonstrate a unique pattern of SN dysfunction in youth exposed to trauma (n = 14) relative to comparison youth (n = 19) matched on age, sex, IQ, and sociodemographic risk. We find that trauma-exposed youth are more susceptible to conflict interference and this correlates with higher fronto-insular responses during conflict. Resting-state functional connectivity data collected in the same participants reveal increased connectivity of the insula to SN seed regions that is associated with diminished reward sensitivity, a critical risk/resilience trait following stress. In addition to altered intrinsic connectivity of the SN, we observed altered connectivity between the SN and default mode network (DMN) in trauma-exposed youth. These data uncover network-level disruptions in brain organization following one of the strongest predictors of illness, early life trauma, and demonstrate the relevance of observed neural effects for behavior and specific symptom dimensions. SN dysfunction may serve as a diathesis that contributes to illness and negative outcomes following childhood trauma.

Causes, effects and connectivity changes in MS-related cognitive decline.

PubMed

Rimkus, Carolina de Medeiros; Steenwijk, Martijn D; Barkhof, Frederik

2016-01-01

Cognitive decline is a frequent but undervalued aspect of multiple sclerosis (MS). Currently, it remains unclear what the strongest determinants of cognitive dysfunction are, with grey matter damage most directly related to cognitive impairment. Multi-parametric studies seem to indicate that individual factors of MS-pathology are highly interdependent causes of grey matter atrophy and permanent brain damage. They are associated with intermediate functional effects (e.g. in functional MRI) representing a balance between disconnection and (mal) adaptive connectivity changes. Therefore, a more comprehensive MRI approach is warranted, aiming to link structural changes with functional brain organization. To better understand the disconnection syndromes and cognitive decline in MS, this paper reviews the associations between MRI metrics and cognitive performance, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage and how they affect network efficiency.

Altered caudate connectivity is associated with executive dysfunction after traumatic brain injury

PubMed Central

De Simoni, Sara; Jenkins, Peter O; Bourke, Niall J; Fleminger, Jessica J; Jolly, Amy E; Patel, Maneesh C; Leech, Robert; Sharp, David J

2018-01-01

Abstract Traumatic brain injury often produces executive dysfunction. This characteristic cognitive impairment often causes long-term problems with behaviour and personality. Frontal lobe injuries are associated with executive dysfunction, but it is unclear how these injuries relate to corticostriatal interactions that are known to play an important role in behavioural control. We hypothesized that executive dysfunction after traumatic brain injury would be associated with abnormal corticostriatal interactions, a question that has not previously been investigated. We used structural and functional MRI measures of connectivity to investigate this. Corticostriatal functional connectivity in healthy individuals was initially defined using a data-driven approach. A constrained independent component analysis approach was applied in 100 healthy adult dataset from the Human Connectome Project. Diffusion tractography was also performed to generate white matter tracts. The output of this analysis was used to compare corticostriatal functional connectivity and structural integrity between groups of 42 patients with traumatic brain injury and 21 age-matched controls. Subdivisions of the caudate and putamen had distinct patterns of functional connectivity. Traumatic brain injury patients showed disruption to functional connectivity between the caudate and a distributed set of cortical regions, including the anterior cingulate cortex. Cognitive impairments in the patients were mainly seen in processing speed and executive function, as well as increased levels of apathy and fatigue. Abnormalities of caudate functional connectivity correlated with these cognitive impairments, with reductions in right caudate connectivity associated with increased executive dysfunction, information processing speed and memory impairment. Structural connectivity, measured using diffusion tensor imaging between the caudate and anterior cingulate cortex was impaired and this also correlated with measures of executive dysfunction. We show for the first time that altered subcortical connectivity is associated with large-scale network disruption in traumatic brain injury and that this disruption is related to the cognitive impairments seen in these patients. PMID:29186356

Altered brain structural connectivity in post-traumatic stress disorder: a diffusion tensor imaging tractography study.

PubMed

Long, Zhiliang; Duan, Xujun; Xie, Bing; Du, Handan; Li, Rong; Xu, Qiang; Wei, Luqing; Zhang, Shao-xiang; Wu, Yi; Gao, Qing; Chen, Huafu

2013-09-25

Post-traumatic stress disorder (PTSD) is characterized by dysfunction of several discrete brain regions such as medial prefrontal gyrus with hypoactivation and amygdala with hyperactivation. However, alterations of large-scale whole brain topological organization of structural networks remain unclear. Seventeen patients with PTSD in motor vehicle accident survivors and 15 normal controls were enrolled in our study. Large-scale structural connectivity network (SCN) was constructed using diffusion tensor tractography, followed by thresholding the mean factional anisotropy matrix of 90 brain regions. Graph theory analysis was then employed to investigate their aberrant topological properties. Both patient and control group showed small-world topology in their SCNs. However, patients with PTSD exhibited abnormal global properties characterized by significantly decreased characteristic shortest path length and normalized characteristic shortest path length. Furthermore, the patient group showed enhanced nodal centralities predominately in salience network including bilateral anterior cingulate and pallidum, and hippocampus/parahippocamus gyrus, and decreased nodal centralities mainly in medial orbital part of superior frontal gyrus. The main limitation of this study is the small sample of PTSD patients, which may lead to decrease the statistic power. Consequently, this study should be considered an exploratory analysis. These results are consistent with the notion that PTSD can be understood by investigating the dysfunction of large-scale, spatially distributed neural networks, and also provide structural evidences for further exploration of neurocircuitry models in PTSD. © 2013 Elsevier B.V. All rights reserved.

The Immune System and Developmental Programming of Brain and Behavior

PubMed Central

Bilbo, Staci D.; Schwarz, Jaclyn M.

2012-01-01

The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone-behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition. PMID:22982535

Previous physical exercise alters the hepatic profile of oxidative-inflammatory status and limits the secondary brain damage induced by severe traumatic brain injury in rats.

PubMed

de Castro, Mauro Robson Torres; Ferreira, Ana Paula de Oliveira; Busanello, Guilherme Lago; da Silva, Luís Roberto Hart; da Silveira Junior, Mauro Eduardo Porto; Fiorin, Fernando da Silva; Arrifano, Gabriela; Crespo-López, Maria Elena; Barcelos, Rômulo Pillon; Cuevas, María J; Bresciani, Guilherme; González-Gallego, Javier; Fighera, Michele Rechia; Royes, Luiz Fernando Freire

2017-09-01

An early inflammatory response and oxidative stress are implicated in the signal transduction that alters both hepatic redox status and mitochondrial function after traumatic brain injury (TBI). Peripheral oxidative/inflammatory responses contribute to neuronal dysfunction after TBI Exercise training alters the profile of oxidative-inflammatory status in liver and protects against acute hyperglycaemia and a cerebral inflammatory response after TBI. Approaches such as exercise training, which attenuates neuronal damage after TBI, may have therapeutic potential through modulation of responses by metabolic organs. The vulnerability of the body to oxidative/inflammatory in TBI is significantly enhanced in sedentary compared to physically active counterparts. Although systemic responses have been described after traumatic brain injury (TBI), little is known regarding potential interactions between brain and peripheral organs after neuronal injury. Accordingly, we aimed to investigate whether a peripheral oxidative/inflammatory response contributes to neuronal dysfunction after TBI, as well as the prophylactic role of exercise training. Animals were submitted to fluid percussion injury after 6 weeks of swimming training. Previous exercise training increased mRNA expression of X receptor alpha and ATP-binding cassette transporter, and decreased inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α and interleukin (IL)-6 expression per se in liver. Interestingly, exercise training protected against hepatic inflammation (COX-2, iNOS, TNF-α and IL-6), oxidative stress (decreases in non-protein sulfhydryl and glutathione, as well as increases in 2',7'-dichlorofluorescein diacetate oxidation and protein carbonyl), which altered hepatic redox status (increases in myeloperoxidase and superoxide dismutase activity, as well as inhibition of catalase activity) mitochondrial function (decreases in methyl-tetrazolium and Δψ, as well as inhibition of citrate synthase activity) and ion gradient homeostasis (inhibition of Na + ,K + -ATPase activity inhibition) when analysed 24 h after TBI. Previous exercise training also protected against dysglycaemia, impaired hepatic signalling (increase in phosphorylated c-Jun NH2-terminal kinase, phosphorylated decreases in insulin receptor substrate and phosphorylated AKT expression), high levels of circulating and neuronal cytokines, the opening of the blood-brain barrier, neutrophil infiltration and Na + ,K + -ATPase activity inhibition in the ipsilateral cortex after TBI. Moreover, the impairment of protein function, neurobehavioural (neuromotor dysfunction and spatial learning) disability and hippocampal cell damage in sedentary rats suggests that exercise training also modulates peripheral oxidative/inflammatory pathways in TBI, which corroborates the ever increasing evidence regarding health-related outcomes with respect to a physically active lifestyle. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Cognitive dysfunction and functional magnetic resonance imaging in systemic lupus erythematosus.

PubMed

Barraclough, M; Elliott, R; McKie, S; Parker, B; Bruce, I N

2015-10-01

Cognitive dysfunction is a common aspect of systemic lupus erythematosus (SLE) and is increasingly reported as a problem by patients. In many cases the exact cause is unclear. Limited correlations between specific autoantibodies or structural brain abnormalities and cognitive dysfunction in SLE have been reported. It may be that the most appropriate biomarkers have yet to be found. Functional magnetic resonance imaging (fMRI) is a technique used in many other conditions and provides sensitive measures of brain functionality during cognitive tasks. It is now beginning to be employed in SLE studies. These studies have shown that patients with SLE often perform similarly to healthy controls in terms of behavioural measures on cognitive tasks. However, SLE patients appear to employ compensatory brain mechanisms, such as increased response in fronto-parietal regions, to maintain adequate cognitive performance. As there have been only a few studies using fMRI in SLE to investigate cognitive dysfunction, many questions remain unanswered. Further research could, however, help to identify biomarkers for cognitive dysfunction in SLE. © The Author(s) 2015.

Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

PubMed

Bar-Klein, Guy; Lublinsky, Svetlana; Kamintsky, Lyn; Noyman, Iris; Veksler, Ronel; Dalipaj, Hotjensa; Senatorov, Vladimir V; Swissa, Evyatar; Rosenbach, Dror; Elazary, Netta; Milikovsky, Dan Z; Milk, Nadav; Kassirer, Michael; Rosman, Yossi; Serlin, Yonatan; Eisenkraft, Arik; Chassidim, Yoash; Parmet, Yisrael; Kaufer, Daniela; Friedman, Alon

2017-06-01

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Brain imaging research in autism spectrum disorders: in search of neuropathology and health across the lifespan.

PubMed

Lainhart, Janet E

2015-03-01

Advances in brain imaging research in autism spectrum disorders (ASD) are rapidly occurring, and the amount of neuroimaging research has dramatically increased over the past 5 years. In this review, advances during the past 12 months and longitudinal studies are highlighted. Cross-sectional neuroimaging research provides evidence that the neural underpinnings of the behavioral signs of ASD involve not only dysfunctional integration of information across distributed brain networks but also basic dysfunction in primary cortices.Longitudinal studies of ASD show abnormally enlarged brain volumes and increased rates of brain growth during early childhood in only a small minority of ASD children. There is evidence of disordered development of white matter microstructure and amygdala growth, and at 2 years of age, network inefficiencies in posterior cerebral regions.From older childhood into adulthood, atypical age-variant and age-invariant changes in the trajectories of total and regional brain volumes and cortical thickness are apparent at the group level. There is evidence of abnormalities in posterior lobes and posterior brain networks during the first 2 years of life in ASD and, even in older children and adults, dysfunction in primary cortical areas.

Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction.

PubMed

Pitel, Anne Lise; Segobin, Shailendra H; Ritz, Ludivine; Eustache, Francis; Beaunieux, Hélène

2015-07-01

Two brain networks are particularly affected by the harmful effect of chronic and excessive alcohol consumption: the circuit of Papez and the frontocerebellar circuit, in both of which the thalamus plays a key role. Shrinkage of the thalamus is more severe in alcoholics with Korsakoff's syndrome (KS) than in those without neurological complication (AL). In accordance with the gradient effect of thalamic abnormalities between AL and KS, the pattern of brain dysfunction in the Papez's circuit results in anterograde amnesia in KS and only mild-to-moderate episodic memory disorders in AL. On the opposite, dysfunction of the frontocerebellar circuit results in a similar pattern of working memory and executive deficits in the AL and KS. Several hypotheses, mutually compatible, can be drawn to explain that the severe thalamic shrinkage observed in KS has different consequences in the neuropsychological profile associated with the two brain networks. Copyright © 2014. Published by Elsevier Ltd.

Local cerebral glucose metabolism in patients with long-term behavioral and cognitive deficits following mild traumatic brain injury.

PubMed

Gross, H; Kling, A; Henry, G; Herndon, C; Lavretsky, H

1996-01-01

A retrospective study of 20 patients with mild traumatic brain injury (MTBI) examined brain regions of interest by comparing [18F]-2-deoxyglucose PET, neuropsychological test results, and continuing behavioral dysfunction. Abnormal local cerebral metabolic rates (rLCMs) were most prominent in midtemporal, anterior cingulate, precuneus, anterior temporal, frontal white, and corpus callosum brain regions. Abnormal rLCMs were significantly correlated statistically with 1) overall clinical complaints, most specifically with inconsistent attention/concentration and 2) overall neuropsychological test results. The authors conclude that 1) even mild TBI may result in continuing brain behavioral deficits; 2) PET can help elucidate dysfunctional brain circuitry in neurobehavioral disorders; and 3) specific brain areas may correlate with deficits in daily neurobehavioral functioning and neuropsychological test findings.

WAIS Digit Span-Based Indicators of Malingered Neurocognitive Dysfunction: Classification Accuracy in Traumatic Brain Injury

ERIC Educational Resources Information Center

Heinly, Matthew T.; Greve, Kevin W.; Bianchini, Kevin J.; Love, Jeffrey M.; Brennan, Adrianne

2005-01-01

The present study determined specificity and sensitivity to malingered neurocognitive dysfunction (MND) in traumatic brain injury (TBI) for several Wechsler Adult Intelligence Scale (WAIS) Digit Span scores. TBI patients (n = 344) were categorized into one of five groups: no incentive, incentive only, suspect, probable MND, and definite MND.…

Feasibility study of cytokine removal by hemoadsorption in brain-dead humans.

PubMed

Kellum, John A; Venkataraman, Ramesh; Powner, David; Elder, Michele; Hergenroeder, Georgene; Carter, Melinda

2008-01-01

Inflammatory cytokines occur in the circulation and in the tissues after brain death and have been associated with dysfunction of donor organs before and after transplantation. To determine the feasibility of removing cytokines using a hemoadsorption device. Two-center, randomized, open-label, feasibility study in which brain-dead subjects were randomized to two treatment groups. Two U.S. academic hospitals. Eight brain-dead subjects deemed unsuitable for organ donation by respective organ procurement organizations. After obtaining consent from families, subjects were treated with hemoadsorption for 4 hrs using CytoSorb. Effects on cytokines (tumor necrosis factor, interleukin [IL]-6, and IL-10) were assessed both across the device and in the plasma over time. Feasibility for cytokine removal was assessed using objective criteria. Cytokine removal across the CytoSorb device ranged from 4% to 30% and was not significantly different from 1 hr to 4 hrs. Overall removal was greatest for IL-6, 28% (p = .006), and least for tumor necrosis factor, 8.5% (p = .13). Plasma concentrations of both IL-6 and tumor necrosis factor, but not IL-10, were significantly reduced after the first hour of therapy; mean differences were -13% +/- 7% for IL-6 (p = .039), -23% +/- 9% for tumor necrosis factor (p = .02), and -2% +/- 7% of IL-10 (p = 23). However, plasma concentrations for all three cytokines increased over time and were above baseline by the end of the intervention. No adverse effects of therapy were observed. However, removal of cortisol and triiodothyronine was similar to removal of cytokines. Hemoadsorption for removal of cytokines in brain-dead subjects is feasible. Evaluation of possible clinical benefit will require controlled trials in actual donors. However, the significant capacity for cytokine removal and absence of adverse events suggest that such trials are warranted.

Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons.

PubMed

Peng, Yunhua; Liu, Jing; Shi, Le; Tang, Ying; Gao, Dan; Long, Jiangang; Liu, Jiankang

2016-06-01

Recent studies have demonstrated brain insulin signaling impairment and mitochondrial dysfunction in diabetes. Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance, and hyperglycemia induces peripheral sensory neuronal impairment and mitochondrial dysfunction. However, how brain glucose at diabetic conditions elicits cortical neuronal insulin signaling impairment and mitochondrial dysfunction remains unknown. In the present study, we cultured primary cortical neurons with high glucose levels and investigated the neuronal mitochondrial function and insulin response. We found that mitochondrial function was declined in presence of 10 mmol/L glucose, prior to the depression of AKT signaling in primary cortical neurons. We further demonstrated that the cerebral cortex of db/db mice exhibited both insulin resistance and loss of mitochondrial complex components. Moreover, we found that adenosine monophosphate-activated protein kinase (AMPK) inactivation is involved in high glucose-induced mitochondrial dysfunction and insulin resistance in primary cortical neurons and neuroblastoma cells, as well as in cerebral cortex of db/db mice, and all these impairments can be rescued by mitochondrial activator, resveratrol. Taken together, our results extend the finding that high glucose (≥10 mmol/L) comparable to diabetic brain extracellular glucose level leads to neuronal mitochondrial dysfunction and resultant insulin resistance, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. We found that high glucose (≥10 mmol/L), comparable to diabetic brain extracellular glucose level, leads to neuronal mitochondrial dysfunction and resultant insulin resistance in an AMPK-dependent manner, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. © 2016 International Society for Neurochemistry.

MicroRNA-146b-5p Identified in Porcine Liver Donation Model is Associated with Early Allograft Dysfunction in Human Liver Transplantation

PubMed Central

Li, Cheukfai; Zhao, Qiang; Zhang, Wei; Chen, Maogen; Ju, Weiqiang; Wu, Linwei; Han, Ming; Ma, Yi; Zhu, Xiaofeng; Wang, Dongping; Guo, Zhiyong; He, Xiaoshun

2017-01-01

Background Poor transplant outcome was observed in donation after brain death followed by circulatory death (DBCD), since the donor organs suffered both cytokine storm of brain death and warm ischemia injury. MicroRNAs (miRNAs) have emerged as promising disease biomarkers, so we sought to establish a miRNA signature of porcine DBCD and verify the findings in human liver transplantation. Material/Methods MiRNA expression was determined with miRNA sequencing in 3 types of the porcine model of organ donation, including donation after brain death (DBD) group, donation after circulatory death (DCD) group, and DBCD group. Bioinformatics analysis was performed to reveal the potential regulatory behavior of target miRNA. Human liver graft biopsy samples after reperfusion detected by fluorescence in situ hybridization were used to verify the expression of target miRNA. Results We compared miRNA expression profiles of the 3 donation types. The porcine liver graft miR-146b was significantly increased and selected in the DBCD group versus in the DBD and DCD groups. The donor liver expression of human miR-146b-5p, which is homologous to porcine miR-146b, was further examined in 42 cases of human liver transplantations. High expression of miR-146b-5p successfully predicted the post-transplant early allograft dysfunction (EAD) with the area under the ROC curve (AUC) 0.759 (P=0.004). Conclusions Our results revealed the miRNA signature of DBCD liver grafts for the first time. The miR-146b-5p may have important clinical implications for monitoring liver graft function and predicating transplant outcomes. PMID:29227984

Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say?

PubMed Central

Zordan, Mauro Agostino; Sandrelli, Federica

2015-01-01

There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease. PMID:25941512

Ethics review: Dark angels – the problem of death in intensive care

PubMed Central

2007-01-01

Critical care medicine has expanded the envelope of debilitating disease through the application of an aggressive and invasive care plan, part of which is designed to identify and reverse organ dysfunction before it proceeds to organ failure. For a select patient population, this care plan has been remarkably successful. But because patient selection is very broad, critical care sometimes yields amalgams of life in death: the state of being unable to participate in human life, unable to die, at least in the traditional sense. This work examines the emerging paradox of somatic versus brain death and why it matters to medical science. PMID:17254317

Impact of the primary aetiology upon the clinical outcome of adults with childhood-onset GH deficiency.

PubMed

Hoybye, Charlotte; Jönsson, Peter; Monson, John P; Koltowska-Häggström, Maria; Hána, Václav; Geffner, Mitchell; Abs, Roger

2007-11-01

The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy. Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement. GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement. The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

Functional dyspepsia pathogenesis and therapeutic options--implications for management.

PubMed

Smith, M Lancaster

2005-08-01

Functional dyspepsia is far more common than dyspepsia due to organic disease, both in the community and general practice. Proposed aetiopathogenic factors include gastric acid, Helicobacter pylori infection, delayed emptying, hypersensitivity or impaired accommodation of the stomach, dysfunction of the duodenum or brain-gut axis, psychosocial morbidity and post-infective mucosal damage. More effective therapy will depend on the development of drugs targeted at these putative pathophysiological mechanisms. On current evidence tricyclic antidepressants appear to be more effective than either acid suppressants or H. pylori eradication.

Advances in understanding ventromedial prefrontal function: the accountant joins the executive.

PubMed

Fellows, Lesley K

2007-03-27

Studies of the brain basis of decision-making and economic behavior are providing a new perspective on the organization and functions of human prefrontal cortex. This line of inquiry has focused particularly on the ventral and medial portions of prefrontal cortex, arguably the most enigmatic regions of the "enigmatic frontal lobes." This review highlights recent advances in the cognitive neuroscience of decision making and neuroeconomics and discusses how these findings can inform clinical thinking about frontal lobe dysfunction.

High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature.

PubMed

Li, Wei; Maloney, Ronald E; Aw, Tak Yee

2015-08-01

We previously demonstrated that in normal glucose (5mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG-occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG-occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature

PubMed Central

Li, Wei; Maloney, Ronald E.; Aw, Tak Yee

2015-01-01

We previously demonstrated that in normal glucose (5 mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6 h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG–occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG–occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. PMID:25867911

Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion.

PubMed

Mai, Nguyen; Prifti, Landa; Rininger, Aric; Bazarian, Hannah; Halterman, Marc W

2017-11-01

Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50μg/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

PubMed

Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

2017-06-01

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Blood–brain barrier dysfunction and epilepsy: Pathophysiologic role and therapeutic approaches

PubMed Central

Marchi, Nicola; Granata, Tiziana; Ghosh, Chaitali; Janigro, Damir

2016-01-01

The blood–brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte–endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB-centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs. PMID:22905812

Slow Spatial Recruitment of Neocortex during Secondarily Generalized Seizures and Its Relation to Surgical Outcome

PubMed Central

Martinet, Louis-Emmanuel; Ahmed, Omar J.; Lepage, Kyle Q.; Cash, Sydney S.

2015-01-01

Understanding the spatiotemporal dynamics of brain activity is crucial for inferring the underlying synaptic and nonsynaptic mechanisms of brain dysfunction. Focal seizures with secondary generalization are traditionally considered to begin in a limited spatial region and spread to connected areas, which can include both pathological and normal brain tissue. The mechanisms underlying this spread are important to our understanding of seizures and to improve therapies for surgical intervention. Here we study the properties of seizure recruitment—how electrical brain activity transitions to large voltage fluctuations characteristic of spike-and-wave seizures. We do so using invasive subdural electrode arrays from a population of 16 patients with pharmacoresistant epilepsy. We find an average delay of ∼30 s for a broad area of cortex (8 × 8 cm) to be recruited into the seizure, at an estimated speed of ∼4 mm/s. The spatiotemporal characteristics of recruitment reveal two categories of patients: one in which seizure recruitment of neighboring cortical regions follows a spatially organized pattern consistent from seizure to seizure, and a second group without consistent spatial organization of activity during recruitment. The consistent, organized recruitment correlates with a more regular, compared with small-world, connectivity pattern in simulation and successful surgical treatment of epilepsy. We propose that an improved understanding of how the seizure recruits brain regions into large amplitude voltage fluctuations provides novel information to improve surgical treatment of epilepsy and highlights the slow spread of massive local activity across a vast extent of cortex during seizure. PMID:26109670

Impaired Pituitary Axes Following Traumatic Brain Injury

PubMed Central

Scranton, Robert A.; Baskin, David S.

2015-01-01

Pituitary dysfunction following traumatic brain injury (TBI) is significant and rarely considered by clinicians. This topic has received much more attention in the last decade. The incidence of post TBI anterior pituitary dysfunction is around 30% acutely, and declines to around 20% by one year. Growth hormone and gonadotrophic hormones are the most common deficiencies seen after traumatic brain injury, but also the most likely to spontaneously recover. The majority of deficiencies present within the first year, but extreme delayed presentation has been reported. Information on posterior pituitary dysfunction is less reliable ranging from 3%–40% incidence but prospective data suggests a rate around 5%. The mechanism, risk factors, natural history, and long-term effect of treatment are poorly defined in the literature and limited by a lack of standardization. Post TBI pituitary dysfunction is an entity to recognize with significant clinical relevance. Secondary hypoadrenalism, hypothyroidism and central diabetes insipidus should be treated acutely while deficiencies in growth and gonadotrophic hormones should be initially observed. PMID:26239686

34 CFR 222.50 - What definitions apply to this subpart?

Code of Federal Regulations, 2013 CFR

2013-07-01

..., autism, traumatic brain injury, other health impairments, or specific learning disabilities; and (ii) Who... conditions such as perceptual disabilities, brain injury, minimal brain dysfunction, dyslexia, and...

34 CFR 222.50 - What definitions apply to this subpart?

Code of Federal Regulations, 2012 CFR

2012-07-01

..., autism, traumatic brain injury, other health impairments, or specific learning disabilities; and (ii) Who... conditions such as perceptual disabilities, brain injury, minimal brain dysfunction, dyslexia, and...

34 CFR 222.50 - What definitions apply to this subpart?

Code of Federal Regulations, 2014 CFR

2014-07-01

..., autism, traumatic brain injury, other health impairments, or specific learning disabilities; and (ii) Who... conditions such as perceptual disabilities, brain injury, minimal brain dysfunction, dyslexia, and...

Mitochondrial dysfunction in obesity.

PubMed

de Mello, Aline Haas; Costa, Ana Beatriz; Engel, Jéssica Della Giustina; Rezin, Gislaine Tezza

2018-01-01

Obesity leads to various changes in the body. Among them, the existing inflammatory process may lead to an increase in the production of reactive oxygen species (ROS) and cause oxidative stress. Oxidative stress, in turn, can trigger mitochondrial changes, which is called mitochondrial dysfunction. Moreover, excess nutrients supply (as it commonly is the case with obesity) can overwhelm the Krebs cycle and the mitochondrial respiratory chain, causing a mitochondrial dysfunction, and lead to a higher ROS formation. This increase in ROS production by the respiratory chain may also cause oxidative stress, which may exacerbate the inflammatory process in obesity. All these intracellular changes can lead to cellular apoptosis. These processes have been described in obesity as occurring mainly in peripheral tissues. However, some studies have already shown that obesity is also associated with changes in the central nervous system (CNS), with alterations in the blood-brain barrier (BBB) and in cerebral structures such as hypothalamus and hippocampus. In this sense, this review presents a general view about mitochondrial dysfunction in obesity, including related alterations, such as inflammation, oxidative stress, and apoptosis, and focusing on the whole organism, covering alterations in peripheral tissues, BBB, and CNS. Copyright © 2017 Elsevier Inc. All rights reserved.

Hemihydranencephaly: living with half brain dysfunction.

PubMed

Pavone, Piero; Nigro, Francesco; Falsaperla, Raffaele; Greco, Filippo; Ruggieri, Martino; Rizzo, Renata; Praticò, Andrea D; Pavone, Lorenzo

2013-01-16

Hemi-hydranencephaly is a very rare condition characterized by complete or almost near-complete unilateral absence of the cortical cortex, which is filled by a sac of cerebrospinal fluid. Prenatal vascular disruption with occlusion of the carotid artery territories ipsilateral to the damaged brain is the presumed pathogenesis.We have selected nine cases that fit the clinical and pathologic characteristics of hemi-hydranencephaly, demonstrating that destruction of one hemisphere may be not always associated with severe neurologic impairment and may allow an almost normal life. This disorder is an example of a possible prenatal re-organization in which the right and left cerebral hemispheres present functional potentiality to make up the damaged brain.The cases reported in the literature are discussed, including a patient previously reported and followed-up for 10 years. A review of the cases is performed with an evaluation of the most important aspect of this rare and mysterious disorder.

Large-Scale Brain Systems in ADHD: Beyond the Prefrontal-Striatal Model

PubMed Central

Castellanos, F. Xavier; Proal, Erika

2012-01-01

Attention-deficit/hyperactivity disorder (ADHD) has long been thought to reflect dysfunction of prefrontal-striatal circuitry, with involvement of other circuits largely ignored. Recent advances in systems neuroscience-based approaches to brain dysfunction enable the development of models of ADHD pathophysiology that encompass a number of different large-scale “resting state” networks. Here we review progress in delineating large-scale neural systems and illustrate their relevance to ADHD. We relate frontoparietal, dorsal attentional, motor, visual, and default networks to the ADHD functional and structural literature. Insights emerging from mapping intrinsic brain connectivity networks provide a potentially mechanistic framework for understanding aspects of ADHD, such as neuropsychological and behavioral inconsistency, and the possible role of primary visual cortex in attentional dysfunction in the disorder. PMID:22169776

Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.

PubMed

Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B; Mocco, J; Raizada, Mohan K

2012-11-01

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension.

Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury

PubMed Central

Yin, Xiang-Jie; Chen, Zhen-Yan; Zhu, Xiao-Na; Hu, Jin-Jia

2017-01-01

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide, which is a major public health problem. Death caused by TBI accounts for a third of all damage related illnesses, which 75% TBI occurred in low and middle income countries. With the increasing use of motor vehicles, the incidence of TBI has been at a high level. The abnormal brain functions of TBI patients often show the acute and long-term neurological dysfunction, which mainly associated with the pathological process of malignant brain edema and neuroinflammation in the brain. Owing to the neuroinflammation lasts for months or even years after TBI, which is a pivotal causative factor that give rise to neurodegenerative disease at late stage of TBI. Studies have shown that platelet activating factor (PAF) inducing inflammatory reaction after TBI could not be ignored. The morphological and behavioral abnormalities after TBI in wild type mice are rescued by general knockout of PAFR gene that neuroinflammation responses and cognitive ability are improved. Our results thus define a key inflammatory molecule PAF that participates in the neuroinflammation and helps bring about cerebral dysfunction during the TBI acute phase. PMID:28094295

Meta-connectomics: human brain network and connectivity meta-analyses.

PubMed

Crossley, N A; Fox, P T; Bullmore, E T

2016-04-01

Abnormal brain connectivity or network dysfunction has been suggested as a paradigm to understand several psychiatric disorders. We here review the use of novel meta-analytic approaches in neuroscience that go beyond a summary description of existing results by applying network analysis methods to previously published studies and/or publicly accessible databases. We define this strategy of combining connectivity with other brain characteristics as 'meta-connectomics'. For example, we show how network analysis of task-based neuroimaging studies has been used to infer functional co-activation from primary data on regional activations. This approach has been able to relate cognition to functional network topology, demonstrating that the brain is composed of cognitively specialized functional subnetworks or modules, linked by a rich club of cognitively generalized regions that mediate many inter-modular connections. Another major application of meta-connectomics has been efforts to link meta-analytic maps of disorder-related abnormalities or MRI 'lesions' to the complex topology of the normative connectome. This work has highlighted the general importance of network hubs as hotspots for concentration of cortical grey-matter deficits in schizophrenia, Alzheimer's disease and other disorders. Finally, we show how by incorporating cellular and transcriptional data on individual nodes with network models of the connectome, studies have begun to elucidate the microscopic mechanisms underpinning the macroscopic organization of whole-brain networks. We argue that meta-connectomics is an exciting field, providing robust and integrative insights into brain organization that will likely play an important future role in consolidating network models of psychiatric disorders.

Cerebrovascular dysfunction is an attractive target for therapy in heat stroke.

PubMed

Chen, Sheng-Hsien; Niu, Ko-Chi; Lin, Mao-Tsun

2006-08-01

1. The aim of the present review is to summarize clinical observations and results of animal models that advance the knowledge of the attenuation of cerebrovascular dysfunction in the setting of heat stroke. It is a narrative review of selected published literature from Medline over the period 1959-2005. 2. All heat-stressed rodents, even under general anaesthesia, have hyperthermia, systemic inflammation, hypercoagulable state, arterial hypotension and tissue ischaemia and injury in multiple organs. These findings demonstrate that rodent heat stroke models can nearly mirror the full spectrum of human heat stroke. Experimental heat stroke fulfills the empirical triad used for the diagnosis of classical human heat stroke, namely hyperthermia, central nervous system alterations and a history of heat stress. 3. These physiological dysfunctions and survival during heat stroke can be improved by whole-body or brain cooling therapy adopted immediately after the onset of heat stroke. 4. However, in the absence of body or brain cooling, these heat stroke reactions can still be reduced by the following measures: (i) fluid replacement with 3% NaCl solution, 10% human albumin or hydroxyethyl starch; (ii) intravenous delivery of anti-inflammatory drugs, free radical scavengers or interleukin-1 receptor antagonists; (iii) hyperbaric oxygen therapy; or (iv) transplantation of human umbilical cord blood cells. 5. In addition, before initiation of heat stress, prior manipulations with one of the following measures was found to be able to protect against heat stroke reactions: (i) systemic delivery of alpha-tocopherol, mannitol, inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin ETA receptor antagonists, serotoninergic nerve depletors or receptor antagonists, or glutamate receptor antagonists; or (ii) heat shock protein 72 preconditioning. 6. There is compelling evidence that cerebrovascular dysfunction is an attractive target for therapy in heat stroke.

Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people.

PubMed

Bridges, Leslie R; Andoh, Joycelyn; Lawrence, Andrew J; Khoong, Cheryl H L; Poon, Wayne; Esiri, Margaret M; Markus, Hugh S; Hainsworth, Atticus H

2014-11-01

The blood-brain barrier protects brain tissue from potentially harmful plasma components. Small vessel disease (SVD; also termed arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis, and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and immunoglobulin G, which are assumed to reflect blood-brain barrier dysfunction, in deep gray matter (DGM; anterior caudate-putamen) and deep subcortical white matter (DWM) in the brains of a well-characterized cohort of donated brains with minimal Alzheimer disease pathology (Braak Stages 0-II) (n = 84; aged 65 years or older). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and immunoglobulin G was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that, in aged brains, plasma extravasation and hence local blood-brain barrier dysfunction are common but do not support an association with SVD.

Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation.

PubMed

Matt, Stephanie M; Johnson, Rodney W

2016-02-01

Microglia, the resident immune cells of the brain, are at the center of communication between the central nervous system and immune system. While these brain-immune interactions are balanced in healthy adulthood, the ability to maintain homeostasis during aging is impaired. Microglia develop a loss of integrated regulatory networks including aberrant signaling from other brain cells, immune sensors, and epigenetic modifiers. The low-grade chronic neuroinflammation associated with this dysfunctional activity likely contributes to cognitive deficits and susceptibility to age-related pathologies. A better understanding of the underlying mechanisms responsible for neuro-immune dysregulation with age is crucial for providing targeted therapeutic strategies to support brain repair and healthy aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

Intravascular lymphomatosis presenting as acute hemispheric dysfunction.

PubMed

Hwang, Woo Sub; Jung, Chul Won; Ko, Young Hye; Seo, Sang Won; Na, Duk L

2012-11-01

Intravascular lymphomatosis (IVL) is known to affect both hemispheres of the brain and manifests clinically as seizures or dementia. To our knowledge, there have been no cases in which acute hemispheric dysfunction is manifested in IVL. We present a 54-year-old man who showed steroid responsive acute hemispheric dysfunction. A technetium 99m-ethyl cysteinate dimer single-photon emission computed tomographic scan of the brain revealed hypoperfusion in the right hemisphere. The bone marrow biopsy specimen confirmed malignant lymphoid cells in vessels, which suggested IVL. Our case signifies the diversity of clinical manifestations in IVL. Copyright © 2012. Published by Elsevier Inc.

[Short-term outcomes of lung transplant recipients using organs from brain death donors].

PubMed

He, W X; Jiang, C; Liu, X G; Huang, W; Chen, C; Jiang, L; Yang, B; Wu, K; Chen, Q K; Yang, Y; Yu, Y M; Jiang, G N

2016-12-01

Objective: To assess short-term outcomes after lung transplantation with organs procured following brain death. Methods: Between April 2015 and July 2016, all 17 recipients after lung transplantation using organs from brain death donors (DBD) at Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine were enrolled in this study. All patients were male, aging (60±7) years, including 11 chronic obstructive pulmonary disease, 5 idiopathic pulmonary fibrosis, 1 silicosis. Seventeen donors were 16 males and 1 female, with 10 traumatic brain injury, 5 cerebrovascular accident and 2 sudden cardiac death. Of 17 recipients receiving DBD lung transplant, 16 were single lung transplant. Data were collected including intubation duration of mechanical ventilation, hospital length of stay, incidence of pulmonary infection bronchus anastomosis complications, primary graft dysfunction (PGD), and acute rejection, bronchiolitis obliterans syndrome (BOS) as well as mortality of 90-day after lung transplantation. Results: Median duration of intubation were 2 (2) days ( M ( Q R )) in recipients after lung transplantation. The incidence of pulmonary infection and bronchus anastomosis complications were 15/17 and 5/17, respectively. Median length of stay in hospital were 56 (19) days. The ratio of readmission 1 month after discharge were 10/17. Mortality of 90-day post-transplant were 2/17. The incidence of PGD and BOS were 1/17 and 2/17, respectively. Conclusion: Recipients with DBD lung transplantation have an acceptable survival during short-term follow-up, but with higher incidences of complications related to infection post-transplantation.

Avocado Oil Improves Mitochondrial Function and Decreases Oxidative Stress in Brain of Diabetic Rats.

PubMed

Ortiz-Avila, Omar; Esquivel-Martínez, Mauricio; Olmos-Orizaba, Berenice Eridani; Saavedra-Molina, Alfredo; Rodriguez-Orozco, Alain R; Cortés-Rojo, Christian

2015-01-01

Diabetic encephalopathy is a diabetic complication related to the metabolic alterations featuring diabetes. Diabetes is characterized by increased lipid peroxidation, altered glutathione redox status, exacerbated levels of ROS, and mitochondrial dysfunction. Although the pathophysiology of diabetic encephalopathy remains to be clarified, oxidative stress and mitochondrial dysfunction play a crucial role in the pathogenesis of chronic diabetic complications. Taking this into consideration, the aim of this work was to evaluate the effects of 90-day avocado oil intake in brain mitochondrial function and oxidative status in streptozotocin-induced diabetic rats (STZ rats). Avocado oil improves brain mitochondrial function in diabetic rats preventing impairment of mitochondrial respiration and mitochondrial membrane potential (ΔΨ m ), besides increasing complex III activity. Avocado oil also decreased ROS levels and lipid peroxidation and improved the GSH/GSSG ratio as well. These results demonstrate that avocado oil supplementation prevents brain mitochondrial dysfunction induced by diabetes in association with decreased oxidative stress.

Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.

PubMed

Zhou, Ting; Zhao, Lei; Zhan, Rui; He, Qihua; Tong, Yawei; Tian, Xiaosheng; Wang, Hecheng; Zhang, Tao; Fu, Yaoyun; Sun, Yang; Xu, Feng; Guo, Xiangyang; Fan, Dongsheng; Han, Hongbin; Chui, Dehua

2014-10-24

Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

Toward an understanding of violence: neurobehavioral aspects of unwarranted physical aggression: Aspen Neurobehavioral Conference consensus statement.

PubMed

Filley, C M; Price, B H; Nell, V; Antoinette, T; Morgan, A S; Bresnahan, J F; Pincus, J H; Gelbort, M M; Weissberg, M; Kelly, J P

2001-01-01

Violence is a global problem that poses a major challenge to individuals and society. This document is a consensus statement on neurobehavioral aspects of violence as one approach to its understanding and control. This consensus group was convened under the auspices of the Aspen Neurobehavioral Conference, an annual consensus conference devoted to the understanding of issues related to mind and brain. The conference is supported by the Brain Injury Association and by individual philanthropic contributions. Participants were selected by conference organizers to represent leading opinion in neurology, neuropsychology, psychiatry, trauma surgery, nursing, evolutionary psychology, medical ethics, and law. A literature review of the role of the brain in violent behavior was conducted and combined with expert opinion from the group. The major goal was to survey this field so as to identify major areas of interest that could be targeted for further research. Additional review was secured from the other attendees at the Aspen Neurobehavioral Conference. The group met in the spring of 1998 and 1999 for two 5-day sessions, between which individual assignments were carried out. The consensus statement was prepared after the second meeting, and agreement on the statement was reached by participants after final review of the document. Violence can result from brain dysfunction, although social and evolutionary factors also contribute. Study of the neurobehavioral aspects of violence, particularly frontal lobe dysfunction, altered serotonin metabolism, and the influence of heredity, promises to lead to a deeper understanding of the causes and solution of this urgent problem.

The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes

PubMed Central

Indrieri, Alessia; Conte, Ivan; Chesi, Giancarlo; Romano, Alessia; Quartararo, Jade; Tatè, Rosarita; Ghezzi, Daniele; Zeviani, Massimo; Goffrini, Paola; Ferrero, Ileana; Bovolenta, Paola; Franco, Brunella

2013-01-01

Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial-dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holo-cytochrome c-type synthase (HCCS) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders. PMID:23239471

Advanced MR Imaging of the Placenta: Exploring the in utero placenta-brain connection

PubMed Central

Andescavage, Nickie Niforatos; DuPlessis, Adre; Limperopoulos, Catherine

2015-01-01

The placenta is a vital organ necessary for the healthy neurodevelopment of the fetus. Despite the known associations between placental dysfunction and neurologic impairment, there is a paucity of tools available to reliably assess in vivo placental health and function. Existing clinical tools for placental assessment remain insensitive in predicting and assessing placental well-being. Advanced MRI techniques hold significant promise for the dynamic, non-invasive, real-time assessment of placental health and identification of early placental-based disorders. In this review, we summarize the available clinical tools for placental assessment including ultrasound, Doppler, and conventional MRI. We then explore the emerging role of advanced placental MR imaging techniques for supporting the developing fetus, appraise the strengths and limitations of quantitative MRI in identifying early markers of placental dysfunction for improved pregnancy monitoring and fetal outcomes. PMID:25765905

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

PubMed

Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy; Tucsek, Zsuzsanna; Hertelendy, Peter; Kiss, Tamas; Gautam, Tripti; Zhang, Xin A; Sonntag, William E; de Cabo, Rafael; Farkas, Eszter; Elliott, Michael H; Kinter, Michael T; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-14

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses involving combined peripheral and central vestibular dysfunction.

PubMed

Arshad, Q; Roberts, R E; Ahmad, H; Lobo, R; Patel, M; Ham, T; Sharp, D J; Seemungal, B M

2017-04-01

We hypothesised that chronic vestibular symptoms (CVS) of imbalance and dizziness post-traumatic head injury (THI) may relate to: (i) the occurrence of multiple simultaneous vestibular diagnoses including both peripheral and central vestibular dysfunction in individual patients increasing the chance of missed diagnoses and suboptimal treatment; (ii) an impaired response to vestibular rehabilitation since the central mechanisms that mediate rehabilitation related brain plasticity may themselves be disrupted. We report the results of a retrospective analysis of both the comprehensive clinical and vestibular laboratory testing of 20 consecutive THI patients with prominent and persisting vestibular symptoms still present at least 6months post THI. Individual THI patients typically had multiple vestibular diagnoses and unique to this group of vestibular patients, often displayed both peripheral and central vestibular dysfunction. Despite expert neuro-otological management, at two years 20% of patients still had persisting vestibular symptoms. In summary, chronic vestibular dysfunction in THI could relate to: (i) the presence of multiple vestibular diagnoses, increasing the risk of 'missed' vestibular diagnoses leading to persisting symptoms; (ii) the impact of brain trauma which may impair brain plasticity mediated repair mechanisms. Apart from alerting physicians to the potential for multiple vestibular diagnoses in THI, future work to identify the specific deficits in brain function mediating poor recovery from post-THI vestibular dysfunction could provide the rationale for developing new therapy for head injury patients whose vestibular symptoms are resistant to treatment. Copyright © 2017. Published by Elsevier B.V.

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer's Disease.

PubMed

Winick-Ng, Warren; Rylett, R Jane

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed.

Number of organ dysfunctions predicts mortality in emergency department patients with suspected infection: a multicenter validation study.

PubMed

Jessen, Marie K; Skibsted, Simon; Shapiro, Nathan I

2017-06-01

The aim of this study was to validate the association between number of organ dysfunctions and mortality in emergency department (ED) patients with suspected infection. This study was conducted at two medical care center EDs. The internal validation set was a prospective cohort study conducted in Boston, USA. The external validation set was a retrospective case-control study conducted in Aarhus, Denmark. The study included adult patients (>18 years) with clinically suspected infection. Laboratory results and clinical data were used to assess organ dysfunctions. Inhospital mortality was the outcome measure. Multivariate logistic regression was used to determine the independent mortality odds for number and types of organ dysfunctions. We enrolled 4952 (internal) and 483 (external) patients. The mortality rate significantly increased with increasing number of organ dysfunctions: internal validation: 0 organ dysfunctions: 0.5% mortality, 1: 3.6%, 2: 9.5%, 3: 17%, and 4 or more: 37%; external validation: 2.2, 6.7, 17, 41, and 57% mortality (both P<0.001 for trend). Age-adjusted and comorbidity-adjusted number of organ dysfunctions remained an independent predictor. The effect of specific types of organ dysfunction on mortality was most pronounced for hematologic [odds ratio (OR) 3.3 (95% confidence interval (CI) 2.0-5.4)], metabolic [OR 3.3 (95% CI 2.4-4.6); internal validation], and cardiovascular dysfunctions [OR 14 (95% CI 3.7-50); external validation]. The number of organ dysfunctions predicts sepsis mortality.

Are Mental Disorders Brain Diseases, and What Does This Mean? A Clinical-Neuropsychological Perspective.

PubMed

Frisch, Stefan

Neuroscientific research has substantially increased our knowledge about mental disorders in recent years. Along with these benefits, radical postulates have been articulated according to which understanding and treatment of mental disorders should generally be based on biological terms, such as neurons/brain areas, transmitters, genes etc. Proponents of such a 'biological psychiatry' claim that mental disorders are analogous to neurological disorders and refer to neurology and neuropsychology to corroborate their claims. The present article argues that, from a clinical-neuropsychological perspective, 'biological psychiatry' is based on a mechanistic, 'cerebrocentric' framework of brain (dys-)function which has its roots in experimental neuroscience but runs up against narrow limits in clinical neurology and neuropsychology. In fact, understanding and treating neurological disorders generally demands a systems perspective including brain, organism and environment as intrinsically entangled. In this way, 'biological' characterizes a 'holistic', nonreductionist level of explanation, according to which the significance of particular mechanisms can only be estimated in the context of the organism (or person). This is evident in the common observation that local brain damage does not just lead to an isolated loss of function, but to multiple attempts of reorganization and readaptation; it initiates new developments. Furthermore, treating brain disorders necessarily includes aspects of individuality and subjectivity, a conclusion that contradicts the purely 'objectivist', third-person stance put forward by some proponents of biological psychiatry. In sum, understanding and treating brain damage sequelae in the clinical neurosciences demands a biopsychosocial perspective, for both conceptual and historical reasons. The same may hold for psychiatry when adopting a brain-based view on mental disorders. In such a perspective, biological psychiatry seems an interesting project but falls short of its original claims. © 2016 S. Karger AG, Basel.

Minimal Brain Dysfunction in Childhood: II. Late Outcome in Relation to Initial Presentation. III. Predictive Factors in Relation to Late Outcome.

ERIC Educational Resources Information Center

Milman, Doris H.

Two studies explore the late outcome of minimal brain dysfunction in 73 patients in relation to their initial presentation and predictive factors. Both studies followed the patients for a period of 10 to 20 years. Findings from the first study of initial presentation in relation to adult outcome showed that there was a strong positive correlation…

Pathological anxiety and function/dysfunction in the brain's fear/defense circuitry.

PubMed

Lang, Peter J; McTeague, Lisa M; Bradley, Margaret M

2014-01-01

Research from the University of Florida Center for the Study of Emotion and Attention aims to develop neurobiological measures that objectively discriminate among symptom patterns in patients with anxiety disorders. From this perspective, anxiety and mood pathologies are considered to be brain disorders, resulting from dysfunction and maladaptive plasticity in the neural circuits that determine fearful/defensive and appetitive/reward behavior (Insel et al., 2010). We review recent studies indicating that an enhanced probe startle reflex during the processing of fear memory cues (mediated by cortico-limbic circuitry and thus indicative of plastic brain changes), varies systematically in strength over a spectrum-wide dimension of anxiety pathology-across and within diagnoses-extending from strong focal fear reactions to a consistently blunted reaction in patients with more generalized anxiety and comorbid mood disorders. Preliminary studies with functional magnetic resonance imaging (fMRI) encourage the hypothesis that fear/defense circuit dysfunction covaries with this same dimension of psychopathology. Plans are described for an extended study of the brain's motivation circuitry in anxiety spectrum patients, with the aim of defining the specifics of circuit dysfunction in severe disorders. A sub-project explores the use of real-time fMRI feedback in circuit analysis and as a modality to up-regulate circuit function in the context of blunted affect.

Lactate Clearance and Normalization and Prolonged Organ Dysfunction in Pediatric Sepsis.

PubMed

Scott, Halden F; Brou, Lina; Deakyne, Sara J; Fairclough, Diane L; Kempe, Allison; Bajaj, Lalit

2016-03-01

To evaluate whether lactate clearance and normalization during emergency care of pediatric sepsis is associated with lower rates of persistent organ dysfunction. This was a prospective cohort study of 77 children <18 years of age in the emergency department with infection and acute organ dysfunction per consensus definitions. In consented patients, lactate was measured 2 and/or 4 hours after an initial lactate; persistent organ dysfunction was assessed through laboratory and physician evaluation at 48 hours. A decrease of ≥ 10% from initial to final level was considered lactate clearance; a final level < 2 mmol/L was considered lactate normalization. Relative risk (RR) with 95% CIs, adjusted in a log-binomial model, was used to evaluate associations between lactate clearance/normalization and organ dysfunction. Lactate normalized in 62 (81%) patients and cleared in 70 (91%). The primary outcome, persistent 48-hour organ dysfunction, was present in 32 (42%). Lactate normalization was associated with decreased risk of persistent organ dysfunction (RR 0.46, 0.29-0.73; adjusted RR 0.47, 0.29-0.78); lactate clearance was not (RR 0.70, 0.35-1.41; adjusted RR 0.75, 0.38-1.50). The association between lactate normalization and decreased risk of persistent organ dysfunction was retained in the subgroups with initial lactate ≥ 2 mmol/L and hypotension. In children with sepsis and organ dysfunction, lactate normalization within 4 hours was associated with decreased persistent organ dysfunction. Serial lactate level measurement may provide a useful prognostic tool during the first hours of resuscitation in pediatric sepsis. Copyright © 2016 Elsevier Inc. All rights reserved.

Combined Therapy of Iron Chelator and Antioxidant Completely Restores Brain Dysfunction Induced by Iron Toxicity

PubMed Central

Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

2014-01-01

Background Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied. Methodology Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results. Conclusion In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload. PMID:24400127

Pituitary Dysfunction after Blast Traumatic Brain Injury: The UK BIOSAP Study

PubMed Central

Baxter, David; Sharp, David J; Feeney, Claire; Papadopoulou, Debbie; Ham, Timothy E; Jilka, Sagar; Hellyer, Peter J; Patel, Maneesh C; Bennett, Alexander N; Mistlin, Alan; McGilloway, Emer; Midwinter, Mark; Goldstone, Anthony P

2013-01-01

Objective Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury. Methods Nineteen male soldiers with moderate to severe bTBI (median age = 28.3 years) and 39 male controls with moderate to severe nonblast TBI (nbTBI; median age = 32.3 years) underwent full dynamic endocrine assessment between 2 and 48 months after injury. In addition, soldiers had structural brain magnetic resonance imaging, including diffusion tensor imaging (DTI), and cognitive assessment. Results Six of 19 (32.0%) soldiers with bTBI, but only 1 of 39 (2.6%) nbTBI controls, had anterior pituitary dysfunction (p = 0.004). Two soldiers had hyperprolactinemia, 2 had growth hormone (GH) deficiency, 1 had adrenocorticotropic hormone (ACTH) deficiency, and 1 had combined GH/ACTH/gonadotrophin deficiency. DTI measures of white matter structure showed greater traumatic axonal injury in the cerebellum and corpus callosum in those soldiers with pituitary dysfunction than in those without. Soldiers with pituitary dysfunction after bTBI also had a higher prevalence of skull/facial fractures and worse cognitive function. Four soldiers (21.1%) commenced hormone replacement(s) for hypopituitarism. Interpretation We reveal a high prevalence of anterior pituitary dysfunction in soldiers suffering moderate to severe bTBI, which was more frequent than in a matched group of civilian moderate to severe nbTBI subjects. We recommend that all patients with moderate to severe bTBI should routinely have comprehensive assessment of endocrine function. Ann Neurol 2013;74:527–536 PMID:23794460

Brain 18F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis.

PubMed

Van Der Gucht, Axel; Aoun Sebaiti, Mehdi; Guedj, Eric; Aouizerate, Jessie; Yara, Sabrina; Gherardi, Romain K; Evangelista, Eva; Chalaye, Julia; Cottereau, Anne-Ségolène; Verger, Antoine; Bachoud-Levi, Anne-Catherine; Abulizi, Mukedaisi; Itti, Emmanuel; Authier, François-Jérôme

2017-03-01

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18 F-FDG. Methods: 18 F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18 F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment ( n = 42), those with frontal subcortical (FSC) dysfunction ( n = 29), those with Papez circuit dysfunction ( n = 22), and those with callosal disconnection ( n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism ( P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 2.

PubMed

Upperman, Jeffrey S; Bucuvalas, John C; Williams, Felicia N; Cairns, Bruce A; Cox, Charles S; Doctor, Allan; Tamburro, Robert F

2017-03-01

To describe a number of conditions and therapies associated with multiple organ dysfunction syndrome presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Multiple Organ Dysfunction Workshop (March 26-27, 2015). In addition, the relationship between burn injuries and multiple organ dysfunction syndrome is also included although it was not discussed at the workshop. Literature review, research data, and expert opinion. Not applicable. Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions and therapies were presented, discussed, and debated with a focus on identifying knowledge gaps and the research priorities. Summary of presentations and discussion supported and supplemented by relevant literature. Sepsis and trauma are the two conditions most commonly associated with multiple organ dysfunction syndrome both in children and adults. However, many other pathophysiologic processes may result in multiple organ dysfunction syndrome. In this article, we discuss conditions such as liver failure and pancreatitis, pathophysiologic processes such as ischemia and hypoxia, and injuries such as trauma and burns. Additionally, therapeutic interventions such as medications, blood transfusions, transplantation may also precipitate and contribute to multiple organ dysfunction syndrome. The purpose of this article is to describe the association of multiple organ dysfunction syndrome with a variety of conditions and therapies in an attempt to identify similarities, differences, and opportunities for therapeutic intervention.

Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice

PubMed Central

Sun, Kaihua; Johnson, Brian S.; Gunn, Teresa M.

2007-01-01

Oxidative stress, ubiquitination defects and mitochondrial dysfunction are commonly associated with neurodegeneration. Mice lacking mahogunin ring finger-1 (MGRN1) or attractin (ATRN) develop age-dependent spongiform neurodegeneration through an unknown mechanism. It has been suggested that they act in a common pathway. As MGRN1 is an E3 ubiquitin ligase, proteomic analysis of Mgrn1 mutant and control brains was performed to explore the hypothesis that loss of MGRN1 causes neurodegeneration via accumulation of its substrates. Many mitochondrial proteins were reduced in Mgrn1 mutants. Subsequent assays confirmed significantly reduced mitochondrial complex IV expression and activity as well as increased oxidative stress in mutant brains. Mitochondrial dysfunction was obvious many months before onset of vacuolation, implicating this as a causative factor. Compatible with the hypothesis that ATRN and MGRN1 act in the same pathway, mitochondrial dysfunction and increased oxidative stress were also observed in the brains of Atrn mutants. Our results suggest that the study of Mgrn1 and Atrn mutant mice will provide insight into a causative molecular mechanism common to many neurodegenerative disorders. PMID:17720281

Hypopituitarism after acute brain injury.

PubMed

Urban, Randall J

2006-07-01

Acute brain injury has many causes, but the most common is trauma. There are 1.5-2.0 million traumatic brain injuries (TBI) in the United States yearly, with an associated cost exceeding 10 billion dollars. TBI is the most common cause of death and disability in young adults less than 35 years of age. The consequences of TBI can be severe, including disability in motor function, speech, cognition, and psychosocial and emotional skills. Recently, clinical studies have documented the occurrence of pituitary dysfunction after TBI and another cause of acute brain injury, subarachnoid hemorrhage (SAH). These studies have consistently demonstrated a 30-40% occurrence of pituitary dysfunction involving at least one anterior pituitary hormone following a moderate to severe TBI or SAH. Growth hormone (GH) deficiency is the most common pituitary hormone disorder, occurring in approximately 20% of patients when multiple tests of GH deficiency are used. Within 7-21 days of acute brain injury, adrenal insufficiency is the primary concern. Pituitary function can fluctuate over the first year after TBI, but it is well established by 1 year. Studies are ongoing to assess the effects of hormone replacement on motor function and cognition in TBI patients. Any subject with a moderate to severe acute brain injury should be screened for pituitary dysfunction.

[Effects of mercazolyl and L-thyroxine on the antiedematous activity of immunotropic preparations during development of toxic brain edema and swelling].

PubMed

Platonov, I A; Anashchenkova, T A; Andreeva, T A

2008-01-01

Dysfunction of thyroid gland plays an important role in the pathogenesis of brain edema and swelling. Toxic brain edema and swelling was modeled under condition of hypo- and hyperfunction of thyroid gland. Mercazolyl and L-thyroxine ambiguously influence the development of toxic brain edema and swelling in rats. L-thyroxin (35.7 microg/kg) favors increase in the water content in brain tissue, which can be considered as synergism with the edematous factor and the formation of brain tissue susceptibility to the development of brain edema and swelling. The administration of mercazolyl (5 mg/kg) and L-thyroxin (35.7 microg/kg) with thymogen (10 microg/kg), thymalin (1.2 mg/kg), cycloferon (0.5 mg/kg) results in decreasing brain tissue density as compared to intact animals. Dysfunction of the thyroid gland leads to changes in pharmacodynamics of immune preparations, which results in a decrease of their antiedematous activity.

Attention and driving in traumatic brain injury: a question of coping with time-pressure.

PubMed

Brouwer, Wiebo H; Withaar, Frederiec K; Tant, Mark L M; van Zomeren, Adriaan H

2002-02-01

Diffuse and focal traumatic brain injury (TBI) can result in perceptual, cognitive, and motor dysfunction possibly leading to activity limitations in driving. Characteristic dysfunctions for severe diffuse TBI are confronted with function requirements derived from the hierarchical task analysis of driving skill. Specifically, we focus on slow information processing, divided attention, and the development of procedural knowledge. Also the effects of a combination of diffuse and focal dysfunctions, specifically homonymous hemianopia and the dysexecutive syndrome, are discussed. Finally, we turn to problems and challenges with regard to assessment and rehabilitation methods in the areas of driving and fitness to drive.

Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: role of tight junction proteins and matrix metalloproteinase-9.

PubMed

Martins, Tânia; Baptista, Sofia; Gonçalves, Joana; Leal, Ermelindo; Milhazes, Nuno; Borges, Fernanda; Ribeiro, Carlos F; Quintela, Oscar; Lendoiro, Elena; López-Rivadulla, Manuel; Ambrósio, António F; Silva, Ana P

2011-09-09

Methamphetamine (METH) is a powerful stimulant drug of abuse that has steadily gained popularity worldwide. It is known that METH is highly neurotoxic and causes irreversible damage of brain cells leading to neurological and psychiatric abnormalities. Recent studies suggested that METH-induced neurotoxicity might also result from its ability to compromise blood-brain barrier (BBB) function. Due to the crucial role of BBB in the maintenance of brain homeostasis and protection against toxic molecules and pathogenic organisms, its dysfunction could have severe consequences. In this study, we investigated the effect of an acute high dose of METH (30mg/kg) on BBB permeability after different time points and in different brain regions. For that, young adult mice were sacrificed 1h, 24h or 72h post-METH administration. METH increased BBB permeability, but this effect was detected only at 24h after administration, being therefore a transitory effect. Interestingly, we also found that the hippocampus was the most susceptible brain region to METH, comparing to frontal cortex and striatum. Moreover, in an attempt to identify the key players in METH-induced BBB dysfunction we further investigated potential alterations in tight junction (TJ) proteins and matrix metalloproteinase-9 (MMP-9). METH was able to decrease the protein levels of zonula occludens (ZO)-1, claudin-5 and occludin in the hippocampus 24h post-injection, and increased the activity and immunoreactivity of MMP-9. The pre-treatment with BB-94 (30mg/kg), a matrix metalloproteinase inhibitor, prevented the METH-induced increase in MMP-9 immunoreactivity in the hippocampus. Overall, the present data demonstrate that METH transiently increases the BBB permeability in the hippocampus, which can be explained by alterations on TJ proteins and MMP-9. Copyright © 2011 Elsevier B.V. All rights reserved.

Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: relevance to hepatic encephalopathy treatment

PubMed Central

Niknahad, Hossein; Jamshidzadeh, Akram; Zarei, Mahdi; Ommati, Mohammad Mehdi

2017-01-01

Introduction Ammonia-induced oxidative stress, mitochondrial dysfunction, and energy crisis are known as some the major mechanisms of brain injury in hepatic encephalopathy (HE). Hyperammonemia also affects the liver and hepatocytes. Therefore, targeting mitochondria seems to be a therapeutic point of intervention in the treatment of HE. Taurine is an abundant amino acid in the human body. Several biological functions including the mitochondrial protective properties are attributed to this amino acid. The aim of this study is to evaluate the effect of taurine administration on ammonia-induced mitochondrial dysfunction. Material and methods Isolated mice liver and brain mitochondria were exposed to different concentrations of ammonia (1, 5, 10, and 20 mM) and taurine (1, 5, and 10 mM), and several mitochondrial indices were assessed. Results It was found that ammonia inhibited mitochondrial dehydrogenases activity caused collapse of mitochondrial membrane potential (MMP), induced mitochondrial swelling (MPP), and increased reactive oxygen species (ROS) in isolated liver and brain mitochondria. Furthermore, a significant amount of lipid peroxidation (LPO), along with glutathione (GSH) and ATP depletion, was detected in ammonia exposed mitochondria. Taurine administration (5 and 10 mM) mitigated ammonia-induced mitochondrial dysfunction. Conclusions The current investigation demonstrates that taurine is instrumental in preserving brain and liver mitochondrial function in a hyperammonemic environment. The data suggest taurine as a potential protective agent with a therapeutic capability against hepatic encephalopathy and hyperammonemia. PMID:29062904

Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro

PubMed Central

Üllen, Andreas; Fauler, Günter; Bernhart, Eva; Nusshold, Christoph; Reicher, Helga; Leis, Hans-Jörg; Malle, Ernst; Sattler, Wolfgang

2012-01-01

2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase–hydrogen peroxide–chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood–brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting. PMID:22982051

Neurovascular signaling in the brain and the pathological consequences of hypertension

PubMed Central

Dunn, Kathryn M.

2013-01-01

The execution and maintenance of all brain functions are dependent on a continuous flow of blood to meet the metabolic needs of the tissue. To ensure the delivery of resources required for neural processing and the maintenance of neural homeostasis, the cerebral vasculature is elaborately and extensively regulated by signaling from neurons, glia, interneurons, and perivascular nerves. Hypertension is associated with impaired neurovascular regulation of the cerebral circulation and culminates in neurodegeneration and cognitive dysfunction. Here, we review the physiological processes of neurovascular signaling in the brain and discuss mechanisms of hypertensive neurovascular dysfunction. PMID:24163077

IgLON5-Associated Encephalitis With Atypical Brain Magnetic Resonance Imaging and Cerebrospinal Fluid Changes.

PubMed

Montagna, Massimiliano; Amir, Rizvana; De Volder, Ilse; Lammens, Martin; Huyskens, Jef; Willekens, Barbara

2018-01-01

IgLON5-associated encephalitis is a syndrome with different clinical presentations consisting of sleep dysfunction, bulbar dysfunction, chorea, and progressive supranuclear palsy-like symptoms whereas dysautonomy and cognitive decline usually appear in later stages of the disease. We report a case of a patient with IgLON5-associated encephalitis presenting with rapidly progressive cognitive decline and atypical inflammatory lesions on brain magnetic resonance imaging, oligoclonal bands on cerebrospinal fluid, anti-IgLON5 antibodies exclusively of the IgG1 class, and a fierce inflammatory reaction on brain biopsy, who responded favorably to immunotherapy.

Oxidative Burst of Circulating Neutrophils Following Traumatic Brain Injury in Human

PubMed Central

Liao, Yiliu; Liu, Peng; Guo, Fangyuan; Zhang, Zhi-Yuan; Zhang, Zhiren

2013-01-01

Besides secondary injury at the lesional site, Traumatic brain injury (TBI) can cause a systemic inflammatory response, which may cause damage to initially unaffected organs and potentially further exacerbate the original injury. Here we investigated plasma levels of important inflammatory mediators, oxidative activity of circulating leukocytes, particularly focusing on neutrophils, from TBI subjects and control subjects with general trauma from 6 hours to 2 weeks following injury, comparing with values from uninjured subjects. We observed increased plasma level of inflammatory cytokines/molecules TNF-α, IL-6 and CRP, dramatically increased circulating leukocyte counts and elevated expression of TNF-α and iNOS in circulating leukocytes from TBI patients, which suggests a systemic inflammatory response following TBI. Our data further showed increased free radical production in leukocyte homogenates and elevated expression of key oxidative enzymes iNOS, COX-2 and NADPH oxidase (gp91phox) in circulating leukocytes, indicating an intense induction of oxidative burst following TBI, which is significantly greater than that in control subjects with general trauma. Furthermore, flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma. It suggests that the highly activated neutrophils might play an important role in the secondary damage, even outside the injured brain. Taken together, the potent systemic inflammatory response induced by TBI, especially the intensively increase oxidative activity of circulating leukocytes, mainly neutrophils, may lead to a systemic damage, dysfunction/damage of bystander tissues/organs and even further exacerbate secondary local damage. Controlling these pathophysiological processes may be a promising therapeutic strategy and will protect unaffected organs and the injured brain from the secondary damage. PMID:23894384

Acute high-altitude hypoxic brain injury: Identification of ten differential proteins

PubMed Central

Li, Jianyu; Qi, Yuting; Liu, Hui; Cui, Ying; Zhang, Li; Gong, Haiying; Li, Yaxiao; Li, Lingzhi; Zhang, Yongliang

2013-01-01

Hypobaric hypoxia can cause severe brain damage and mitochondrial dysfunction, and is involved in hypoxic brain injury. However, little is currently known about the mechanisms responsible for mitochondrial dysfunction in hypobaric hypoxic brain damage. In this study, a rat model of hypobaric hypoxic brain injury was established to investigate the molecular mechanisms associated with mitochondrial dysfunction. As revealed by two-dimensional electrophoresis analysis, 16, 21, and 36 differential protein spots in cerebral mitochondria were observed at 6, 12, and 24 hours post-hypobaric hypoxia, respectively. Furthermore, ten protein spots selected from each hypobaric hypoxia subgroup were similarly regulated and were identified by mass spectrometry. These detected proteins included dihydropyrimidinase-related protein 2, creatine kinase B-type, isovaleryl-CoA dehydrogenase, elongation factor Ts, ATP synthase beta-subunit, 3-mercaptopyruvate sulfurtransferase, electron transfer flavoprotein alpha-subunit, Chain A of 2-enoyl-CoA hydratase, NADH dehydrogenase iron-sulfur protein 8 and tropomyosin beta chain. These ten proteins are all involved in the electron transport chain and the function of ATP synthase. Our findings indicate that hypobaric hypoxia can induce the differential expression of several cerebral mitochondrial proteins, which are involved in the regulation of mitochondrial energy production. PMID:25206614

Brain lesion-pattern analysis in patients with olfactory dysfunctions following head trauma

PubMed Central

Lötsch, Jörn; Ultsch, Alfred; Eckhardt, Maren; Huart, Caroline; Rombaux, Philippe; Hummel, Thomas

2016-01-01

The presence of cerebral lesions in patients with neurosensory alterations provides a unique window into brain function. Using a fuzzy logic based combination of morphological information about 27 olfactory-eloquent brain regions acquired with four different brain imaging techniques, patterns of brain damage were analyzed in 127 patients who displayed anosmia, i.e., complete loss of the sense of smell (n = 81), or other and mechanistically still incompletely understood olfactory dysfunctions including parosmia, i.e., distorted perceptions of olfactory stimuli (n = 50), or phantosmia, i.e., olfactory hallucinations (n = 22). A higher prevalence of parosmia, and as a tendency also phantosmia, was observed in subjects with medium overall brain damage. Further analysis showed a lower frequency of lesions in the right temporal lobe in patients with parosmia than in patients without parosmia. This negative direction of the differences was unique for parosmia. In anosmia, and also in phantosmia, lesions were more frequent in patients displaying the respective symptoms than in those without these dysfunctions. In anosmic patients, lesions in the right olfactory bulb region were much more frequent than in patients with preserved sense of smell, whereas a higher frequency of carriers of lesions in the left frontal lobe was observed for phantosmia. We conclude that anosmia, and phantosmia, are the result of lost function in relevant brain areas whereas parosmia is more complex, requiring damaged and intact brain regions at the same time. PMID:26937377

PubMed

Sarman, Ihsan; Rangmar, Jenny

2017-08-03

Fetal alcohol syndrome is not the only consequence of prenatal alcohol exposure  The prevalence of fetal alcohol syndrome and fetal alcohol spectrum disorders in larger communities in USA is now updated to 0.4 % and 4.8 % respectively. Affected individuals bear witness to disease symptoms from many organ systems in addition to the brain and behavioural dysfunctions. In the light of modern epigenetic research, early alcohol exposure appears to play a hidden role in fetal reprogramming. The underlying mechanisms explain the »developmental origin of health and disease«, which has an impact on complex interactions between genome, environment and epigenetics.

Altered brain functional networks in people with Internet gaming disorder: Evidence from resting-state fMRI.

PubMed

Wang, Lingxiao; Wu, Lingdan; Lin, Xiao; Zhang, Yifen; Zhou, Hongli; Du, Xiaoxia; Dong, Guangheng

2016-08-30

Although numerous neuroimaging studies have detected structural and functional abnormality in specific brain regions and connections in subjects with Internet gaming disorder (IGD), the topological organization of the whole-brain network in IGD remain unclear. In this study, we applied graph theoretical analysis to explore the intrinsic topological properties of brain networks in Internet gaming disorder (IGD). 37 IGD subjects and 35 matched healthy control (HC) subjects underwent a resting-state functional magnetic resonance imaging scan. The functional networks were constructed by thresholding partial correlation matrices of 90 brain regions. Then we applied graph-based approaches to analysis their topological attributes, including small-worldness, nodal metrics, and efficiency. Both IGD and HC subjects show efficient and economic brain network, and small-world topology. Although there was no significant group difference in global topology metrics, the IGD subjects showed reduced regional centralities in the prefrontal cortex, left posterior cingulate cortex, right amygdala, and bilateral lingual gyrus, and increased functional connectivity in sensory-motor-related brain networks compared to the HC subjects. These results imply that people with IGD may be associated with functional network dysfunction, including impaired executive control and emotional management, but enhanced coordination among visual, sensorimotor, auditory and visuospatial systems. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Levels of unified metabolites and thyroid hormones in blood and oral fluid of children with minimal brain dysfunction].

PubMed

Gil'miiarova, F N; Pervova, Iu V; Radomskaia, V M; Gergel', N I; Tarasova, S V

2004-01-01

Minimal brain dysfunctions in children with various perinatal complications are accompanied by metabolic imbalance manifested by decreased total protein content, the tendency to reduced triglycerides, increased cholesterol concentrations in the oral fluid, the trend to hypoproteinaemia, hypoglycaemia, hypotriglyceridaemia. The most significant changes in the redox systems alpha-ketoglutarate-glutamate, oxaloacetate-malate, pyruvate-lactate, dioxyacetone phosphate-alpha-glycerophosphate in biological fluids were revealed in cases of antenatal alcoholisation. A certain correlation was found between anemia in pregnant women and hypothyroidal background in children. In addition, a high level of free and total thyroxine, that of total triiodthyronine were found in the oral fluid. Hypophysis--thyroid dysregulation in children with minimal brain dysfunction associated with gestosis in their mothers during pregnancy, was manifested by decreased content of total and free T4 and T3 in blood serum and increased level of the thyroid-stimulating hormone.

Protective effect of hydroxytyrosol in arsenic-induced mitochondrial dysfunction in rat brain.

PubMed

Soni, Manisha; Prakash, Chandra; Sehwag, Sfurti; Kumar, Vijay

2017-07-01

The present study was planned to investigate the protective effect of hydroxytyrosol (HT) against arsenic (As)-induced mitochondrial dysfunction in rat brain. Rats exposed to sodium arsenite (25 ppm for 8 weeks) showed decreased mitochondrial complexes (I, II, IV) activities, mitochondrial superoxide dismutase (MnSOD), and catalase activities in brain mitochondria. As-treated rats showed reduced mRNA expression of complex I (ND-1, ND-2), IV (COX-1, COX-4) subunits, and uncoupling protein-2 (UCP-2). In addition to this, As exposure downregulated the protein expression of MnSOD. Administration of HT with As restored the enzymatic activities of mitochondrial complexes, MnSOD and catalase, increased the mRNA levels of complexes subunits and UCP-2 as well as proteins level of MnSOD. These results suggest that HT efficiently restores mitochondrial dysfunction in As neurotoxicity and might be used as potential mitoprotective agent in future. © 2017 Wiley Periodicals, Inc.

Further Commentary on Mitochondrial Dysfunction in Autism Spectrum Disorder: Assessment and Treatment Considerations

ERIC Educational Resources Information Center

Dager, Stephen R.; Corrigan, Neva M.; Estes, Annette; Shaw, Dennis W. W.

2012-01-01

The authors respond to a recent letter (Rossignol and Frye 2011) critical of their paper, "Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder" (Corrigan et al. 2011). Further considerations regarding the assessment of mitochondrial dysfunction in autism…

Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

PubMed Central

2014-01-01

This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood–brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer’s disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke. PMID:25120903

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.

PubMed

Ballarini, Tommaso; Iaccarino, Leonardo; Magnani, Giuseppe; Ayakta, Nagehan; Miller, Bruce L; Jagust, William J; Gorno-Tempini, Maria Luisa; Rabinovici, Gil D; Perani, Daniela

2016-12-01

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer's disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18 F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty-five percent of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18 F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

N-Benzoyl-D-phenylalanine attenuates brain acetylcholinesterase in neonatal streptozotocin-diabetic rats.

PubMed

Ashokkumar, Natarajan; Pari, Leelavinothan; Ramkumar, Kunga Mohan

2006-09-01

The effect of hyperglycaemia due to experimental diabetes in male Wistar rats causes a decrease in the level of acetylcholinesterase (AChE) with significant increase in lipid peroxidative markers: thiobarbituric acid-reactive substances (TBARS) and hydroperoxides in brains of experimental animals. The decreased activity of both salt soluble and detergent soluble acetylcholinesterase observed in diabetes may be attributed to lack of insulin which causes specific alterations in the level of neurotransmitter, thus causing brain dysfunction. Administration of non-sulfonylurea drug N-benzoyl-D-phenylalanine (NBDP) could protect against direct action of lipid peroxidation on brain AChE and in this way it might be useful in the prevention of cholinergic neural dysfunction, which is one of the major complications in diabetes.

PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework proceeds from a general (e.g., not chemical specific) molecular mode of action, designated as a MIE, through stepwise changes in biological status, defined as key events (KEs), to a final AO that can be used in risk assessment. Because aromatase-inhibiting pharmaceuticals are widely used to treat breast cancer patients, we explored the unintended consequences that might occur in fish exposed to these chemicals through wastewater discharge into the aquatic environment. Unlike mammals, fish have two isoforms of aromatase, one that predominates in the ovary (cyp19a1a) and a second (cyp19a1b) that prevails in the brain. Aromatase activity in fish brain can be 100 to 1000 times that in mammals and is associated with reproduction. We have developed a putative AOP for inhibition of brain aromatase in fish leading to reproductive dysfunction based on review of relevant literature and reproductive experiments with the marine fish cunner (Tautogolabrus adspersus) exposed to aromatase-inhibiting pharmaceuticals in the laboratory. The first KE in this AOP is a decrease in brain aromatase activity due to exposure to an aromatase inhibitor. KEs then progress through subsequent steps including decreas

Sparing functional anatomical structures during intensity-modulated radiotherapy: an old problem, a new solution.

PubMed

Tan, Wenyong; Han, Guang; Wei, Shaozhong; Hu, Desheng

2014-08-01

During intensity-modulated radiotherapy, an organ is usually assumed to be functionally homogeneous and, generally, its anatomical and spatial heterogeneity with respect to radiation response are not taken into consideration. However, advances in imaging and radiation techniques as well as an improved understanding of the radiobiological response of organs have raised the possibility of sparing the critical functional structures within various organs at risk during intensity-modulated radiotherapy. Here, we discuss these structures, which include the critical brain structure, or neural nuclei, and the nerve fiber tracts in the CNS, head and neck structures related to radiation-induced salivary and swallowing dysfunction, and functional structures in the heart and lung. We suggest that these structures can be used as potential surrogate organs at risk in order to minimize their radiation dose and/or irradiated volume without compromising the dose coverage of the target volume during radiation treatment.

Neuroinflamm-aging and neurodegenerative diseases: an overview.

PubMed

Pizza, Vincenzo; Agresta, Anella; D'Acunto, Cosimo W; Festa, Michela; Capasso, Anna

2011-08-01

Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.

Thiamin deficiency on fetal brain development with and without prenatal alcohol exposure.

PubMed

Kloss, Olena; Eskin, N A Michael; Suh, Miyoung

2018-04-01

Adequate thiamin levels are crucial for optimal health through maintenance of homeostasis and viability of metabolic enzymes, which require thiamine as a co-factor. Thiamin deficiency occurs during pregnancy when the dietary intake is inadequate or excessive alcohol is consumed. Thiamin deficiency leads to brain dysfunction because thiamin is involved in the synthesis of myelin and neurotransmitters (e.g., acetylcholine, γ-aminobutyric acid, glutamate), and its deficiency increases oxidative stress by decreasing the production of reducing agents. Thiamin deficiency also leads to neural membrane dysfunction, because thiamin is a structural component of mitochondrial and synaptosomal membranes. Similarly, in-utero exposure to alcohol leads to fetal brain dysfunction, resulting in negative effects such as fetal alcohol spectrum disorder (FASD). Thiamin deficiency and prenatal exposure to alcohol could act synergistically to produce negative effects on fetal development; however, this area of research is currently under-studied. This minireview summarizes the evidence for the potential role of thiamin deficiency in fetal brain development, with or without prenatal exposure to alcohol. Such evidence may influence the development of new nutritional strategies for preventing or mitigating the symptoms of FASD.

Olfaction evaluation and correlation with brain atrophy in Bardet-Biedl syndrome.

PubMed

Braun, J-J; Noblet, V; Durand, M; Scheidecker, S; Zinetti-Bertschy, A; Foucher, J; Marion, V; Muller, J; Riehm, S; Dollfus, H; Kremer, S

2014-12-01

Bardet-Biedl syndrome (BBS) is a well-recognized ciliopathy characterized by cardinal features namely: early onset retinitis pigmentosa, polydactyly, obesity, hypogonadism, renal and cognitive impairment. Recently, disorders of olfaction (anosmia, hyposmia) have been also described in BBS patients. Moreover, morphological brain anomalies have been reported and prompt for further investigations to determine whether they are primary or secondary to peripheral organ involvement (i.e. visual or olfactory neuronal tissue). The objective of this article is to evaluate olfactory disorders in BBS patients and to investigate putative correlation with morphological cerebral anomalies. To this end, 20 BBS patients were recruited and evaluated for olfaction using the University of Pennsylvania Smell Identification Test (UPSIT). All of them underwent a structural magnetic resonance imaging (MRI) scan. We first investigated brain morphological differences between BBS subjects and 14 healthy volunteers. Then, we showed objective olfaction disorders in BBS patients and highlight correlation between gray matter volume reduction and olfaction dysfunction in several brain areas. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.

PubMed

Jahrling, Jordan B; Lin, Ai-Ling; DeRosa, Nicholas; Hussong, Stacy A; Van Skike, Candice E; Girotti, Milena; Javors, Martin; Zhao, Qingwei; Maslin, Leigh Ann; Asmis, Reto; Galvan, Veronica

2018-01-01

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR -/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

Evaluation of the effects of Eserine and JWH-133 on brain dysfunction associated with experimental endotoxemia.

PubMed

Gamal, Maha; Moawad, Jackline; Rashed, Laila; El-Eraky, Wafaa; Saleh, Dalia; Lehmann, Christian; Sharawy, Nivin

2015-04-15

Sepsis is associated with neuronal damage and cognitive impairment, with the participation of pro-inflammatory cytokines and oxidative-nitrous stress. It is known that activated microglia plays a vital role in neuro-inflammation and neuro-degeneration. Thus, the objective of this study was to evaluate therapeutic roles of two microglia regulating agents, JWH-133 and Eserine, on the neuroinflammatory associated brain dysfunctions. To achieve our aim, we used control rats or submitted rats to lipopolysaccharide (LPS) challenge. 30 min after LPS challenge, the animals received either saline, Eserine, JWH-133 or Eserine+JWH-133. After 24h, animals were submitted to the habituation to T maze, Rotarod and activity cage tests. The rats were killed after and were evaluated for central and peripheral inflammatory and oxidative parameters. We observed that the use of Eserine, JWH-133 or Eserine + JWH-133 reverted the increases in the inflammatory markers [interleukin 6 (IL6), vascular cell adhesion molecule 1(VCAM-1) and Eselectin] and oxidative-nitrous stress MDM, and that the anti-inflammatory, antioxidant properties of both JWH-133 and Eserine successfully improve the LPS induced brain dysfunction. The results observed in this study reinforce the role of microglia activation regulating agents, in particular, JWH-133 and Eserine, in the brain dysfunction associated with endotoxemia. Copyright © 2015 Elsevier B.V. All rights reserved.

Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro.

PubMed

Ullen, Andreas; Fauler, Günter; Bernhart, Eva; Nusshold, Christoph; Reicher, Helga; Leis, Hans-Jörg; Malle, Ernst; Sattler, Wolfgang

2012-11-01

2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood-brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting. Copyright © 2012 Elsevier Inc. All rights reserved.

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

PubMed

Hainsworth, Atticus H; Minett, Thais; Andoh, Joycelyn; Forster, Gillian; Bhide, Ishaan; Barrick, Thomas R; Elderfield, Kay; Jeevahan, Jamuna; Markus, Hugh S; Bridges, Leslie R

2017-10-01

We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T 2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P =0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P =0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P =0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P =0.007). Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers. © 2017 American Heart Association, Inc.

Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress.

PubMed

Garza-Lombó, Carla; Posadas, Yanahi; Quintanar, Liliana; Gonsebatt, María E; Franco, Rodrigo

2018-06-20

Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated. In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems. Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.

Striatal Circuits as a Common Node for Autism Pathophysiology

PubMed Central

Fuccillo, Marc V.

2016-01-01

Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains—deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD. PMID:26903795

Neuronopathic lysosomal storage disorders: Approaches to treat the central nervous system.

PubMed

Scarpa, Maurizio; Bellettato, Cinzia Maria; Lampe, Christina; Begley, David J

2015-03-01

Pharmacological research has always focused on developing new therapeutic strategies capable of modifying a disease's natural history and improving patients' quality of life. Despite recent advances within the fields of medicine and biology, some diseases still represent a major challenge for successful therapy. Neuronopathic lysosomal storage disorders, in particular, have high rates of morbidity and mortality and a devastating socio-economic effect. Many of the available therapies, such as enzyme replacement therapy, can reverse the natural history of the disease in peripheral organs but, unfortunately, are still unable to reach the central nervous system effectively because they cannot cross the blood-brain barrier that surrounds and protects the brain. Moreover, many lysosomal storage disorders are characterized by a number of blood-brain barrier dysfunctions, which may further contribute to disease neuropathology and accelerate neuronal cell death. These issues, and their context in the development of new therapeutic strategies, will be discussed in detail in this chapter. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

PubMed Central

2016-01-01

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca2+ influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca2+ homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases. PMID:27630777

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer’s Disease

PubMed Central

Dulla, Chris G.; Coulter, Douglas A.; Ziburkus, Jokubas

2015-01-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer’s disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. PMID:25948650

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease.

PubMed

Dulla, Chris G; Coulter, Douglas A; Ziburkus, Jokubas

2016-06-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer's disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. © The Author(s) 2015.

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

PubMed Central

2013-01-01

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches. PMID:24289502

The role of immune dysfunction in the pathophysiology of autism

PubMed Central

Onore, Charity; Careaga, Milo; Ashwood, Paul

2012-01-01

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD. PMID:21906670

Prevalence of multiple organ dysfunction in the pediatric intensive care unit: Pediatric Risk of Mortality III versus Pediatric Logistic Organ Dysfunction scores for mortality prediction

PubMed Central

Hamshary, Azza Abd Elkader El; Sherbini, Seham Awad El; Elgebaly, HebatAllah Fadel; Amin, Samah Abdelkrim

2017-01-01

Objectives To assess the frequency of primary multiple organ failure and the role of sepsis as a causative agent in critically ill pediatric patients; and calculate and evaluate the accuracy of the Pediatric Risk of Mortality III (PRISM III) and Pediatric Logistic Organ Dysfunction (PELOD) scores to predict the outcomes of critically ill children. Methods Retrospective study, which evaluated data from patients admitted from January to December 2011 in the pediatric intensive care unit of the Children's Hospital of the University of Cairo. Results Out of 237 patients in the study, 72% had multiple organ dysfunctions, and 45% had sepsis with multiple organ dysfunctions. The mortality rate in patients with multiple organ dysfunction was 73%. Independent risk factors for death were mechanical ventilation and neurological failure [OR: 36 and 3.3, respectively]. The PRISM III score was more accurate than the PELOD score in predicting death, with a Hosmer-Lemeshow X2 (Chi-square value) of 7.3 (df = 8, p = 0.5). The area under the curve was 0.723 for PRISM III and 0.78 for PELOD. Conclusion A multiple organ dysfunctions was associated with high mortality. Sepsis was the major cause. Pneumonia, diarrhea and central nervous system infections were the major causes of sepsis. PRISM III had a better calibration than the PELOD for prognosis of the patients, despite the high frequency of the multiple organ dysfunction syndrome. PMID:28977260

Application and validation of the barrow neurological institute screen for higher cerebral functions in a control population and in patient groups commonly seen in neurorehabilitation.

PubMed

Hofgren, Caisa; Esbjörnsson, Eva; Aniansson, Hans; Sunnerhagen, Katharina Stibrant

2007-09-01

To determine whether the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) can differentiate brain-dysfunctional patients from controls. A case-control study. A total of 92 controls and 120 patients from a neuro-rehabilitation clinic with a diagnosis of: right and left hemisphere stroke, traumatic brain injury, Parkinson's disease or anoxic brain damage. The BNIS has a maximum total score of 50 points, < 47 indicates cognitive dysfunction. Group comparisons and exploration of variables influencing the BNIS total score were made. A significant difference was found between the control group and the total patient group for the BNIS total score and for the subscales (p < 0.0005). Sensitivity was 88% and specificity 78%. Presence of disease and educational level had the greatest influence on the results of the BNIS. Patients with Parkinson's disease were shown to be the least cognitively affected and those with anoxic brain damage the most affected. The BNIS has potential value as a screening instrument for cognitive functions and is sufficiently sensitive to differentiate brain-dysfunctional patients from a control population. It appears to be applicable in a neurological rehabilitation setting, and can be used early in the process, giving a baseline cognitive functional level.

PITUITARY DEFICIENCY FOLLOWING TRAUMATIC BRAIN INJURY IN EARLY CHILDHOOD: A REVIEW OF THE LITERATURE.

PubMed

Soliman, A T; Adel, A; Soliman, N A; Elalaily, R; De Sanctis, V

2015-01-01

AIMS OF REVIEW: the intent of the current manuscript is to critically review the studies on pituitary gland dysfunction in early childhood following traumatic brain injury (TBI), in comparison with those in adults. Search of the literature: The MEDLINE database was accessed through PubMed in April 2015. Results were restricted to the past 15 years and English language of articles. Both transient and permanent hypopituitarisms are not uncommon after TBI. Early after the TBI, pituitary dysfunction/s differ than those occurring after few weeks and months. Growth hormone deficiency (GHD) and alterations in puberty are the most common. After the one to more years of TBI, pituitary dysfunction tends to improve in some patients but may deteriorate in others. GH deficiency as well as Hypogonadism and thyroid dysfunction are the most common permanent lesions. Many of the symptoms of these endocrine defects can pass unnoticed because of the psychomotor defects associated with the TBI like depression and apathy. Unfortunately pituitary dysfunction appear to negatively affect psycho-neuro-motor recovery as well as growth and pubertal development of children and adolescents after TBI. Therefore, the current review highlights the importance of closely following patients, especially children and adolescents for growth and other symptoms and signs suggestive of endocrine dysfunction. In addition, all should be screened serially for possible endocrine disturbances early after the TBI as well as few months to a year after the injury. Risk factors for pituitary dysfunction after TBI include relatively serious TBI (Glasgow Coma Scale score < 10 and MRI showing damage to the hypothalamic pituitary area), diffuse brain swelling and the occurrence of hypotensive and/or hypoxic episodes. There is a considerable risk of developing pituitary dysfunction after TBI in children and adolescents. These patients should be clinically followed and screened for these abnormalities according to an agreed protocol of investigations. Further multicenter and multidisciplinary prospective studies are required to explore in details the occurrence of permanent pituitary dysfunction after TBI in larger numbers of children with TBI. This requires considerable organisation and communication between many disciplines such as neurosurgery, neurology, endocrinology, rehabilitation and developmental paediatrics.

Intersection between metabolic dysfunction, high fat diet consumption, and brain aging.

PubMed

Uranga, Romina M; Bruce-Keller, Annadora J; Morrison, Christopher D; Fernandez-Kim, Sun Ok; Ebenezer, Philip J; Zhang, Le; Dasuri, Kalavathi; Keller, Jeffrey N

2010-07-01

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high-fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high-fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.

[Neuroendocrine dysfunction and brain damage. A consensus statement].

PubMed

Leal-Cerro, Alfonso; Rincón, María Dolores; Domingo, Manel Puig

2009-01-01

This consensus statement aims to enhance awareness of the incidence and risks of hypopituitarism in patients with traumatic brain injury (TBI) and/or brain hemorrhages among physicians treating patients with brain damage. The importance of this problem is related not only to the frequency of TBI but also to its prevalence in younger populations. The consequences of TBI are characterized by a series of symptoms that depend on the type of sequels related to neuroendocrine dysfunction. The signs and symptoms of hypopituitarism are often confused with those of other sequels of TBI. Consequently, patients with posttraumatic hypopituitarism may receive suboptimal rehabilitation unless the underlying hormone deficiency is identified and treated. This consensus is based on the recommendation supported by expert opinion that patients with a TBI and/or brain hemorrhage should undergo endocrine evaluation in order to assess pituitary function and, if deficiency is detected, should receive hormone replacement therapy.

Microglia: new roles for the synaptic stripper.

PubMed

Kettenmann, Helmut; Kirchhoff, Frank; Verkhratsky, Alexei

2013-01-09

Any pathologic event in the brain leads to the activation of microglia, the immunocompetent cells of the central nervous system. In recent decades diverse molecular pathways have been identified by which microglial activation is controlled and by which the activated microglia affects neurons. In the normal brain microglia were considered "resting," but it has recently become evident that they constantly scan the brain environment and contact synapses. Activated microglia can remove damaged cells as well as dysfunctional synapses, a process termed "synaptic stripping." Here we summarize evidence that molecular pathways characterized in pathology are also utilized by microglia in the normal and developing brain to influence synaptic development and connectivity, and therefore should become targets of future research. Microglial dysfunction results in behavioral deficits, indicating that microglia are essential for proper brain function. This defines a new role for microglia beyond being a mere pathologic sensor. Copyright © 2013 Elsevier Inc. All rights reserved.

Peripheral DNA methylation, cognitive decline and brain aging: pilot findings from the Whitehall II imaging study.

PubMed

Chouliaras, Leonidas; Pishva, Ehsan; Haapakoski, Rita; Zsoldos, Eniko; Mahmood, Abda; Filippini, Nicola; Burrage, Joe; Mill, Jonathan; Kivimäki, Mika; Lunnon, Katie; Ebmeier, Klaus P

2018-05-01

The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.

[Obsessive-compulsive disorder, a new model of basal ganglia dysfunction? Elements from deep brain stimulation studies].

PubMed

Haynes, W I A; Millet, B; Mallet, L

2012-01-01

Deep brain stimulation was first developed for movement disorders but is now being offered as a therapeutic alternative in severe psychiatric disorders after the failure of conventional therapies. One of such pathologies is obsessive-compulsive disorder. This disorder which associates intrusive thoughts (obsessions) and repetitive irrepressible rituals (compulsions) is characterized by a dysfunction of a cortico-subcortical loop. After having reviewed the pathophysiological evidence to show why deep brain stimulation was an interesting path to take for severe and resistant cases of obsessive-compulsive disorder, we will present the results of the different clinical trials. Finally, we will provide possible mechanisms for the effects of deep brain stimulation in this pathology. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Neural Oscillations and Synchrony in Brain Dysfunction and Neuropsychiatric Disorders: It's About Time.

PubMed

Mathalon, Daniel H; Sohal, Vikaas S

2015-08-01

Neural oscillations are rhythmic fluctuations over time in the activity or excitability of single neurons, local neuronal populations or "assemblies," and/or multiple regionally distributed neuronal assemblies. Synchronized oscillations among large numbers of neurons are evident in electrocorticographic, electroencephalographic, magnetoencephalographic, and local field potential recordings and are generally understood to depend on inhibition that paces assemblies of excitatory neurons to produce alternating temporal windows of reduced and increased excitability. Synchronization of neural oscillations is supported by the extensive networks of local and long-range feedforward and feedback bidirectional connections between neurons. Here, we review some of the major methods and measures used to characterize neural oscillations, with a focus on gamma oscillations. Distinctions are drawn between stimulus-independent oscillations recorded during resting states or intervals between task events, stimulus-induced oscillations that are time locked but not phase locked to stimuli, and stimulus-evoked oscillations that are both time and phase locked to stimuli. Synchrony of oscillations between recording sites, and between the amplitudes and phases of oscillations of different frequencies (cross-frequency coupling), is described and illustrated. Molecular mechanisms underlying gamma oscillations are also reviewed. Ultimately, understanding the temporal organization of neuronal network activity, including interactions between neural oscillations, is critical for elucidating brain dysfunction in neuropsychiatric disorders.

[Carrier-mediated Transport of Cationic Drugs across the Blood-Tissue Barrier].

PubMed

Kubo, Yoshiyuki

2015-01-01

Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti-angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB.

Experimental Evidences Supporting the Benefits of Exercise Training in Heart Failure.

PubMed

Ichige, Marcelo H A; Pereira, Marcelo G; Brum, Patrícia C; Michelini, Lisete C

2017-01-01

Heart Failure (HF), a common end point for many cardiovascular diseases, is a syndrome with a very poor prognosis. Although clinical trials in HF have achieved important outcomes in reducing mortality, little is known about functional mechanisms conditioning health improvement in HF patients. In parallel with clinical studies, basic science has been providing important discoveries to understand the mechanisms underlying the pathophysiology of HF, as well as to identify potential targets for the treatment of this syndrome. In spite of being the end-point of cardiovascular derangements caused by different etiologies, autonomic dysfunction, sympathetic hyperactivity, oxidative stress, inflammation and hormonal activation are common factors involved in the progression of this syndrome. Together these causal factors create a closed link between three important organs: brain, heart and the skeletal muscle. In the past few years, we and other groups have studied the beneficial effects of aerobic exercise training as a safe therapy to avoid the progression of HF. As summarized in this chapter, exercise training, a non-pharmacological tool without side effects, corrects most of the HF-induced neurohormonal and local dysfunctions within the brain, heart and skeletal muscles. These adaptive responses reverse oxidative stress, reduce inflammation, ameliorate neurohormonal control and improve both cardiovascular and skeletal muscle function, thus increasing the quality of life and reducing patients' morbimortality.

Brain imaging in methamphetamine-treated mice using a nitroxide contrast agent for EPR imaging of the redox status and a gadolinium contrast agent for MRI observation of blood-brain barrier function.

PubMed

Emoto, M C; Yamato, M; Sato-Akaba, H; Yamada, K; Matsuoka, Y; Fujii, H G

2015-01-01

Methamphetamine (METH)-induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. The aims of the present study conducted in the mouse brain repetitively treated with METH were to (1) examine the redox status using the redox-sensitive imaging probe 3-methoxycarbonyl-2,2,5,5-tetramethylpiperidine-1-oxyl (MCP) and (2) non-invasively visualize the brain redox status with electron paramagnetic resonance (EPR) imaging. The rate of reduction of MCP was measured from a series of temporal EPR images of mouse heads, and this rate was used to construct a two-dimensional map of rate constants called a "redox map." The obtained redox map clearly illustrated the change in redox balance in the METH-treated mouse brain that is a known result of oxidative damage. Biochemical assays also showed that the level of thiobarbituric acid-reactive substance, an index of lipid peroxidation, was increased in mouse brains by METH. The enhanced reduction in MCP observed in mouse brains was remarkably suppressed by treatment with the dopamine synthase inhibitor, α-methyl-p-tyrosine, suggesting that enhancement of the reduction reaction of MCP resulted from enzymatic reduction in the mitochondrial respiratory chain. Furthermore, magnetic resonance imaging (MRI) of METH-treated mice using a blood-brain barrier (BBB)-impermeable paramagnetic contrast agent revealed BBB dysfunction after treatment with METH for 7 days. MRI also indicated that the impaired BBB recovered after withdrawal of METH. EPR imaging and MRI are useful tools not only for following changes in the redox status and BBB dysfunction in mouse brains repeatedly administered METH, but also for tracing the drug effect after withdrawal of METH.

Defining biotypes for depression and anxiety based on large-scale circuit dysfunction: A theoretical review of the evidence and future directions for clinical translation

PubMed Central

Williams, Leanne M

2016-01-01

Complex emotional, cognitive and self-reflective functions rely on the activation and connectivity of large-scale neural circuits. These circuits offer a relevant scale of focus for conceptualizing a taxonomy for depression and anxiety based on specific profiles (or biotypes) of neural circuit dysfunction. Here, the theoretical review first outlined the current consensus as to what constitutes the organization of large-scale circuits in the human brain identified using parcellation and meta-analysis. The focus is on neural circuits implicated in resting reflection (“default mode”), detection of “salience”, affective processing (“threat” and “reward”), “attention” and “cognitive control”. Next, the current evidence regarding which type of dysfunctions in these circuits characterize depression and anxiety disorders was reviewed, with an emphasis on published meta-analyses and reviews of circuit dysfunctions that have been identified in at least two well-powered case:control studies. Grounded in the review of these topics, a conceptual framework is proposed for considering neural circuit-defined “biotypes”. In this framework, biotypes are defined by profiles of extent of dysfunction on each large-scale circuit. The clinical implications of a biotype approach for guiding classification and treatment of depression and anxiety is considered. Future research directions will develop the validity and clinical utility of a neural circuit biotype model that spans diagnostic categories and helps to translate neuroscience into clinical practice in the real world. PMID:27653321

Harmful Effects of Hyperoxia in Postcardiac Arrest, Sepsis, Traumatic Brain Injury, or Stroke: The Importance of Individualized Oxygen Therapy in Critically Ill Patients.

PubMed

Vincent, Jean-Louis; Taccone, Fabio Silvio; He, Xinrong

2017-01-01

The beneficial effects of oxygen are widely known, but the potentially harmful effects of high oxygenation concentrations in blood and tissues have been less widely discussed. Providing supplementary oxygen can increase oxygen delivery in hypoxaemic patients, thus supporting cell function and metabolism and limiting organ dysfunction, but, in patients who are not hypoxaemic, supplemental oxygen will increase oxygen concentrations into nonphysiological hyperoxaemic ranges and may be associated with harmful effects. Here, we discuss the potentially harmful effects of hyperoxaemia in various groups of critically ill patients, including postcardiac arrest, traumatic brain injury or stroke, and sepsis. In all these groups, there is evidence that hyperoxia can be harmful and that oxygen prescription should be individualized according to repeated assessment of ongoing oxygen requirements.

The impact of duration of organ dysfunction on the outcome of patients with severe sepsis and septic shock.

PubMed

Freitas, Flávio G R; Salomão, Reinaldo; Tereran, Nathalia; Mazza, Bruno Franco; Assunção, Murillo; Jackiu, Mirian; Fernandes, Haggeas; Machado, Flávia Ribeiro

2008-08-01

This study aimed to assess the impact of the duration of organ dysfunction on the outcome of patients with severe sepsis or septic shock. Clinical data were collected from hospital charts of patients with severe sepsis and septic shock admitted to a mixed intensive care unit from November 2003 to February 2004. The duration of organ dysfunction prior to diagnosis was correlated with mortality. Results were considered significant if p<0.05. Fifty-six patients were enrolled. Mean age was 55.6+/-20.7 years, mean APACHE II score was 20.6+/-6.9, and mean SOFA score was 7.9+/-3.7. Thirty-six patients (64.3%) had septic shock. The mean duration of organ dysfunction was 1.9+/-1.9 days. Within the univariate analysis, the variables correlated with hospital mortality were: age (p=0.015), APACHE II (p=0.008), onset outside the intensive care unit (p=0.05), blood glucose control (p=0.05) and duration of organ dysfunction (p=0.0004). In the multivariate analysis, only a duration of organ dysfunction persisting longer than 48 hours correlated with mortality (p=0.004, OR: 8.73 (2.37-32.14)), whereas the APACHE II score remained only a slightly significant factor (p=0.049, OR: 1.11 (1.00-1.23)). Patients who received therapeutic interventions within the first 48 hours after the onset of organ dysfunction exhibited lower mortality (32.1% vs. 82.1%, p=0.0001). These findings suggest that the diagnosis of organ dysfunction is not being made in a timely manner. The time elapsed between the onset of organ dysfunction and initiation of therapeutic intervention can be quite long, and this represents an important determinant of survival in cases of severe sepsis and septic shock.

Hypopituitarism in pediatric survivors of inflicted traumatic brain injury.

PubMed

Auble, Bethany A; Bollepalli, Sureka; Makoroff, Kathi; Weis, Tammy; Khoury, Jane; Colliers, Tracy; Rose, Susan R

2014-02-15

Endocrine dysfunction is common after accidental traumatic brain injury (TBI). Prevalence of endocrine dysfunction after inflicted traumatic brain injury (iTBI) is not known. The aim of this study was to examine endocrinopathy in children after moderate-to-severe iTBI. Children with previous iTBI (n=14) were evaluated for growth/endocrine dysfunction, including anthropometric measurements and hormonal evaluation (nocturnal growth hormone [GH], thyrotropin surge, morning and low-dose adrenocorticotropin stimulated cortisol, insulin-like growth factor 1, IGF-binding protein 3, free thyroxine, prolactin [PRL], and serum/urine osmolality). Analysis used Fisher's exact test and Wilcoxon's rank-sum test, as appropriate. Eighty-six percent of subjects had endocrine dysfunction with at least one abnormality, whereas 50% had two or more abnormalities, significantly increased compared to an estimated 2.5% with endocrine abnormality in the general population (p<0.001). Elevated prolactin was common (64%), followed by abnormal thyroid function (33%), short stature (29%), and low GH peak (17%). High prolactin was common in subjects with other endocrine abnormalities. Two were treated with thyroid hormone and 2 may require GH therapy. In conclusion, children with a history of iTBI show high risk for endocrine dysfunction, including elevated PRL and growth abnormalities. This effect of iTBI has not been well described in the literature. Larger, multi-center, prospective studies would provide more data to determine the extent of endocrine dysfunction in iTBI. We recommend that any child with a history of iTBI be followed closely for growth velocity and pubertal changes. If growth velocity is slow, PRL level and a full endocrine evaluation should be performed.

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer’s Disease

PubMed Central

Winick-Ng, Warren; Rylett, R. Jane

2018-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed. PMID:29541020

Prospective study of hypothalamo-hypophyseal dysfunction in children and adolescents following traumatic brain injury.

PubMed

Krahulik, David; Aleksijevic, Darina; Smolka, Vratislav; Klaskova, Eva; Venhacova, Petra; Vaverka, Miroslav; Mihal, Vladimir; Zapletalova, Jirina

2017-03-01

Retrospective studies of TBI have found a neuroendocrine dysfunction following traumatic brain injury in 23 to 60% of adults and 15 to 21% of children. Our aims were to determine the prevalence of hypothalamo-hypophyseal dysfunction in children following brain injury, assess its relationship to the type of injury and the course of the acute post-traumatic phase. Body development (growth, pubertal development, and skeletal maturity) were evaluated in 58 patients (21 girls) after a brain injury rated 3 to 12 on the Glasgow Coma Scale (GCS). The patients underwent standard endocrine tests - TSH, fT4, IGF-1, PRL, morning cortisol, FSH, LH, and testosterone in boys and estradiol in girls - in the early post-traumatic period (2 to 14 days; T0) and at 3, 6, and 12 months after the injury (T3, T6, and T12). Dynamic tests were carried out in patients with abnormalities in their clinical examination and/or laboratory results. An MRI was performed on all patients at T12. The median age at the time of injury was 11.3 (0.5 to 18.7) years. Of the 58 patients, 23 had GCS < 8, corresponding to severe brain injury. At T0, diabetes insipidus (DI) was diagnosed in 12 patients, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) was found in 4 patients. Frequent hormonal changes simulated central hypothyroidism (in 45% of patients) and hypogonadotropic hypogonadism (in 25% of adolescents who were already pubertal at the time of injury > Tanner II). Examination at T3 (n = 58) confirmed a combined pituitary hormone deficiency in two boys and DI in another one. At T6 (n = 49), hormonal dysfunctions were diagnosed in two boys (precocious puberty and growth hormone deficiency). At T12 (n = 39), a new endocrine dysfunction was diagnosed in five patients (growth hormone deficiency in two, hypogonadotropic hypogonadism in two, and in one patient, already diagnosed with a growth hormone deficiency, central hypothyroidism, as well). Brain MRI revealed an empty sella in two patients with growth hormone deficiency. Patients with GCS < 8 had more symptoms of SIADH or DI in the early post-traumatic period 11/23 vs. patients with GCS of 8 to 13 (4/35), and more frequent hormonal disorder (6/23) than individuals with moderate trauma (3/35), P = 0.0135. The incidence of endocrine dysfunction at T0 significantly correlated with the severity of injury (P = 0.05), but it was not an indicator for the development of a late hormonal disorder. Within a year after injury, a hormonal disorder was found in 17.6% of the patients. Neuroendocrine dysfunction as a late consequence of craniocerebral trauma in children and adolescents was less frequent than in adults. Risk factors for its development are the gravity of the injury, brain scan pathology, and possibly the development of DI, SIADH, or CSWS in the acute post-traumatic phase.

Disrupted Small-World Networks in Schizophrenia

ERIC Educational Resources Information Center

Liu, Yong; Liang, Meng; Zhou, Yuan; He, Yong; Hao, Yihui; Song, Ming; Yu, Chunshui; Liu, Haihong; Liu, Zhening; Jiang, Tianzi

2008-01-01

The human brain has been described as a large, sparse, complex network characterized by efficient small-world properties, which assure that the brain generates and integrates information with high efficiency. Many previous neuroimaging studies have provided consistent evidence of "dysfunctional connectivity" among the brain regions in…

Biomarkers and Brain Mechanisms of Gulf War Illness

DTIC Science & Technology

2017-09-01

serve as biomarkers of the disorder. 15. SUBJECT TERMS Gulf War illness, neuroinflammation, oxidative stress , mitochondrial dysfunction, magnetic...Oxidative Stress , Mitochondrial Dysfunction; Magnetic Resonance Imaging, Positron Emission Tomography Page | 5 Subtask 2: Develop complementary or...30 Major Task 3: To conduct 1H and 31P MRS studies for assessment of oxidative stress and mitochondrial dysfunction in vivo. Assess cerebral blood

Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa.

PubMed

Dantzer, Robert

2018-01-01

Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from each other. This has particularly been the case for the immune system. As a consequence of its ties with pathology and microbiology, immunology as a discipline has largely grown independently of physiology. Accordingly, it has taken a long time for immunologists to accept the concept that the immune system is not self-regulated but functions in close association with the nervous system. These associations are present at different levels of organization. At the local level, there is clear evidence for the production and use of immune factors by the central nervous system and for the production and use of neuroendocrine mediators by the immune system. Short-range interactions between immune cells and peripheral nerve endings innervating immune organs allow the immune system to recruit local neuronal elements for fine tuning of the immune response. Reciprocally, immune cells and mediators play a regulatory role in the nervous system and participate in the elimination and plasticity of synapses during development as well as in synaptic plasticity at adulthood. At the whole organism level, long-range interactions between immune cells and the central nervous system allow the immune system to engage the rest of the body in the fight against infection from pathogenic microorganisms and permit the nervous system to regulate immune functioning. Alterations in communication pathways between the immune system and the nervous system can account for many pathological conditions that were initially attributed to strict organ dysfunction. This applies in particular to psychiatric disorders and several immune-mediated diseases. This review will show how our understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions. The necessary complementarity of these two modes of communication will then be discussed. Finally, a few examples will illustrate how dysfunction in these communication pathways results in what was formerly considered in psychiatry and immunology to be strict organ pathologies.

Management and outcome of mechanically ventilated neurologic patients.

PubMed

Pelosi, Paolo; Ferguson, Niall D; Frutos-Vivar, Fernando; Anzueto, Antonio; Putensen, Christian; Raymondos, Konstantinos; Apezteguia, Carlos; Desmery, Pablo; Hurtado, Javier; Abroug, Fekri; Elizalde, José; Tomicic, Vinko; Cakar, Nahit; Gonzalez, Marco; Arabi, Yaseen; Moreno, Rui; Esteban, Andres

2011-06-01

To describe and compare characteristics, ventilatory practices, and associated outcomes among mechanically ventilated patients with different types of brain injury and between neurologic and nonneurologic patients. Secondary analysis of a prospective, observational, and multicenter study on mechanical ventilation. Three hundred forty-nine intensive care units from 23 countries. We included 552 mechanically ventilated neurologic patients (362 patients with stroke and 190 patients with brain trauma). For comparison we used a control group of 4,030 mixed patients who were ventilated for nonneurologic reasons. None. We collected demographics, ventilatory settings, organ failures, and complications arising during ventilation and outcomes. Multivariate logistic regression analysis was performed with intensive care unit mortality as the dependent variable. At admission, a Glasgow Coma Scale score ≤8 was observed in 68% of the stroke, 77% of the brain trauma, and 29% of the nonneurologic patients. Modes of ventilation and use of a lung-protective strategy within the first week of mechanical ventilation were similar between groups. In comparison with nonneurologic patients, patients with neurologic disease developed fewer complications over the course of mechanical ventilation with the exception of a higher rate of ventilator-associated pneumonia in the brain trauma cohort. Neurologic patients showed higher rates of tracheotomy and longer duration of mechanical ventilation. Mortality in the intensive care unit was significantly (p < .001) higher in patients with stroke (45%) than in brain trauma (29%) and nonneurologic disease (30%). Factors associated with mortality were: stroke (in comparison to brain trauma), Glasgow Coma Scale score on day 1, and severity at admission in the intensive care unit. In our study, one of every five mechanically ventilated patients received this therapy as a result of a neurologic disease. This cohort of patients showed a higher mortality rate than nonneurologic patients despite a lower incidence of extracerebral organ dysfunction.

The glia doctrine: addressing the role of glial cells in healthy brain ageing.

PubMed

Nagelhus, Erlend A; Amiry-Moghaddam, Mahmood; Bergersen, Linda H; Bjaalie, Jan G; Eriksson, Jens; Gundersen, Vidar; Leergaard, Trygve B; Morth, J Preben; Storm-Mathisen, Jon; Torp, Reidun; Walhovd, Kristine B; Tønjum, Tone

2013-10-01

Glial cells in their plurality pervade the human brain and impact on brain structure and function. A principal component of the emerging glial doctrine is the hypothesis that astrocytes, the most abundant type of glial cells, trigger major molecular processes leading to brain ageing. Astrocyte biology has been examined using molecular, biochemical and structural methods, as well as 3D brain imaging in live animals and humans. Exosomes are extracelluar membrane vesicles that facilitate communication between glia, and have significant potential for biomarker discovery and drug delivery. Polymorphisms in DNA repair genes may indirectly influence the structure and function of membrane proteins expressed in glial cells and predispose specific cell subgroups to degeneration. Physical exercise may reduce or retard age-related brain deterioration by a mechanism involving neuro-glial processes. It is most likely that additional information about the distribution, structure and function of glial cells will yield novel insight into human brain ageing. Systematic studies of glia and their functions are expected to eventually lead to earlier detection of ageing-related brain dysfunction and to interventions that could delay, reduce or prevent brain dysfunction. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

EPA Science Inventory

The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

The role of mitochondrial superoxide anion (O2(-)) on physiological aging in C57BL/6J mice.

PubMed

Miyazawa, Masaki; Ishii, Takamasa; Yasuda, Kayo; Noda, Setsuko; Onouchi, Hiromi; Hartman, Philip S; Ishii, Naoaki

2009-01-01

Much attention has been focused on the mitochondrial superoxide anion (O2(-)), which is also a critical free radial produced by ionizing radiation. The specific role of the mitochondrial O2(-) on physiological aging in mammals is still unclear despite wide-spread evidence that oxidative stress is involved in aging and age-related diseases. The major endogenous source of O2(-) is generated as a byproduct of energy metabolism from mitochondria. In order to better understand how O2(-)relates to metazoan aging, we have comprehensively examined age-related changes in the levels of oxidative damage, mitochondrial O2(-) production, mitochondrial antioxidant enzyme activity and apoptosis induction in key organs of an inbred mouse strain (C57BL/6J). Oxidative damage accumulated and excess apoptosis occurred in the brain, oculus and kidney with aging, but comparatively little occurred in the heart and muscle. These rates are correlated with O2(-) levels. Mitochondrial O2(-) production levels increased with aging in the brain, oculus and kidney, and did not significantly increased in the heart and muscle. In contrast to O2(-) production, mitochondrial SOD activities increased in heart and muscle, and remained unchanged in the brain, oculus and kidney with aging. These results suggest that O2(-) production has high organ specificity, and oxidative damage by O2(-) from mitochondria mediated apoptosis can lead to organ atrophy and physiological dysfunction. In addition, O2(-) from mitochondria plays a core role in physiological aging.

Mutism and amnesia following high-voltage electrical injury: psychogenic symptomatology triggered by organic dysfunction?

PubMed

Mishra, Nishant K; Russmann, Heike; Granziera, Cristina; Maeder, Philippe; Annoni, Jean-Marie

2011-01-01

Mutism and dense retrograde amnesia are found both in organic and dissociative contexts. Moreover, dissociative symptoms may be modulated by right prefrontal activity. A single case, M.R., developed left hemiparesis, mutism and retrograde amnesia after a high-voltage electric shock without evidence of lasting brain lesions. M.R. suddenly recovered from his mutism following a mild brain trauma 2 years later. M.R.'s neuropsychological pattern and anatomoclinical correlations were studied through (i) language and memory assessment to characterize his deficits, (ii) functional neuroimaging during a standard language paradigm, and (iii) assessment of frontal and left insular connectivity through diffusion tractography imaging and transcranial magnetic stimulation. A control evaluation was repeated after recovery. M.R. recovered from the left hemiparesis within 90 days of the accident, which indicated a transient right brain impairment. One year later, neurobehavioral, language and memory evaluations strongly suggested a dissociative component in the mutism and retrograde amnesia. Investigations (including MRI, fMRI, diffusion tensor imaging, EEG and r-TMS) were normal. Twenty-seven months after the electrical injury, M.R. had a very mild head injury which was followed by a rapid recovery of speech. However, the retrograde amnesia persisted. This case indicates an interaction of both organic and dissociative mechanisms in order to explain the patient's symptoms. The study also illustrates dissociation in the time course of the two different dissociative symptoms in the same patient. Copyright © 2011 S. Karger AG, Basel.

Regulation of Mitochondrial Function and Glutamatergic System Are the Target of Guanosine Effect in Traumatic Brain Injury.

PubMed

Dobrachinski, Fernando; da Rosa Gerbatin, Rogério; Sartori, Gláubia; Ferreira Marques, Naiani; Zemolin, Ana Paula; Almeida Silva, Luiz Fernando; Franco, Jeferson Luis; Freire Royes, Luiz Fernando; Rechia Fighera, Michele; Antunes Soares, Félix Alexandre

2017-04-01

Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Experimental trauma involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Mitochondrial dysfunction and glutamatergic excitotoxicity are the hallmark mechanisms of damage. Accordingly, a successful pharmacological intervention requires a multi-faceted approach. Guanosine (GUO) is known for its neuromodulator effects in various models of brain pathology, specifically those that involve the glutamatergic system. The aim of the study was to investigate the GUO effects against mitochondrial damage in hippocampus and cortex of rats subjected to TBI, as well as the relationship of this effect with the glutamatergic system. Adult male Wistar rats were subjected to a unilateral moderate fluid percussion brain injury (FPI) and treated 15 min later with GUO (7.5 mg/kg) or vehicle (saline 0.9%). Analyses were performed in hippocampus and cortex 3 h post-trauma and revealed significant mitochondrial dysfunction, characterized by a disrupted membrane potential, unbalanced redox system, decreased mitochondrial viability, and complex I inhibition. Further, disruption of Ca 2+ homeostasis and increased mitochondrial swelling was also noted. Our results showed that mitochondrial dysfunction contributed to decreased glutamate uptake and levels of glial glutamate transporters (glutamate transporter 1 and glutamate aspartate transporter), which leads to excitotoxicity. GUO treatment ameliorated mitochondrial damage and glutamatergic dyshomeostasis. Thus, GUO might provide a new efficacious strategy for the treatment acute physiological alterations secondary to TBI.

Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory

PubMed Central

Nekovarova, Tereza; Fajnerova, Iveta; Horacek, Jiri; Spaniel, Filip

2014-01-01

Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. However, the etiology of this disorder has yet to be fully understood. Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of a triple brain network model of the dysfunctional switching between default mode and central executive network (CEN) related to the aberrant activity of the salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of self (self-awareness and self-representation) and theory of mind (ToM) dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of self and ToM in schizophrenia together with neuroimaging data that support the triple brain network model as a common neuronal substrate of this dysfunction. PMID:24910597

Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically.

PubMed

Agrawal, Sonal; Fox, Julia; Thyagarajan, Baskaran; Fox, Jonathan H

2018-05-20

Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 μM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective. Copyright © 2018 Elsevier Inc. All rights reserved.

Functional Magnetic Resonance Imaging with Concurrent Urodynamic Testing Identifies Brain Structures Involved in Micturition Cycle in Patients with Multiple Sclerosis.

PubMed

Khavari, Rose; Karmonik, Christof; Shy, Michael; Fletcher, Sophie; Boone, Timothy

2017-02-01

Neurogenic lower urinary tract dysfunction, which is common in patients with multiple sclerosis, has a significant impact on quality of life. In this study we sought to determine brain activity processes during the micturition cycle in female patients with multiple sclerosis and neurogenic lower urinary tract dysfunction. We report brain activity on functional magnetic resonance imaging and simultaneous urodynamic testing in 23 ambulatory female patients with multiple sclerosis. Individual functional magnetic resonance imaging activation maps at strong desire to void and at initiation of voiding were calculated and averaged at Montreal Neuroimaging Institute. Areas of significant activation were identified in these average maps. Subgroup analysis was performed in patients with elicitable neurogenic detrusor overactivity or detrusor-sphincter dyssynergia. Group analysis of all patients at strong desire to void yielded areas of activation in regions associated with executive function (frontal gyrus), emotional regulation (cingulate gyrus) and motor control (putamen, cerebellum and precuneus). Comparison of the average change in activation between previously reported healthy controls and patients with multiple sclerosis showed predominantly stronger, more focal activation in the former and lower, more diffused activation in the latter. Patients with multiple sclerosis who had demonstrable neurogenic detrusor overactivity and detrusor-sphincter dyssynergia showed a trend toward distinct brain activation at full urge and at initiation of voiding respectively. We successfully studied brain activation during the entire micturition cycle in female patients with neurogenic lower urinary tract dysfunction and multiple sclerosis using a concurrent functional magnetic resonance imaging/urodynamic testing platform. Understanding the central neural processes involved in specific parts of micturition in patients with neurogenic lower urinary tract dysfunction may identify areas of interest for future intervention. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Neuropsychiatric Subsyndromes and Brain Metabolic Network Dysfunctions in Early Onset Alzheimer’s Disease

PubMed Central

Tommaso, Ballarini; Leonardo, Iaccarino; Giuseppe, Magnani; Nagehan, Ayakta; Bruce L, Miller; William J, Jagust; Luisa, Gorno-Tempini Maria; Gil D, Rabinovici; Daniela, Perani

2017-01-01

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer’s disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective and psychotic SSy). 85% of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N=51) and Healthy Controls (N=57). The apathetic, hyperactivity and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. PMID:27412866

Thermodynamic laws apply to brain function.

PubMed

Salerian, Alen J

2010-02-01

Thermodynamic laws and complex system dynamics govern brain function. Thus, any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content may cause region-specific brain dysfunction. This is the premise for the Salerian Theory of Brain built upon a new paradigm for neuropsychiatric disorders: the governing influence of neuroanatomy, neurophysiology, thermodynamic laws. The principles of region-specific brain function thermodynamics are reviewed. The clinical and supporting evidence including the paradoxical effects of various agents that alter brain homeostasis is demonstrated.

Aging with a traumatic brain injury: Could behavioral morbidities and endocrine symptoms be influenced by microglial priming?

PubMed

Ziebell, Jenna M; Rowe, Rachel K; Muccigrosso, Megan M; Reddaway, Jack T; Adelson, P David; Godbout, Jonathan P; Lifshitz, Jonathan

2017-01-01

A myriad of factors influence the developmental and aging process and impact health and life span. Mounting evidence indicates that brain injury, even moderate injury, can lead to lifetime of physical and mental health symptoms. Therefore, the purpose of this mini-review is to discuss how recovery from traumatic brain injury (TBI) depends on age-at-injury and how aging with a TBI affects long-term recovery. TBI initiates pathophysiological processes that dismantle circuits in the brain. In response, reparative and restorative processes reorganize circuits to overcome the injury-induced damage. The extent of circuit dismantling and subsequent reorganization depends as much on the initial injury parameters as other contributing factors, such as genetics and age. Age-at-injury influences the way the brain is able to repair itself, as a result of developmental status, extent of cellular senescence, and injury-induced inflammation. Moreover, endocrine dysfunction can occur with TBI. Depending on the age of the individual at the time of injury, endocrine dysfunction may disrupt growth, puberty, influence social behaviors, and possibly alter the inflammatory response. In turn, activation of microglia, the brain's immune cells, after injury may continue to fuel endocrine dysfunction. With age, the immune system develops and microglia become primed to subsequent challenges. Sustained inflammation and microglial activation can continue for weeks to months post-injury. This prolonged inflammation can influence developmental processes, behavioral performance and age-related decline. Overall, brain injury may influence the aging process and expedite glial and neuronal alterations that impact mental health. Copyright © 2016 Elsevier Inc. All rights reserved.

Memory Function Before and After Whole Brain Radiotherapy in Patients With and Without Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welzel, Grit; Fleckenstein, Katharina; Department of Radiation Oncology, Duke University Medical Center, Durham, NC

2008-12-01

Purpose: To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. Methods and Materials: Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. Results: Before therapy,more » prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. Conclusions: The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.« less

The Epidemiology of Hospital Death Following Pediatric Severe Sepsis: When, Why, and How Children With Sepsis Die.

PubMed

Weiss, Scott L; Balamuth, Fran; Hensley, Josey; Fitzgerald, Julie C; Bush, Jenny; Nadkarni, Vinay M; Thomas, Neal J; Hall, Mark; Muszynski, Jennifer

2017-09-01

The epidemiology of in-hospital death after pediatric sepsis has not been well characterized. We investigated the timing, cause, mode, and attribution of death in children with severe sepsis, hypothesizing that refractory shock leading to early death is rare in the current era. Retrospective observational study. Emergency departments and ICUs at two academic children's hospitals. Seventy-nine patients less than 18 years old treated for severe sepsis/septic shock in 2012-2013 who died prior to hospital discharge. None. Time to death from sepsis recognition, cause and mode of death, and attribution of death to sepsis were determined from medical records. Organ dysfunction was assessed via daily Pediatric Logistic Organ Dysfunction-2 scores for 7 days preceding death with an increase greater than or equal to 5 defined as worsening organ dysfunction. The median time to death was 8 days (interquartile range, 1-12 d) with 25%, 35%, and 49% of cumulative deaths within 1, 3, and 7 days of sepsis recognition, respectively. The most common cause of death was refractory shock (34%), then multiple organ dysfunction syndrome after shock recovery (27%), neurologic injury (19%), single-organ respiratory failure (9%), and nonseptic comorbidity (6%). Early deaths (≤ 3 d) were mostly due to refractory shock in young, previously healthy patients while multiple organ dysfunction syndrome predominated after 3 days. Mode of death was withdrawal in 72%, unsuccessful cardiopulmonary resuscitation in 22%, and irreversible loss of neurologic function in 6%. Ninety percent of deaths were attributable to acute or chronic manifestations of sepsis. Only 23% had a rise in Pediatric Logistic Organ Dysfunction-2 that indicated worsening organ dysfunction. Refractory shock remains a common cause of death in pediatric sepsis, especially for early deaths. Later deaths were mostly attributable to multiple organ dysfunction syndrome, neurologic, and respiratory failure after life-sustaining therapies were limited. A pattern of persistent, rather than worsening, organ dysfunction preceded most deaths.

Death from undiagnosed glioblastoma multiforme and toxic self-medication presenting with concurrent dysfunctional behavior.

PubMed

Carson, Henry J; Eilers, Stanley G

2008-08-01

We encountered a decedent with an unexpected glioblastoma multiforme. A 61-year-old retired African-American woman was found dead in her home, fully clothed in her bathtub, with a pillow under her head. At autopsy, the brain showed a glioblastoma multiforme. Toxicology showed elevated hydrocodone, propoxyphene, acetaminophen, and positive paroxetine. The presence of a brain tumor likely caused a severe headache. The use of her medications could have indicated a reaction to the escalating pain of the brain trauma, and overuse could be consistent with escalating pain or loss of rational thought processes. The present case is interesting in that it had evidence of behavioral dysfunction that could be related to the brain tumor, and death arising from the glioblastoma multiforme (cerebral hemorrhage and edema) with concurrent multiple drug intoxication.

Brain Microstructural Correlates of Cognitive Dysfunction in Clinically and Biochemically Normal Hepatitis C Virus Infection.

PubMed

Kumar, Ajay; Deep, Amar; Gupta, Rakesh K; Atam, Virendra; Mohindra, Samir

2017-09-01

This study examined correlates of the brain's neurocognitive performance among clinically and biochemically normal adult patient with hepatitis C virus (HCV). We hypothesized that anti-HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using diffusion tensor tractrography (DTT) metrics. Anti-HCV positive patient ( n  = 40), and healthy controls ( n  = 31), fulfilling inclusion criteria (incidentally detected anti-HCV positive) and able to provide informed consent were screened and recruited for the study. All these subjects and controls underwent subjective assessment of their quality of life related symptoms, neuropsychometric tests (NPT) and magnetic resonance imaging. The patients were subjected to neuroimaging as well as psychological testing. There was no significant difference in basic laboratory parameters in these two groups. Independent t -test reveals significantly lower neuropsychological functioning as compared to healthy control. A significantly decreased FA values and myoinsitol were observed in HCV subjects on sensory, inferior longitudinal fascicules, and STR fiber bundles as compared to healthy control. Bivariate correlation analysis reveals that neuropsychological scores are significantly positive. Our result show that HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using DTT metrics.

Mitochondrial impairments contribute to spatial learning and memory dysfunction induced by chronic tramadol administration in rat: Protective effect of physical exercise.

PubMed

Mehdizadeh, Hajar; Pourahmad, Jalal; Taghizadeh, Ghorban; Vousooghi, Nasim; Yoonessi, Ali; Naserzadeh, Parvaneh; Behzadfar, Ladan; Rouini, Mohammad Reza; Sharifzadeh, Mohammad

2017-10-03

Despite the worldwide use of tramadol, few studies have been conducted about its effects on memory and mitochondrial function, and controversial results have been reported. Recently, there has been an increasing interest in physical exercise as a protective approach to neuronal and cognitive impairments. Therefore, the aim of this study was to investigate the effects of physical exercise on spatial learning and memory and brain mitochondrial function in tramadol-treated rats. After completion of 2-week (short-term) and 4-week (long-term) treadmill exercise regimens, male Wistar rats received tramadol (20, 40, 80mg/kg/day) intraperitoneally for 30days. Then spatial learning and memory was assessed by Morris water maze test (MWM). Moreover, brain mitochondrial function was evaluated by determination of mitochondrial reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release from mitochondria. Chronic administration of tramadol impaired spatial learning and memory as well as brain mitochondrial function as indicated by increased ROS level, MMP collapse, increased mitochondrial swelling and cytochrome c release from mitochondria. Conversely, treadmill exercise significantly attenuated the impairments of spatial learning and memory and brain mitochondrial dysfunction induced by tramadol. The results revealed that chronic tramadol treatment caused memory impairments through induction of brain mitochondrial dysfunction. Furthermore, pre-exposure to physical exercise markedly mitigated these impairments through its positive effects on brain mitochondrial function. Copyright © 2017. Published by Elsevier Inc.

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide.

PubMed

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, W E

2010-05-01

beta-Amyloid peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Abeta-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Abeta and on neurite outgrowth in PC12 cells were investigated. Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Abeta(1-42). Similar protective effects against Abeta(1-42) were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Abeta load was markedly diminished in the brain of those animals after treatment with piracetam. Abeta production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Abeta-induced mitochondrial dysfunction and Abeta-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Abeta on brain function.

The predictive value of resting heart rate following osmotherapy in brain injury: back to basics.

PubMed

Hasanpour Mir, Mahsa; Yousefshahi, Fardin; Abdollahi, Mohammad; Ahmadi, Arezoo; Nadjafi, Atabak; Mojtahedzadeh, Mojtaba

2012-12-30

The importance of resting heart rate as a prognostic factor was described in several studies. An elevated heart rate is an independent risk factor for adverse cardiovascular events and total mortality in patients with coronary artery disease, chronic heart failure, and the general population. Also heart rate is elevated in the Multi Organ Dysfunction Syndrome (MODS) and the mortality due to MODS is highly correlated with inadequate sinus tachycardia.To evaluate the value of resting heart rate in predicting mortality in patients with traumatic brain injury along scoring systems like Acute Physiology and Chronic Health Evaluation(APACHE II), Sequential Organ Failure Assessment (SOFA) and Glasgow Coma Score (GCS). By analyzing data which was collected from an open labeled randomized clinical trial that compared the different means of osmotherapy (mannitol vs bolus or infusion hypertonic saline), heart rate, GCS, APACHE II and SOFA score were measured at baseline and daily for 7 days up to 60 days and the relationship between elevated heart rate and mortality during the first 7 days and 60th day were assessed. After adjustments for confounding factors, although there was no difference in mean heart rate between either groups of alive and expired patients, however, we have found a relative correlation between 60th day mortality rate and resting heart rate (P=0.07). Heart rate can be a prognostic factor for estimating mortality rate in brain injury patients along with APACHE II and SOFA scores in patients with brain injury.

Functional Brain Network Abnormalities during Verbal Working Memory Performance in Adolescents and Young Adults with Dyslexia

ERIC Educational Resources Information Center

Wolf, Robert Christian; Sambataro, Fabio; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Vasic, Nenad

2010-01-01

Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional…

Integrating Functional Brain Neuroimaging and Developmental Cognitive Neuroscience in Child Psychiatry Research

ERIC Educational Resources Information Center

Pavuluri, Mani N.; Sweeney, John A.

2008-01-01

The use of cognitive neuroscience and functional brain neuroimaging to understand brain dysfunction in pediatric psychiatric disorders is discussed. Results show that bipolar youths demonstrate impairment in affective and cognitive neural systems and in these two circuits' interface. Implications for the diagnosis and treatment of psychiatric…

76 FR 68460 - Findings of Research Misconduct

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-04

... Plasticity after Head Injury,'' D.A. Hovda, P.I. R01 NS052406, ``Age-dependent Ketone Metabolism after Brain Injury,'' M.L. Prims, P.I. K08 NS002197, ``NMDA Receptor Dysfunction after Traumatic Brain Injury,'' C.C... of calcium influx and modulation of local neurotransmitters as hallmarks of pediatric traumatic brain...

Roles of inflammation and apoptosis in experimental brain death-induced right ventricular failure.

PubMed

Belhaj, Asmae; Dewachter, Laurence; Rorive, Sandrine; Remmelink, Myriam; Weynand, Birgit; Melot, Christian; Galanti, Laurence; Hupkens, Emeline; Sprockeels, Thomas; Dewachter, Céline; Creteur, Jacques; McEntee, Kathleen; Naeije, Robert; Rondelet, Benoît

2016-12-01

Right ventricular (RV) dysfunction remains the leading cause of early death after cardiac transplantation. Methylprednisolone is used to improve graft quality; however, evidence for that remains empirical. We sought to determine whether methylprednisolone, acting on inflammation and apoptosis, might prevent brain death-induced RV dysfunction. After randomization to placebo (n = 11) or to methylprednisolone (n = 8; 15 mg/kg), 19 pigs were assigned to a brain-death procedure. The animals underwent hemodynamic evaluation at 1 and 5 hours after Cushing reflex (i.e., hypertension and bradycardia). The animals euthanized, and myocardial tissue was sampled. This was repeated in a control group (n = 8). At 5 hours after the Cushing reflex, brain death resulted in increased pulmonary artery pressure (27 ± 2 vs 18 ± 1 mm Hg) and in a 30% decreased ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Cardiac output and right atrial pressure did not change. This was prevented by methylprednisolone. Brain death-induced RV dysfunction was associated with increased RV expression of heme oxygenase-1, interleukin (IL)-6, IL-10, IL-1β, tumor necrosis factor (TNF)-α, IL-1 receptor-like (ST)-2, signal transducer and activator of transcription-3, intercellular adhesion molecules-1 and -2, vascular cell adhesion molecule-1, and neutrophil infiltration, whereas IL-33 expression decreased. RV apoptosis was confirmed by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling staining. Methylprednisolone pre-treatment prevented RV-arterial uncoupling and decreased RV expression of TNF-α, IL-1 receptor-like-2, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and neutrophil infiltration. RV Ees/Ea was inversely correlated to RV TNF-α and IL-6 expression. Brain death-induced RV dysfunction is associated with RV activation of inflammation and apoptosis and is partly limited by methylprednisolone. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Health Status and Performance of United States Air Force Airmen Following Mild Traumatic Brain Injury

DTIC Science & Technology

2010-09-01

adrenal insufficiency, hypopituitarism, hypothyroidism , growth- hormone deficiency and posterior pituitary dysfunction [53, 54, 56-60]. Growth...central hypothyroidism which can result in fatigue, apathy, decreased strength and cognitive dysfunction, symptoms commonly observed in PTSD [54

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2014-11-01

Award Number: W81XWH-11-2-0011 TITLE: Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury PRINCIPAL INVESTIGATOR...Oct 2014 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...fluid percussion, traumatic brain injury, blood brain barrier, neuroinflammation, neurological dysfunction, endocannabinoids , microglia and 16

A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice.

PubMed

Jia, Tingting; Sun, Zhiguo; Lu, Ying; Gao, Jie; Zou, Hao; Xie, Fangyuan; Zhang, Guoqing; Xu, Hao; Sun, Duxin; Yu, Yuan; Zhong, Yanqiang

2016-01-01

Due to the impermeability of the blood-brain barrier and the nonselective distribution of drugs in the brain, the therapeutic access to intractable neurological disorders is challenging. In this study, dual brain-targeting polymersomes (POs) functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) promoted the transportation of curcumin into the brain and provided neuroprotection. The modification of the ligands that bind to the surface of POs was revealed by X-ray photoelectron spectroscopy analysis. The cell uptake of a coculture model of mouse brain capillary endothelial cells with neurons showed that the Tf/Tet-1-POs had significant transportation properties and possessed affinity for neurons. The pharmacokinetic analysis showed that the blood-brain barrier permeability-surface efficiency of the Tf/Tet-1-POs was 0.28 mL/h/g and that the brain tissue uptake rate (% ID/g) was 0.08, which were significant compared with the controls (P<0.05). The curcumin-encapsulated Tf/Tet-1-POs provided neuroprotection and ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice. These results suggest that the dual brain-targeting POs are more capable of drug delivery to the brain that can be exploited as a multiple noninvasive vehicle for targeting therapeutics.

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2012-11-01

DATES COVERED 4 October 2011- 3 October 2012 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a...interventions aimed at modulation of the endocannabinoid (EC) system targeting degradation of 20arachidonoyl glycerlol (2- AG) and N-arachidonoyl...percussion, traumatic brain injury, blood brain barrier, neuroinflammination, neurological dysfunction, endocannabinoids . 16. SECURITY CLASSIFICATION

The consequence of spatial visual processing dysfunction caused by traumatic brain injury (TBI).

PubMed

Padula, William V; Capo-Aponte, Jose E; Padula, William V; Singman, Eric L; Jenness, Jonathan

2017-01-01

A bi-modal visual processing model is supported by research to affect dysfunction following a traumatic brain injury (TBI). TBI causes dysfunction of visual processing affecting binocularity, spatial orientation, posture and balance. Research demonstrates that prescription of prisms influence the plasticity between spatial visual processing and motor-sensory systems improving visual processing and reducing symptoms following a TBI. The rationale demonstrates that visual processing underlies the functional aspects of binocularity, balance and posture. The bi-modal visual process maintains plasticity for efficiency. Compromise causes Post Trauma Vision Syndrome (PTVS) and Visual Midline Shift Syndrome (VMSS). Rehabilitation through use of lenses, prisms and sectoral occlusion has inter-professional implications in rehabilitation affecting the plasticity of the bi-modal visual process, thereby improving binocularity, spatial orientation, posture and balance Main outcomes: This review provides an opportunity to create a new perspective of the consequences of TBI on visual processing and the symptoms that are often caused by trauma. It also serves to provide a perspective of visual processing dysfunction that has potential for developing new approaches of rehabilitation. Understanding vision as a bi-modal process facilitates a new perspective of visual processing and the potentials for rehabilitation following a concussion, brain injury or other neurological events.

Quantitative assessment of brain stem and cerebellar atrophy in spinocerebellar ataxia types 3 and 6: impact on clinical status.

PubMed

Eichler, L; Bellenberg, B; Hahn, H K; Köster, O; Schöls, L; Lukas, C

2011-05-01

Cerebellar and brain stem atrophy are important features in SCA3, whereas SCA6 has been regarded as a "pure" cerebellar disease. However, recent neuropathologic studies have described additional brain stem involvement in SCA6. We, therefore, aimed to investigate the occurrence and impact of regional infratentorial brain volume differences in patients with SCA3 and SCA6. Thirty-four patients with genetically proved SCA (SCA3, n = 17; SCA6, n = 17) and age-matched healthy control subjects (n = 51) were included. In all subjects, high-resolution T1-weighted images were acquired with a 1.5T MR imaging scanner. Individual brain stem and cerebellar volumes were calculated by using semiautomated volumetry approaches. For all patients with SCA, clinical dysfunction was scored according to the ICARS. Multiple regression analysis was used to identify the contribution of regional volumes to explain the variance in clinical dysfunction in each SCA genotype. Cerebellar volumes were lower in patients with SCA6 compared with controls and with those with SCA3. In contrast to controls, brain stem volume loss was observed in patients with SCA3 (P < .001) and, to a lesser extent, in those with SCA6 (P = .027). Significant linear dependencies were found between ICARS and cerebellum volume (SCA3: R(2) = 0.29, P = .02; SCA6: R(2) = 0.29, P = .03) and between ICARS and brain stem volume (SCA3: R(2) = 0.49, P = .002; SCA6: R(2) = 0.39, P < .01) in both subtypes. Both cerebellar and brain stem atrophy contributed independently to the variance in clinical dysfunction in SCA6, while in SCA3, only brain stem atrophy was of relevance. Our current findings in accordance with recent neuroradiologic and pathoanatomic studies suggest brain stem and cerebellar volume loss as attractive surrogate markers of disease severity in SCA3 and SCA6.

Psychological Effects of Stimulant Drugs in Children with Minimal Brain Dysfunction

ERIC Educational Resources Information Center

Conners, C. Keith

1972-01-01

Two technical studies involving the drugs dextroamphetamine, methylphenidate, and magnesium pemoline were reported in regard to the psychological characteristics and effects of stimulant drugs in children with minimal brain injuries. (CB)

Dysautonomia, a heuristic approach to a revised model for etiology of disease.

PubMed

Lonsdale, Derrick

2009-03-01

Dysautonomia refers to a disease where the autonomic nervous system is dysfunctional. This may be a central control mechanism, as in genetically determined familial dysautonomia (Riley-Day Syndrome), or peripherally in the distribution of the sympathetic and parasympathetic systems. There are multiple reports of a number of different diseases associated with dysautonomia. The etiology of this association has never been explained. There are also multiple publications on dysautonomia associated with specific non-caloric nutritional deficiencies. Beriberi is the prototype of autonomic dysfunction. It is the best known nutritional deficiency disease caused by an imbalance between ingested calories and the vitamins required for their oxidation, particularly thiamin. Long thought to be abolished in modern medical thinking, there are occasional isolated reports of the full-blown disease in developed Western cultures. Apart from genetically and epigenetically determined disease, evidence is presented that marginal high calorie malnutrition, particularly with reference to simple carbohydrates, is responsible for widespread dysautonomia. The brain and heart are the organs that have a fast rate of oxidative metabolism and are affected early by any mechanism that reduces oxidative efficiency. It is hypothesized that this results in a chaotic state of the hypothalamic/autonomic/endocrine axis. Due to the lack of adequate automatic controls, this may be responsible in some cases for breakdown of organ systems through long-standing energy deficiency, thus leading eventually to organic disease.

The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome.

PubMed

Miller, Suzanne L; Huppi, Petra S; Mallard, Carina

2016-02-15

Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Executive Dysfunction in Obsessive-Compulsive Disorder and Anterior Cingulate-Based Resting State Functional Connectivity

PubMed Central

Yun, Je-Yeon; Jang, Joon Hwan; Jung, Wi Hoon; Shin, Na Young; Kim, Sung Nyun; Hwang, Jae Yeon

2017-01-01

Objective Executive dysfunction might be an important determinant for response to pharmacotherapy in obsessive-compulsive disorder (OCD), and could be sustained independently of symptom relief. The anterior cingulate cortex (ACC) has been indicated as a potential neural correlate of executive functioning in OCD. The present study examined the brain-executive function relationships in OCD from the ACC-based resting state functional connectivity networks (rs-FCNs), which reflect information processing mechanisms during task performance. Methods For a total of 58 subjects [OCD, n=24; healthy controls (HCs), n=34], four subdomains of executive functioning were measured using the Rey-Osterrieth Complex Figure Test (RCFT), the Stroop Color-Word Test (SCWT), the Wisconsin Card Sorting Test (WCST), and the Trail Making Test part B (TMT-B). To probe for differential patterns of the brain-cognition relationship in OCD compared to HC, the ACC-centered rs-FCN were calculated using five seed regions systemically placed throughout the ACC. Results Significant differences between the OCD group and the HCs with respect to the WCST perseverative errors, SCWT interference scores, and TMT-B reaction times (p<0.05) were observed. Moreover, significant interactions between diagnosis×dorsal ACC [S3]-based rs-FCN strength in the right dorsolateral prefrontal cortex for RCFT organization summary scores as well as between diagnosis×perigenual ACC [S7]-based rs-FCN strength in the left frontal eye field for SCWT color-word interference scores were unveiled. Conclusion These network-based neural foundations for executive dysfunction in OCD could become a potential target of future treatment, which could improve global domains of functioning broader than symptomatic relief. PMID:28539952

Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer's disease.

PubMed

Gu, Xue-Mei; Huang, Han-Chang; Jiang, Zhao-Feng

2012-10-01

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β (Aβ) deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways of Aβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.

Pathophysiology and Treatment of Memory Dysfunction after Traumatic Brain Injury

PubMed Central

Paterno, Rosalia; Folweiler, Kaitlin A.; Cohen, Akiva S.

2018-01-01

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI are alterations in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase i.e., encoding, maintenance or retrieval is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury. PMID:28500417

Aceruloplasminaemia with progressive atrophy without brain iron overload: treatment with oral chelation.

PubMed

Skidmore, F M; Drago, V; Foster, P; Schmalfuss, I M; Heilman, K M; Streiff, R R

2008-04-01

Hereditary aceruloplasminaemia is a disorder of iron metabolism that is characterised by iron accumulation in the brain and other visceral organs. In previously reported cases, individuals with the disorder were noted to have evidence of iron accumulation in the brain. Oral chelating agents have not been used in neurological diseases of iron metabolism. A 54-year-old woman who presented with ataxia, lower extremity spasticity and chorea was evaluated for evidence of the source of neurological dysfunction. Blood studies revealed no detectable ceruloplasmin. Marked iron overload was defined by a liver biopsy, which showed a variegated pattern consistent with a primary cause of iron overload. Review of MRI scans showed progressive brain atrophy without visible iron accumulation occurring over a 5-year period. The history suggested that neurodegeneration was coincident with aggressive oral iron replacement. Oral chelation improved many symptoms. Our findings in this patient suggest that disorders of iron transport such as aceruloplasminaemia can be a cause of neurological symptoms such as chorea and cognitive decline, as well as progressive neurodegeneration in the absence of visible iron on MRI scans. We found that oral iron chelation was effective at improving symptoms.

Psychophysiological correlates of aggression and violence: an integrative review.

PubMed

Patrick, Christopher J

2008-08-12

This paper reviews existing psychophysiological studies of aggression and violent behaviour including research employing autonomic, electrocortical and neuroimaging measures. Robust physiological correlates of persistent aggressive behaviour evident in this literature include low baseline heart rate, enhanced autonomic reactivity to stressful or aversive stimuli, enhanced EEG slow wave activity, reduced P300 brain potential response and indications from structural and functional neuroimaging studies of dysfunction in frontocortical and limbic brain regions that mediate emotional processing and regulation. The findings are interpreted within a conceptual framework that draws on two integrative models in the literature. The first is a recently developed hierarchical model of impulse control (externalizing) problems, in which various disinhibitory syndromes including aggressive and addictive behaviours of different kinds are seen as arising from common as well as distinctive aetiologic factors. This model represents an approach to organizing these various interrelated phenotypes and investigating their common and distinctive aetiologic substrates. The other is a neurobiological model that posits impairments in affective regulatory circuits in the brain as a key mechanism for impulsive aggressive behaviour. This model provides a perspective for integrating findings from studies employing different measures that have implicated varying brain structures and physiological systems in violent and aggressive behaviour.

The effect of aging on brain barriers and the consequences for Alzheimer's disease development.

PubMed

Gorlé, Nina; Van Cauwenberghe, Caroline; Libert, Claude; Vandenbroucke, Roosmarijn E

2016-08-01

Life expectancy has increased in most developed countries, which has led to an increase in the proportion of elderly people in the world's population. However, this increase in life expectancy is not accompanied by a lengthening of the health span since aging is characterized with progressive deterioration in cellular and organ functions. The brain is particularly vulnerable to disease, and this is reflected in the onset of age-related neurodegenerative diseases such as Alzheimer's disease. Research shows that dysfunction of two barriers in the central nervous system (CNS), the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB), plays an important role in the progression of these neurodegenerative diseases. The BBB is formed by the endothelial cells of the blood capillaries, whereas the BCSFB is formed by the epithelial cells of the choroid plexus (CP), both of which are affected during aging. Here, we give an overview of how these barriers undergo changes during aging and in Alzheimer's disease, thereby disturbing brain homeostasis. Studying these changes is needed in order to gain a better understanding of the mechanisms of aging at the brain barriers, which might lead to the development of new therapies to lengthen the health span (including mental health) and reduce the chances of developing Alzheimer's disease.

Altered Levels of Zinc and N-methyl-D-aspartic Acid Receptor Underlying Multiple Organ Dysfunctions After Severe Trauma

PubMed Central

Wang, Guanghuan; Yu, Xiaojun; Wang, Dian; Xu, Xiaohu; Chen, Guang; Jiang, Xuewu

2015-01-01

Background Severe trauma can cause secondary multiple organ dysfunction syndrome (MODS) and death. Oxidative stress and/or excitatory neurotoxicity are considered as the final common pathway in nerve cell injuries. Zinc is the cofactor of the redox enzyme, and the effect of the excitatory neurotoxicity is related to N-methyl-D-aspartic acid receptor (NMDAR). Material/Methods We investigated the levels of zinc and brainstem NMDAR in a rabbit model of severe trauma. Zinc and serum biochemical profiles were determined. Immunohistochemistry was used to detect brainstem N-methyl-D-aspartic acid receptor 1 (NR1), N-methyl-D-aspartic acid receptor 2A (NR2A), and N-methyl-D-aspartic acid receptor 2B (NR2B) expression. Results Brain and brainstem Zn levels increased at 12 h, but serum Zn decreased dramatically after the trauma. NR1 in the brainstem dorsal regions increased at 6 h after injury and then decreased. NR2A in the dorsal regions decreased to a plateau at 12 h after trauma. The levels of NR2B were lowest in the death group in the brainstem. Serum zinc was positively correlated with NR2A and 2B and negatively correlated with zinc in the brain. Correlations were also found between the brainstem NR2A and that of the dorsal brainstem, as well as between brainstem NR2A and changes in NR2B. There was a negative correlation between zinc and NR2A. Conclusions Severe trauma led to an acute reduction of zinc enhancing oxidative stress and the changes of NMDAR causing the neurotoxicity of the nerve cells. This may be a mechanism for the occurrence of MODS or death after trauma. PMID:26335029

A Randomized Trial of the Effects of Nebulized Albuterol on Pulmonary Edema in Brain Dead Organ Donors

PubMed Central

Ware, Lorraine B.; Landeck, Megan; Koyama, Tatsuki; Zhao, Zhiguo; Singer, Jonathan; Kern, Ryan; Neidlinger, Nikole; Nguyen, John; Johnson, Elizabeth; Janz, David R.; Bernard, Gordon R.; Lee, Jae W.; Matthay, Michael A.

2013-01-01

Donor lung utilization rates are persistently low primarily due to donor lung dysfunction. We hypothesized that a treatment that enhances the resolution of pulmonary edema by stimulating the rate of alveolar fluid clearance would improve donor oxygenation and increase donor lung utilization. We conducted a randomized, blinded, placebo-controlled trial of aerosolized albuterol (5 mg q4h) versus saline placebo during active donor management in 506 organ donors. The primary outcome was change in oxygenation (PaO2/FiO2) from enrollment to organ procurement. The albuterol (n=260) and placebo (n=246) groups were well matched for age, gender, ethnicity, smoking, and cause of brain death. The change in PaO2/FiO2 from enrollment to organ procurement did not differ between treatment groups (p=0.54) nor did donor lung utilization (albuterol 29% vs. placebo 32%, p=0.44). Donors in the albuterol vs. placebo group were more likely to have the study drug dose reduced (13% vs. 1%, p<0.001) or stopped (8% vs. 0%, p<0.001) for tachycardia. In summary, treatment with high dose inhaled albuterol during the donor management period did not improve donor oxygenation or increase donor lung utilization but did cause tachycardia. High dose aerosolized albuterol should not be used in donors to enhance the resolution of pulmonary edema. PMID:24730050

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

PubMed Central

Shekhar, Shashank; Liu, Ruen; Travis, Olivia K; Roman, Richard J; Fan, Fan

2017-01-01

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of cerebral arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function. PMID:29333537

Prevalence of hypothalamo pituitary dysfunction in patients of traumatic brain injury.

PubMed

Hari Kumar, K V S; Swamy, M N; Khan, M A

2016-01-01

Traumatic brain injury (TBI) is common in young soldiers of armed forces leading to significant morbidity and mortality. We studied the prevalence of hypopituitarism following TBI and its association with trauma severity. We conducted a 12-month prospective study of 56 TBI patients for the presence of hormonal dysfunction. Hormonal parameters were estimated during the early phase (0-10 days posttraumatically) and after 6 and 12 months. Dynamic testing was done when required, and the results were analyzed by appropriate statistical methods. Hormonal dysfunction was seen in 39 of the 56 (70%) patients at initial assessment. Persisting pituitary deficiencies are seen in 7 and 8 patients at the end of 6 months and 12 months, respectively. Hypogonadotropic hypogonadism, hypothyroidism, and growth hormone deficiency are the most common diagnoses. Initial severe TBI and plurihormonal involvement predicted the long-term hypopituitarism. Early hypopituitarism was common in severe TBI, but recovers in majority. Evaluation for the occult pituitary dysfunction is required during the rehabilitation of TBI patients.

Estradiol-dependent modulation of auditory processing and selectivity in songbirds

PubMed Central

Maney, Donna; Pinaud, Raphael

2011-01-01

The steroid hormone estradiol plays an important role in reproductive development and behavior and modulates a wide array of physiological and cognitive processes. Recently, reports from several research groups have converged to show that estradiol also powerfully modulates sensory processing, specifically, the physiology of central auditory circuits in songbirds. These investigators have discovered that (1) behaviorally-relevant auditory experience rapidly increases estradiol levels in the auditory forebrain; (2) estradiol instantaneously enhances the responsiveness and coding efficiency of auditory neurons; (3) these changes are mediated by a non-genomic effect of brain-generated estradiol on the strength of inhibitory neurotransmission; and (4) estradiol regulates biochemical cascades that induce the expression of genes involved in synaptic plasticity. Together, these findings have established estradiol as a central regulator of auditory function and intensified the need to consider brain-based mechanisms, in addition to peripheral organ dysfunction, in hearing pathologies associated with estrogen deficiency. PMID:21146556

Review of thalamocortical resting-state fMRI studies in schizophrenia

PubMed Central

Giraldo-Chica, Monica; Woodward, Neil D.

2017-01-01

Brain circuitry underlying cognition, emotion, and perception is abnormal in schizophrenia. There is considerable evidence that the neuropathology of schizophrenia includes the thalamus, a key hub of cortical-subcortical circuitry and an important regulator of cortical activity. However, the thalamus is a heterogeneous structure composed of several nuclei with distinct inputs and cortical connections. Limitations of conventional neuroimaging methods and conflicting findings from post-mortem investigations have made it difficult to determine if thalamic pathology in schizophrenia is widespread or limited to specific thalamocortical circuits. Resting-state fMRI has proven invaluable for understanding the large-scale functional organization of the brain and investigating neural circuitry relevant to psychiatric disorders. This article summarizes resting-state fMRI investigations of thalamocortical functional connectivity in schizophrenia. Particular attention is paid to the course, diagnostic specificity, and clinical correlates of thalamocortical network dysfunction. PMID:27531067

Uranium and the Central Nervous System: What Should We Learn from Recent New Tools and Findings?

PubMed

Dinocourt, Céline

2017-01-01

Increasing industrial and military use of uranium has led to environmental pollution, which may result in uranium reaching the brain and causing cerebral dysfunction. A recent literature review has discussed data published over the last 10 years on uranium and its effects on brain function (Dinocourt C, Legrand M, Dublineau I, et al., Toxicology 337:58-71, 2015). New models of uranium exposure during neonatal brain development and the emergence of new technologies (omics and epigenetics) are of value in identifying new specific targets of uranium. Here we review the latest studies of neurogenesis, epigenetics, and metabolic dysfunctions and the identification of new biomarkers used to establish potential pathophysiological states of neurodevelopmental and neurodegenerative diseases.

Monosodium Luminol for Improving Brain Function in Gulf War Illness

DTIC Science & Technology

2016-10-01

Specific Aim 2 studies are focused on examining whether long - term administration of an apt dose of MSL-GVT would alleviate mood and memory dysfunction...and inflammation. 15. SUBJECT TERMS DEET, Gulf war illness, hippocampal neurogenesis, Memory dysfunction, Mood dysfunction, neuroinflammation...doses of MSL-GVT, in comparison to age-matched naive control rats. Thus, short - term (3 weeks of) MSL-GVT treatment is not efficacious for enhancing

Transient ventricular dysfunction after an asphyxiation event: stress or hypoxia?

PubMed

Valletta, Mary E; Haque, Ikram; Al-Mousily, Faris; Udassi, Jai; Saidi, Arwa

2008-11-01

This report of a pediatric patient with acute upper airway obstruction causing asphyxiation emphasizes the need to maintain clinical suspicion for acquired myocardial dysfunction, despite the presumed role of noncardiogenic causes for pulmonary edema after an acute upper airway obstruction. Case report. A tertiary pediatric intensive care unit. A 10-year-old girl with no significant medical history who developed flash pulmonary edema and acute myocardial dysfunction after an acute upper airway obstruction. Serial echocardiograms, exercise stress test, and coronary angiography were performed. Serial pro-brain natriuretic peptide, troponins, and CK-MB levels were also followed. Troponin level normalized approximately 7 days after the acute event. CK-MB and pro-brain natriuretic peptide levels decreased but had not completely normalized by time of discharge. The patient was discharged home 10 days after the event on an anticipated 6-month course of metoprolol without any signs or symptoms of cardiac dysfunction. Myocardial dysfunction is rarely documented in children after an acute upper airway obstruction or an asphyxiation event. Pediatric intensivists and hospitalists should maintain a high degree of clinical suspicion and screen for possible myocardial dysfunction in the pediatric patient with an acute severe hypoxic event especially when accompanied by pulmonary edema. Prompt evaluation ensures appropriate support. Additionally, some role may exist for early adrenergic receptor blockade.

Functional neuroanatomy of disorders of consciousness.

PubMed

Di Perri, Carol; Stender, Johan; Laureys, Steven; Gosseries, Olivia

2014-01-01

Our understanding of the mechanisms of loss and recovery of consciousness, following severe brain injury or during anesthesia, is changing rapidly. Recent neuroimaging studies have shown that patients with chronic disorders of consciousness and subjects undergoing general anesthesia present a complex dysfunctionality in the architecture of brain connectivity. At present, the global hallmark of impaired consciousness appears to be a multifaceted dysfunctional connectivity pattern with both within-network loss of connectivity in a widespread frontoparietal network and between-network hyperconnectivity involving other regions such as the insula and ventral tegmental area. Despite ongoing efforts, the mechanisms underlying the emergence of consciousness after severe brain injury are not thoroughly understood. Important questions remain unanswered: What triggers the connectivity impairment leading to disorders of consciousness? Why do some patients recover from coma, while others with apparently similar brain injuries do not? Understanding these mechanisms could lead to a better comprehension of brain function and, hopefully, lead to new therapeutic strategies in this challenging patient population. © 2013.

[Neurological soft signs in schizophrenia: correlations with age, sex, educational status and psychopathology].

PubMed

Panagiotidis, P; Kaprinis, G; Iacovides, A; Fountoulakis, K

2013-01-01

Though the pathobiology of schizophrenia can be examined in multiple levels, the organic notion of brain disease suggests that neurological features will be present. One straightforward, inexpensive method of investigating brain dysfunction in schizophrenia is thought the bedside assessment of neurological abnormalities with a standard neurological examination. Neurological abnormalities are traditionally classified as "hard signs" (impairments in basic motor, sensory, and reflex behaviors, which do not appear to be affected in schizophrenia) and "soft signs", which refer to more complex phenomena such as abnormalities in motor control, integrative sensory function, sensorimotor integration, and cerebral laterality. Additionally, neurological soft signs (NSS) are minor motor and sensory abnormalities that are considered to be normal in the course of early development but abnormal when elicited in later life or persist beyond childhood. Soft signs also, have no definitive localizing significance but are indicative of subtle brain dysfunction. Most authors believe that they are a reflection not only of deficient integration between the sensory and motor systems, but also of dysfunctional neuronal circuits linking subcortical brain structures such as the basal ganglia, the brain stem, and the limbic system. Throughout the last four decades, studies have consistently shown that NSS are more frequently present in patients with schizophrenia than in normal subjects and non-psychotic psychiatric patients. However, the functional relevance of NSS remains unclear and their specificity has often been challenged, even though there is indication for a relative specificity with regard to diagnosis, or symptomatology. Many studies have considered soft signs as categorical variables thus hampering the evaluation of fluctuation with symptomatology and/or treatment, whereas other studies included insufficient number of assessed signs, or lacked a comprehensive assessment of extrapyramidal symptomatology. Factors such as sex, age or family history of schizophrenia, are said to influence the performance of neurological examination, whereas relative few studies have provided longitudinal follow-up data on neurological soft signs in a sufficient number of patients, in order to address a possible deterioration of neurological functions. Finally, one additional difficulty when analyzing the NSS literature lies in the diversity of symptoms that are evaluated in the studies and/or non-standardized procedures or scoring. We will review some basic issues concerning recurrent difficulties in the measurement and definition of soft signs, as well as controversies on the significance of these signs with respect to clinical subtyping of schizophrenia, and social and demographic variables.

Animal Research on Effects of Experience on Brain and Behavior: Implications for Rehabilitation.

ERIC Educational Resources Information Center

Rosenzweig, Mark R.

2002-01-01

This article first considers how plasticity of the brain in response to differential experience was discovered in research with laboratory rats around 1960. Animal research soon followed on effects of enriched experience as therapy for brain dysfunction. Relations between animal research and some human therapies are considered. (Contains…

Blueberries and strawberries activate neuronal housekeeping in critical brain regions of stress-induced young rats

USDA-ARS?s Scientific Manuscript database

Dysfunctional autophagy, where accumulation of damaged or complex cellular components in neurons in response to sublethal cell stress has been implicated in an array of brain disorders. This phenomenon plays a pivotal role in aging, because of the increased vulnerability of the aging brain to incre...

Investigating Metacognition, Cognition, and Behavioral Deficits of College Students with Acute Traumatic Brain Injuries

ERIC Educational Resources Information Center

Martinez, Sarah; Davalos, Deana

2016-01-01

Objective: Executive dysfunction in college students who have had an acute traumatic brain injury (TBI) was investigated. The cognitive, behavioral, and metacognitive effects on college students who endorsed experiencing a brain injury were specifically explored. Participants: Participants were 121 college students who endorsed a mild TBI, and 121…

Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease.

PubMed

Sharoar, M G; Shi, Q; Ge, Y; He, W; Hu, X; Perry, G; Zhu, X; Yan, R

2016-09-01

Pathological features in Alzheimer's brains include mitochondrial dysfunction and dystrophic neurites (DNs) in areas surrounding amyloid plaques. Using a mouse model that overexpresses reticulon 3 (RTN3) and spontaneously develops age-dependent hippocampal DNs, here we report that DNs contain both RTN3 and REEPs, topologically similar proteins that can shape tubular endoplasmic reticulum (ER). Importantly, ultrastructural examinations of such DNs revealed gradual accumulation of tubular ER in axonal termini, and such abnormal tubular ER inclusion is found in areas surrounding amyloid plaques in biopsy samples from Alzheimer's disease (AD) brains. Functionally, abnormally clustered tubular ER induces enhanced mitochondrial fission in the early stages of DN formation and eventual mitochondrial degeneration at later stages. Furthermore, such DNs are abrogated when RTN3 is ablated in aging and AD mouse models. Hence, abnormally clustered tubular ER can be pathogenic in brain regions: disrupting mitochondrial integrity, inducing DNs formation and impairing cognitive function in AD and aging brains.

Caffeine and adenosine.

PubMed

Ribeiro, Joaquim A; Sebastião, Ana M

2010-01-01

Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.

Development, Prevention, and Treatment of Alcohol-Induced Organ Injury: The Role of Nutrition

PubMed Central

Barve, Shirish; Chen, Shao-Yu; Kirpich, Irina; Watson, Walter H.; McClain, Craig

2017-01-01

Alcohol and nutrition have the potential to interact at multiple levels. For example, heavy alcohol consumption can interfere with normal nutrition, resulting in overall malnutrition or in deficiencies of important micronutrients, such as zinc, by reducing their absorption or increasing their loss. Interactions between alcohol consumption and nutrition also can affect epigenetic regulation of gene expression by influencing multiple regulatory mechanisms, including methylation and acetylation of histone proteins and DNA. These effects may contribute to alcohol-related organ or tissue injury. The impact of alcohol–nutrition interactions has been assessed for several organs and tissues, including the intestine, where heavy alcohol use can increase intestinal permeability, and the liver, where the degree of malnutrition can be associated with the severity of liver injury and liver disease. Alcohol–nutrition interactions also play a role in alcohol-related lung injury, brain injury, and immune dysfunction. Therefore, treatment involving nutrient supplementation (e.g., with zinc or S-adenosylmethionine) may help prevent or attenuate some types of alcohol-induced organ damage. PMID:28988580

Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

PubMed

van Wijk, Nick; Broersen, Laus M; de Wilde, Martijn C; Hageman, Robert J J; Groenendijk, Martine; Sijben, John W C; Kamphuis, Patrick J G H

2014-01-01

Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

Validating the WHO Maternal Near Miss Tool in a high-income country.

PubMed

Witteveen, Tom; de Koning, Ilona; Bezstarosti, Hans; van den Akker, Thomas; van Roosmalen, Jos; Bloemenkamp, Kitty W

2016-01-01

This study was performed to assess the applicability of the WHO Maternal Near Miss Tool (MNM Tool) and the organ dysfunction criteria in a high-income country. The MNM tool was applied to 2552 women who died of pregnancy-related causes or sustained severe acute maternal morbidity between August 2004 and August 2006 in one of the 98 hospitals with a maternity unit in the Netherlands. Fourteen (0.6%) cases had insufficient data for application. Each case was assessed according to the three main "MNM categories" specified in the MNM tool and their subcategory criteria: five disease-, four intervention- and seven organ dysfunction-based criteria. Potentially life-threatening conditions (disease-based inclusions) and life-threatening cases (organ dysfunction-based inclusions) were differentiated according to WHO methodology. Outcomes were incidence of all (sub)categories and case-fatality rates. Of the 2538 cases, 2308 (90.9%) women fulfilled disease-based, 2116 (83.4%) intervention-based and 1024 (40.3%) organ dysfunction-based criteria. Maternal death occurred in 48 women, of whom 23 (47.9%) fulfilled disease-based, 33 (68.8%) intervention-based and 31 (64.6%) organ dysfunction-based criteria. Case-fatality rates were 23/2308 (1.0%) for cases fulfilling the disease-based criteria, 33/2116 (1.6%) for intervention-based criteria and 31/1024 (3.0%) for women fulfilling the organ dysfunction-based criteria. In the Netherlands, where advanced laboratory and clinical monitoring are available, organ dysfunction-based criteria of the MNM tool failed to identify nearly two-thirds of sustained severe acute maternal morbidity cases and more than one-third of maternal deaths. Disease-based criteria remain important, and using only organ dysfunction-based criteria would lead to underestimating severe acute maternal morbidity. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells.

PubMed

Bernhart, Eva; Kogelnik, Nora; Prasch, Jürgen; Gottschalk, Benjamin; Goeritzer, Madeleine; Depaoli, Maria Rosa; Reicher, Helga; Nusshold, Christoph; Plastira, Ioanna; Hammer, Astrid; Fauler, Günter; Malli, Roland; Graier, Wolfgang F; Malle, Ernst; Sattler, Wolfgang

2018-05-01

Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H 2 O 2 -chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a 'clickable' alkyne derivative (2-ClHyA) that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2-ClHyA in the endoplasmic reticulum (ER) and mitochondria of human BMVEC (hCMEC/D3 cell line). 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL)-6 as well as IL-8. 2-ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Endotoxin-induced lung alveolar cell injury causes brain cell damage.

PubMed

Rodríguez-González, Raquel; Ramos-Nuez, Ángela; Martín-Barrasa, José Luis; López-Aguilar, Josefina; Baluja, Aurora; Álvarez, Julián; Rocco, Patricia R M; Pelosi, Paolo; Villar, Jesús

2015-01-01

Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome. © 2014 by the Society for Experimental Biology and Medicine.

TNF-α receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats.

PubMed

Yu, Yang; Wei, Shun-Guang; Weiss, Robert M; Felder, Robert B

2017-10-01

In systolic heart failure (HF), circulating proinflammatory cytokines upregulate inflammation and renin-angiotensin system (RAS) activity in cardiovascular regions of the brain, contributing to sympathetic excitation and cardiac dysfunction. Important among these is the subfornical organ (SFO), a forebrain circumventricular organ that lacks an effective blood-brain barrier and senses circulating humors. We hypothesized that the tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1) in the SFO contributes to sympathetic excitation and cardiac dysfunction in HF rats. Rats received SFO microinjections of a TNFR1 shRNA or a scrambled shRNA lentiviral vector carrying green fluorescent protein, or vehicle. One week later, some rats were euthanized to confirm the accuracy of the SFO microinjections and the transfection potential of the lentiviral vector. Other rats underwent coronary artery ligation (CL) to induce HF or a sham operation. Four weeks after CL, vehicle- and scrambled shRNA-treated HF rats had significant increases in TNFR1 mRNA and protein, NF-κB activity, and mRNA for inflammatory mediators, RAS components and c-Fos protein in the SFO and downstream in the hypothalamic paraventricular nucleus, along with increased plasma norepinephrine levels and impaired cardiac function, compared with vehicle-treated sham-operated rats. In HF rats treated with TNFR1 shRNA, TNFR1 was reduced in the SFO but not paraventricular nucleus, and the central and peripheral manifestations of HF were ameliorated. In sham-operated rats treated with TNFR1 shRNA, TNFR1 expression was also reduced in the SFO but there were no other effects. These results suggest a key role for TNFR1 in the SFO in the pathophysiology of systolic HF. NEW & NOTEWORTHY Activation of TNF-α receptor 1 in the subfornical organ (SFO) contributes to sympathetic excitation in heart failure rats by increasing inflammation and renin-angiotensin system activity in the SFO and downstream in the hypothalamic paraventricular nucleus. Cytokine receptors in the SFO may be a target for central intervention in cardiovascular conditions characterized by peripheral inflammation.

Methylmalonate Induces Inflammatory and Apoptotic Potential: A Link to Glial Activation and Neurological Dysfunction.

PubMed

Gabbi, Patricia; Ribeiro, Leandro Rodrigo; Jessié Martins, Gutierres; Cardoso, Alexandra Seide; Haupental, Fernanda; Rodrigues, Fernanda Silva; Machado, Alencar Kolinski; Sperotto Brum, Juliana; Medeiros Frescura Duarte, M M; Schetinger, Maria Rosa Chitolina; da Cruz, Ivana Beatrice Mânica; Flávia Furian, Ana; Oliveira, Mauro Schneider; Dos Santos, Adair Roberto Soares; Royes, Luiz Fernando Freire; Fighera, Michele Rechia; de Freitas, Mayara Lutchemeyer

2017-03-01

Methylmalonic acid (MMA) accumulates in tissues in methylmalonic acidemia, a heterogeneous group of inherited childhood diseases characterized by neurological dysfunction, oxidative stress and neuroinflammation; it is associated with degeneration of striatal neurons and cerebral cortical atrophy. It is presently unknown, however, whether transient exposure to MMA in the neonatal period is sufficient to trigger inflammatory and apoptotic processes that lead to brain structural damage. Here, newborn mice were given a single intracerebroventricular dose of MMA at 12 hours after birth. Maze testing of 21- and 40-day-old mice showed that MMA-injected animals exhibited deficit in the working memory test but not in the reference test. MMA-injected mice showed increased levels of the reactive oxygen species marker 2',7'-dichlorofluorescein diacetate, tumor necrosis factor, interleukin-1β, caspases 1, 3, and 8, and increased acetylcholinesterase activity in the cortex, hippocampus and striatum. This was associated with increased astrocyte and microglial immunoreactivity in all brain regions. These findings suggest that transient exposure to MMA may alter the redox state and cause neuroinflammatory/apoptotic processes and glial activation during critical periods of brain development. Similar processes may underlie brain dysfunction and cognitive impairment in patients with methylmalonic acidemia. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

Effects of Grape Skin Extract on Age-Related Mitochondrial Dysfunction, Memory and Life Span in C57BL/6J Mice.

PubMed

Asseburg, Heike; Schäfer, Carmina; Müller, Madeleine; Hagl, Stephanie; Pohland, Maximilian; Berressem, Dirk; Borchiellini, Marta; Plank, Christina; Eckert, Gunter P

2016-09-01

Dementia contributes substantially to the burden of disability experienced at old age, and mitochondrial dysfunction (MD) was identified as common final pathway in brain aging and Alzheimer's disease. Due to its early appearance, MD is a promising target for nutritional prevention strategies and polyphenols as potential neurohormetic inducers may be strong neuroprotective candidates. This study aimed to investigate the effects of a polyphenol-rich grape skin extract (PGE) on age-related dysfunctions of brain mitochondria, memory, life span and potential hormetic pathways in C57BL/6J mice. PGE was administered at a dose of 200 mg/kg body weight/d in a 3-week short-term, 6-month long-term and life-long study. MD in the brains of aged mice (19-22 months old) compared to young mice (3 months old) was demonstrated by lower ATP levels and by impaired mitochondrial respiratory complex activity (except for mice treated with antioxidant-depleted food pellets). Long-term PGE feeding partly enhanced brain mitochondrial respiration with only minor beneficial effect on brain ATP levels and memory of aged mice. Life-long PGE feeding led to a transient but significant shift of survival curve toward higher survival rates but without effect on the overall survival. The moderate effects of PGE were associated with elevated SIRT1 but not SIRT3 mRNA expressions in brain and liver tissue. The beneficial effects of the grape extract may have been influenced by the profile of bioavailable polyphenols and the starting point of interventions.

Role of brain iron accumulation in cognitive dysfunction: evidence from animal models and human studies.

PubMed

Schröder, Nadja; Figueiredo, Luciana Silva; de Lima, Maria Noêmia Martins

2013-01-01

Over the last decades, studies from our laboratory and other groups using animal models have shown that iron overload, resulting in iron accumulation in the brain, produces significant cognitive deficits. Iron accumulation in the hippocampus and the basal ganglia has been related to impairments in spatial memory, aversive memory, and recognition memory in rodents. These results are corroborated by studies showing that the administration of iron chelators attenuates cognitive deficits in a variety of animal models of cognitive dysfunction, including aging and Alzheimer's disease models. Remarkably, recent human studies using magnetic resonance image techniques have also shown a consistent correlation between cognitive dysfunction and iron deposition, mostly in the hippocampus, cortical areas, and basal ganglia. These findings may have relevant implications in the light of the knowledge that iron accumulates in brain regions of patients suffering from neurodegenerative diseases. A better understanding of the functional consequences of iron dysregulation in aging and neurological diseases may help to identify novel targets for treating memory problems that afflict a growing aging population.

Altered Effective Connectivity among Core Neurocognitive Networks in Idiopathic Generalized Epilepsy: An fMRI Evidence

PubMed Central

Wei, Huilin; An, Jie; Shen, Hui; Zeng, Ling-Li; Qiu, Shijun; Hu, Dewen

2016-01-01

Idiopathic generalized epilepsy (IGE) patients with generalized tonic-clonic seizures (GTCS) suffer long-term cognitive impairments, and present a higher incidence of psychosocial and psychiatric disturbances than healthy people. It is possible that the cognitive dysfunctions and higher psychopathological risk in IGE-GTCS derive from disturbed causal relationship among core neurocognitive brain networks. To test this hypothesis, we examined the effective connectivity across the salience network (SN), default mode network (DMN), and central executive network (CEN) using resting-state functional magnetic resonance imaging (fMRI) data collected from 27 IGE-GTCS patients and 29 healthy controls. In the study, a combination framework of time domain and frequency domain multivariate Granger causality analysis was firstly proposed, and proved to be valid and accurate by simulation experiments. Using this method, we then observed significant differences in the effective connectivity graphs between the patient and control groups. Specifically, between-group statistical analysis revealed that relative to the healthy controls, the patients established significantly enhanced Granger causal influence from the dorsolateral prefrontal cortex to the dorsal anterior cingulate cortex, which is coherent both in the time and frequency domains analyses. Meanwhile, time domain analysis also revealed decreased Granger causal influence from the right fronto-insular cortex to the posterior cingulate cortex in the patients. These findings may provide new evidence for functional brain organization disruption underlying cognitive dysfunctions and psychopathological risk in IGE-GTCS. PMID:27656137

Intra-operative multi-site stimulation: Expanding methodology for cortical brain mapping of language functions

PubMed Central

Korn, Akiva; Kirschner, Adi; Perry, Daniella; Hendler, Talma; Ram, Zvi

2017-01-01

Direct cortical stimulation (DCS) is considered the gold-standard for functional cortical mapping during awake surgery for brain tumor resection. DCS is performed by stimulating one local cortical area at a time. We present a feasibility study using an intra-operative technique aimed at improving our ability to map brain functions which rely on activity in distributed cortical regions. Following standard DCS, Multi-Site Stimulation (MSS) was performed in 15 patients by applying simultaneous cortical stimulations at multiple locations. Language functioning was chosen as a case-cognitive domain due to its relatively well-known cortical organization. MSS, performed at sites that did not produce disruption when applied in a single stimulation point, revealed additional language dysfunction in 73% of the patients. Functional regions identified by this technique were presumed to be significant to language circuitry and were spared during surgery. No new neurological deficits were observed in any of the patients following surgery. Though the neuro-electrical effects of MSS need further investigation, this feasibility study may provide a first step towards sophistication of intra-operative cortical mapping. PMID:28700619

Over a century of neuron culture: from the hanging drop to microfluidic devices.

PubMed

Millet, Larry J; Gillette, Martha U

2012-12-01

The brain is the most intricate, energetically active, and plastic organ in the body. These features extend to its cellular elements, the neurons and glia. Understanding neurons, or nerve cells, at the cellular and molecular levels is the cornerstone of modern neuroscience. The complexities of neuron structure and function require unusual methods of culture to determine how aberrations in or between cells give rise to brain dysfunction and disease. Here we review the methods that have emerged over the past century for culturing neurons in vitro, from the landmark finding by Harrison (1910) - that neurons can be cultured outside the body - to studies utilizing culture vessels, micro-islands, Campenot and brain slice chambers, and microfluidic technologies. We conclude with future prospects for neuronal culture and considerations for advancement. We anticipate that continued innovation in culture methods will enhance design capabilities for temporal control of media and reagents (chemotemporal control) within sub-cellular environments of three-dimensional fluidic spaces (microfluidic devices) and materials (e.g., hydrogels). They will enable new insights into the complexities of neuronal development and pathology.

Over a Century of Neuron Culture: From the Hanging Drop to Microfluidic Devices

PubMed Central

Millet, Larry J.; Gillette, Martha U.

2012-01-01

The brain is the most intricate, energetically active, and plastic organ in the body. These features extend to its cellular elements, the neurons and glia. Understanding neurons, or nerve cells, at the cellular and molecular levels is the cornerstone of modern neuroscience. The complexities of neuron structure and function require unusual methods of culture to determine how aberrations in or between cells give rise to brain dysfunction and disease. Here we review the methods that have emerged over the past century for culturing neurons in vitro, from the landmark finding by Harrison (1910) — that neurons can be cultured outside the body — to studies utilizing culture vessels, micro-islands, Campenot and brain slice chambers, and microfluidic technologies. We conclude with future prospects for neuronal culture and considerations for advancement. We anticipate that continued innovation in culture methods will enhance design capabilities for temporal control of media and reagents (chemotemporal control) within sub-cellular environments of three-dimensional fluidic spaces (microfluidic devices) and materials (e.g., hydrogels). They will enable new insights into the complexities of neuronal development and pathology. PMID:23239951

Intra-operative multi-site stimulation: Expanding methodology for cortical brain mapping of language functions.

PubMed

Gonen, Tal; Gazit, Tomer; Korn, Akiva; Kirschner, Adi; Perry, Daniella; Hendler, Talma; Ram, Zvi

2017-01-01

Direct cortical stimulation (DCS) is considered the gold-standard for functional cortical mapping during awake surgery for brain tumor resection. DCS is performed by stimulating one local cortical area at a time. We present a feasibility study using an intra-operative technique aimed at improving our ability to map brain functions which rely on activity in distributed cortical regions. Following standard DCS, Multi-Site Stimulation (MSS) was performed in 15 patients by applying simultaneous cortical stimulations at multiple locations. Language functioning was chosen as a case-cognitive domain due to its relatively well-known cortical organization. MSS, performed at sites that did not produce disruption when applied in a single stimulation point, revealed additional language dysfunction in 73% of the patients. Functional regions identified by this technique were presumed to be significant to language circuitry and were spared during surgery. No new neurological deficits were observed in any of the patients following surgery. Though the neuro-electrical effects of MSS need further investigation, this feasibility study may provide a first step towards sophistication of intra-operative cortical mapping.

Stress hormonal changes in the brain and plasma after acute noise exposure in mice.

PubMed

Jin, Sang Gyun; Kim, Min Jung; Park, So Young; Park, Shi Nae

2017-06-01

To investigate the effects of acute noise stress on two amine stress hormones, norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain and plasma of mice after noise exposure. Mice were grouped into the control and noise groups. Mice in the noise group were exposed to white noise of 110dB sound pressure level for 60min. Auditory brainstem response thresholds, distortion product otoacoustic emissions, the organ of Corti grading scores, western blots of NE/5-HIAA in the whole brain and hippocampus, and the plasma levels of NE/5-HIAA were compared between the two groups. Significant hearing loss and cochlear damage were demonstrated in the noise group. NE and 5-HIAA in the hippocampus were elevated in the noise group (p=0.019/0.022 for NE/5-HIAA vs. the control). Plasma levels of NE and 5-HIAA were not statistically different between the groups (p=0.052/0.671 for NE/5-HIAA). Hearing loss with outer hair cell dysfunction and morphological changes of the organ of Corti after noise exposure in C57BL/6 mice proved the reliability of our animal model as an acute noise stress model. NE and 5-HIAA are suggested to be the potential biomarkers for acute noise stress in the hippocampus. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Nutritional genomics: defining the dietary requirement and effects of choline.

PubMed

Zeisel, Steven H

2011-03-01

As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N-methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor.

Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair

PubMed Central

Zárate, Sandra; Stevnsner, Tinna; Gredilla, Ricardo

2017-01-01

Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly. Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity. Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer’s disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain. PMID:29311911

Thermosensory signaling by TRPM is processed by brain serotonergic neurons to produce planarian thermotaxis.

PubMed

Inoue, Takeshi; Yamashita, Taiga; Agata, Kiyokazu

2014-11-19

For most organisms, sensitive recognition of even slight changes in environmental temperature is essential for adjusting their behavioral strategies to ensure homeostasis and survival. However, much remains to be understood about the molecular and cellular processes that regulate thermosensation and the corresponding behavioral responses. Planarians display clear thermotaxis, although they have a relatively simple brain. Here, we devised a quantitative thermotaxis assay and unraveled a neural pathway involved in planarian thermotaxis by combinatory behavioral assays and RNAi analysis. We found that thermosensory neurons that expressed a planarian Dugesia japonica homolog of the Transient Receptor Potential Melastatin family a (DjTRPMa) gene were required for the thermotaxis. Interestingly, although these thermosensory neurons are distributed throughout their body, planarians with a dysfunctional brain due to regeneration-dependent conditional gene knockdown (Readyknock) of the synaptotagmin gene completely lost their thermotactic behavior. These results suggest that brain function is required as a central processor for the thermosensory response. Therefore, we investigated the type(s) of brain neurons involved in processing the thermal signals by gene knockdown of limiting enzymes for neurotransmitter biosynthesis in the brain. We found that serotonergic neurons with dendrites that were elongated toward DjTRPMa-expressing thermosensory neurons might be required for the processing of signals from thermosensory neurons that results in thermotaxis. These results suggest that serotonergic neurons in the brain may interact with thermosensory neurons activated by TRPM ion channels to produce thermotaxis in planarians. Copyright © 2014 the authors 0270-6474/14/3415701-14$15.00/0.

Antibodies and the brain: antiribosomal P protein antibody and the clinical effects in patients with systemic lupus erythematosus.

PubMed

González, Alfonso; Massardo, Loreto

2018-06-01

Analysis of antiribosomal P protein autoantibodies (anti-P) pathogenicity in diffuse brain manifestations of neuropsychiatric lupus, emphasizing cognitive dysfunction and the recently emerged role of cross-reacting neuronal surface P antigen (NSPA) in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-Methyl-D-Aspartate receptor glutamatergic transmission. Circulating anti-P antibodies associate with executive planning dysfunction and attention impairments in lupus patients and perturb glutamatergic transmission through NSPA in mice hippocampus, translating into impaired synaptic plasticity and spatial memory. Planning impairment impacts quality of life. In addition to the known association with lupus psychosis, new clinical and experimental evidence reveal a pathogenic role of anti-P antibodies in cognitive dysfunction, mechanistically explained by the anti-P interaction with NSPA as a target involved in glutamatergic synaptic plasticity.

Cognitive impairment and olfactory panic from occupational exposure to VOCs.

PubMed

Reinhartz, Abe

2006-10-01

A Canadian government clerical worker in her early thirties developed frontal lobe dysfunction from inhalation of volatile organic compounds off-gassed during an office renovation. Pulmonary function, bronchial provocation, allergy testing, and a brain (SPECT) scan were performed. SPECT scanning showed frontotemporal hypoperfusion and neuropsychologic testing revealed deficits in verbal learning and poor organizational memory. A significant component of this worker's impairment was the development of "olfactory panic," a debilitating aversion to odor accompanied by symptoms of panic. The Ontario Workplace Safety and Insurance Appeals Tribunal granted entitlement for her cognitive difficulties and olfactory panic as a result of her toxic exposure.

Mental health screening in women with severe pelvic organ prolapse, chronic fourth-degree obstetric tear and genital tract fistula in western Uganda.

PubMed

Krause, Hannah G; Hall, Barbara A; Ng, Shu-Kay; Natukunda, Harriet; Singasi, Isaac; Goh, Judith T W

2017-06-01

High levels of mental health dysfunction have been identified in women with genital tract fistula. The aim of this study was to use the General Health Questionnaire-28 (GHQ-28) to screen women in western Uganda with severe pelvic organ prolapse, chronic fourth-degree obstetric tear and genital tract fistula for risk of mental health dysfunction. Women undergoing surgery for severe pelvic organ prolapse, chronic fourth-degree obstetric tear, and genital tract fistula were interviewed using the GHQ-28 to screen for the risk of mental health dysfunction. A total of 125 women completed the GHQ-28, including 22 with pelvic organ prolapse, 47 with fourth-degree obstetric tear, 21 with genital tract fistula, and 35 controls. Nearly all women with these serious gynaecological conditions were positive for the risk of mental health dysfunction. In the domain assessing symptoms of severe depression, women with fourth-degree obstetric tear and genital tract fistula scored higher than women with pelvic organ prolapse. A significant risk of mental health dysfunction was identified in women with severe pelvic organ prolapse and chronic fourth-degree obstetric tear. These rates are similar to the high rates of mental health dysfunction in women with genital tract fistula. Identification and management of mental health dysfunction in women with these conditions should be a priority.

Prevalence and Pattern of Executive Dysfunction in School Age Children with Congenital Heart Disease

PubMed Central

Sanz, Jacqueline H.; Berl, Madison M.; Armour, Anna C.; Wang, Jichuan; Cheng, Yao I.; Donofrio, Mary T.

2016-01-01

Objective Executive Function, a set of cognitive skills important to social and academic outcomes, is a specific area of cognitive weakness in children with congenital heart disease (CHD). We evaluated the prevalence and profile of executive dysfunction in a heterogeneous sample of school aged children with CHD, examined whether children with executive dysfunction are receiving school services and support, and identified risk factors for executive dysfunction at school age. Design 91 school aged patients completed questionnaires, including the Behavior Rating Inventory of Executive Function (BRIEF) and a medical history questionnaire. An age and gender matched control sample was drawn from a normativedatabase. Results CHD patients had a higher rate of parent reported executive dysfunction (OR=4.37, p<0.0001), especially for working memory (OR=8.22, p<0.0001) and flexibility (OR=8.05, p<0.0001). Those with executive dysfunction were not more likely to be receiving school services (p>0.05). Gender, premature birth (≤37 weeks), and CHD with aortic obstruction were predictive of executive dysfunction, especially for behavior regulation skills. Conclusions School aged children with CHD have an increased prevalence of executive dysfunction, especially problems with working memory and flexibility, and are underserved by the school system. The increased risk for executive dysfunction in those with CHD and prematurity or CHD with aortic obstruction suggests an etiology of delayed brain development in the fetal and neonatal periods, while male gender may increase susceptibility to brain injury. This study highlights the need for regular neurodevelopmental follow up in children with CHD, and a need to better understand mechanisms that contribute to adverse neurodevelopmental outcomes. PMID:27863079

Prevalence and pattern of executive dysfunction in school age children with congenital heart disease.

PubMed

Sanz, Jacqueline H; Berl, Madison M; Armour, Anna C; Wang, Jichuan; Cheng, Yao I; Donofrio, Mary T

2017-03-01

Executive function, a set of cognitive skills important to social and academic outcomes, is a specific area of cognitive weakness in children with congenital heart disease (CHD). We evaluated the prevalence and profile of executive dysfunction in a heterogeneous sample of school aged children with CHD, examined whether children with executive dysfunction are receiving school services and support, and identified risk factors for executive dysfunction at school age. Ninety-one school aged patients completed questionnaires, including the Behavior Rating Inventory of Executive Function (BRIEF) and a medical history questionnaire. An age- and gender- matched control sample was drawn from a normative database. Children with CHD had a higher rate of parent reported executive dysfunction (OR = 4.37, P < .0001), especially for working memory (OR = 8.22, P < .0001) and flexibility (OR = 8.05, P < .0001). Those with executive dysfunction were not more likely to be receiving school services (P > .05). Gender, premature birth (≤37 weeks), and CHD with aortic obstruction were predictive of executive dysfunction, especially for behavior regulation skills. School aged children with CHD have an increased prevalence of executive dysfunction, especially problems with working memory and flexibility, and are underserved by the school system. The increased risk for executive dysfunction in those with CHD and prematurity or CHD with aortic obstruction suggests an etiology of delayed brain development in the fetal and neonatal periods, while male gender may increase susceptibility to brain injury. This study highlights the need for regular neurodevelopmental follow up in children with CHD, and a need to better understand mechanisms that contribute to adverse neurodevelopmental outcomes. © 2016 Wiley Periodicals, Inc.

Legacy Clinical Data from the Epo TBI Trial

DTIC Science & Technology

2016-06-01

investigators through the Federal Interagency Traumatic Brain Injury (FITBIR) Informatics System. This trial was funded by National Institute of Neurological...Effects of Erythropoietin (Epo) on Cerebral Vascular Dysfunction and Anemia in Traumatic Brain Injury (TBI)” which we will share with other...the format required by FITBIR. 2. KEYWORDS: Traumatic brain injury Erythropoietin Anemia Transfusion threshold 3. ACCOMPLISHMENTS: What

Structural Dissociation of Attentional Control and Memory in Adults with and without Mild Traumatic Brain Injury

ERIC Educational Resources Information Center

Niogi, Sumit N.; Mukherjee, Pratik; Ghajar, Jamshid; Johnson, Carl E.; Kolster, Rachel; Lee, Hana; Suh, Minah; Zimmerman, Robert D.; Manley, Geoffrey T.; McCandliss, Bruce D.

2008-01-01

Memory and attentional control impairments are the two most common forms of dysfunction following mild traumatic brain injury (TBI) and lead to significant morbidity in patients, yet these functions are thought to be supported by different brain networks. This 3 T magnetic resonance diffusion tensor imaging (DTI) study investigates whether…

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2013-11-01

COVERED 4 October 201 - 3 October 201 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a. CONTRACT...injury, blood brain barrier, neuroinflammation, neurological dysfunction, endocannabinoids Table of Contents Introduction...promote neuroinflammation and potentially lead to neurodegeneration. We have previously demonstrated that treatments to the endocannabinoid system 2

Protection of brain and pancreas from high-fat diet: effects of catechin and caffeine.

PubMed

Unno, Keiko; Yamamoto, Hiroyuki; Maeda, Ken-Ichi; Takabayashi, Fumiyo; Yoshida, Hirotoshi; Kikunaga, Naomi; Takamori, Nina; Asahina, Shunsuke; Iguchi, Kazuaki; Sayama, Kazutoshi; Hoshino, Minoru

2009-02-16

To investigate the effect of a high-fat diet on brain and pancreas functions, we used SAMP10 mice that have characteristics of brain atrophy and cognitive dysfunction with aging. Simultaneously, we investigated the effect of green tea catechin consumption on high-fat diet feeding, because green tea catechin has been reported to improve brain atrophy, brain dysfunction and obesity. The body weight of mice fed a high-fat diet from 2 to 12 months was higher than that of the control, although the calorie intake was not. The high-fat diet also increased insulin secretion; however, the hypersecretion of insulin and obesity were suppressed when mice were fed a high-fat diet with green tea catechin and caffeine. Furthermore, brain atrophy was suppressed and the working memory, tested using Y-maze, improved in mice fed a high-fat diet containing green tea catechin and caffeine. The secretion of insulin might affect both obesity and brain function. A strong correlation was found between working memory and insulin release in mice fed a high-fat diet with green tea catechin and/or caffeine. The results indicate the protective effect of green tea catechin and caffeine on the functions of brain and pancreas in mice fed a high-fat diet.

Brain lesions in septic shock: a magnetic resonance imaging study.

PubMed

Sharshar, Tarek; Carlier, Robert; Bernard, Francis; Guidoux, Céline; Brouland, Jean-Philippe; Nardi, Olivier; de la Grandmaison, Geoffroy Lorin; Aboab, Jérôme; Gray, Françoise; Menon, David; Annane, Djillali

2007-05-01

Understanding of sepsis-induced brain dysfunction remains poor, and relies mainly on data from animals or post-mortem studies in patients. The current study provided findings from magnetic resonance imaging of the brain in septic shock. Nine patients with septic shock and brain dysfunction [7 women, median age 63 years (interquartile range 61-79 years), SAPS II: 48 (44-56), SOFA: 8 (6-10)] underwent brain magnetic resonance imaging including gradient echo T1-weighted, fluid-attenuated inversion recovery (FLAIR), T2-weighted and diffusion isotropic images, and mapping of apparent diffusion coefficient. Brain imaging was normal in two patients, showed multiple ischaemic strokes in two patients, and in the remaining patients showed white matter lesions at the level of the centrum semiovale, predominating around Virchow-Robin spaces, ranging from small multiple areas to diffuse lesions, and characterised by hyperintensity on FLAIR images. The main lesions were also characterised by reduced signal on diffusion isotropic images and increased apparent diffusion coefficient. The lesions of the white matter worsened with increasing duration of shock and were correlated with Glasgow Outcome Score. This preliminary study showed that sepsis-induced brain lesions can be documented by magnetic resonance imaging. These lesions predominated in the white matter, suggesting increased blood-brain barrier permeability, and were associated with poor outcome.

Selective Cognitive Dysfunction Is Related to a Specific Pattern of Cerebral Damage in Persons With Severe Traumatic Brain Injury.

PubMed

Di Paola, Margherita; Phillips, Owen; Costa, Alberto; Ciurli, Paola; Bivona, Umberto; Catani, Sheila; Formisano, Rita; Caltagirone, Carlo; Carlesimo, Giovanni Augusto

2015-01-01

Cognitive dysfunction is a common sequela of traumatic brain injury (TBI); indeed, patients show a heterogeneous pattern of cognitive deficits. This study was aimed at investigating whether patients who show selective cognitive dysfunction after TBI present a selective pattern of cerebral damage. Post-Coma Unit, IRCCS Santa Lucia Foundation, Rome, Italy. We collected data from 8 TBI patients with episodic memory disorder and without executive deficits, 7 patients with executive function impairment and preserved episodic memory capacities, and 16 healthy controls. We used 2 complementary analyses: (1) an exploratory and qualitative approach in which we investigated the distribution of lesions in the TBI groups, and (2) a hypothesis-driven and quantitative approach in which we calculated the volume of hippocampi of individuals in the TBI and control groups. Neuropsychological scores and hippocampal volumes. We found that patients with TBI and executive functions impairment presented focal lesions involving the frontal lobes, whereas patients with TBI and episodic memory disorders showed atrophic changes of the mesial temporal structure (hippocampus). The complexity of TBI is due to several heterogeneous factors. Indeed, studying patients with TBI and selective cognitive dysfunction should lead to a better understanding of correlations with specific brain impairment and damage, better follow-up of long-term outcome scenarios, and better planning of selective and focused rehabilitation programs.

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

PubMed Central

Bleau, Christian; Filliol, Aveline; Samson, Michel

2015-01-01

ABSTRACT Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-β) production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCE Coronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain access to the CNS at the BBB level. Herein we report for the first time that CoVs exhibit the ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with virus-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion. PMID:26202229

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells.

PubMed

Bleau, Christian; Filliol, Aveline; Samson, Michel; Lamontagne, Lucie

2015-10-01

Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-β) production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. Coronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain access to the CNS at the BBB level. Herein we report for the first time that CoVs exhibit the ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with virus-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Growth, Hypothalamic Function, and Brain Ventricle Size in Mentally Retarded Subjects

ERIC Educational Resources Information Center

Leisti, S.; Iianainen, M.

1978-01-01

To determine whether moderate enlargement of the third brain ventricle or the temporal horns of the lateral ventricles was associated with hypothalamic dysfunction, 15 mentally retarded Ss (ages 12-25 years) with such characteristics were studies. (DLS)

Can the Pediatric Logistic Organ Dysfunction-2 Score on Day 1 Be Used in Clinical Criteria for Sepsis in Children?

PubMed

Leclerc, Francis; Duhamel, Alain; Deken, Valérie; Grandbastien, Bruno; Leteurtre, Stéphane

2017-08-01

A recent task force has proposed the use of Sequential Organ Failure Assessment in clinical criteria for sepsis in adults. We sought to evaluate the predictive validity for PICU mortality of the Pediatric Logistic Organ Dysfunction-2 and of the "quick" Pediatric Logistic Organ Dysfunction-2 scores on day 1 in children with suspected infection. Secondary analysis of the database used for the development and validation of the Pediatric Logistic Organ Dysfunction-2. Nine university-affiliated PICUs in Europe. Only children with hypotension-low systolic blood pressure or low mean blood pressure using age-adapted cutoffs-and lactatemia greater than 2 mmol/L were considered in shock. We developed the quick Pediatric Logistic Organ Dysfunction-2 score on day 1 including tachycardia, hypotension, and altered mentation (Glasgow < 11): one point for each variable (range, 0-3). Outcome was mortality at PICU discharge. Discrimination (Area under receiver operating characteristic curve-95% CI) and calibration (goodness of fit test) of the scores were studied. This study included 862 children with suspected infection (median age: 12.3 mo; mortality: n = 60 [7.0%]). Area under the curve of the Pediatric Logistic Organ Dysfunction-2 score on day 1 was 0.91 (0.86-0.96) in children with suspected infection, 0.88 (0.79-0.96) in those with low systolic blood pressure and hyperlactatemia, and 0.91 (0.85-0.97) in those with low mean blood pressure and hyperlactatemia; calibration p value was 0.03, 0.36, and 0.49, respectively. A Pediatric Logistic Organ Dysfunction-2 score on day 1 greater than or equal to 8 reflected an overall risk of mortality greater than or equal to 9.3% in children with suspected infection. Area under the curve of the quick Pediatric Logistic Organ Dysfunction-2 score on day 1 was 0.82 (0.76-0.87) with systolic blood pressure or mean blood pressure; calibration p value was 0.89 and 0.72, respectively. A score greater than or equal to 2 reflected a mortality risk greater than or equal to 19.8% with systolic blood pressure and greater than or equal to 15.9% with mean blood pressure. Among children admitted to PICU with suspected infection, Pediatric Logistic Organ Dysfunction-2 score on day 1 was highly predictive of PICU mortality suggesting its use to standardize definitions and diagnostic criteria of pediatric sepsis. Further studies are needed to determine the usefulness of the quick Pediatric Logistic Organ Dysfunction-2 score on day 1 outside of the PICU.

Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction.

PubMed

Xu, Jin; Casas-Ferreira, Ana M; Ma, Yun; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, Maltina; Tena, Maria; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido-Quigley, Cristina

2015-12-04

Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation.

Fractal Dimension of EEG Activity Senses Neuronal Impairment in Acute Stroke

PubMed Central

Zappasodi, Filippo; Olejarczyk, Elzbieta; Marzetti, Laura; Assenza, Giovanni; Pizzella, Vittorio; Tecchio, Franca

2014-01-01

The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal) properties. Under the hypothesis that the fractal dimension (FD) of the electroencephalographic signal (EEG) is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD’s ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4–10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss) was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy) and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105) and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures’ activities in stroke recovery. PMID:24967904

Fractal dimension of EEG activity senses neuronal impairment in acute stroke.

PubMed

Zappasodi, Filippo; Olejarczyk, Elzbieta; Marzetti, Laura; Assenza, Giovanni; Pizzella, Vittorio; Tecchio, Franca

2014-01-01

The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal) properties. Under the hypothesis that the fractal dimension (FD) of the electroencephalographic signal (EEG) is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD's ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4-10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss) was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy) and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105) and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures' activities in stroke recovery.

The predictive value of resting heart rate following osmotherapy in brain injury: back to basics

PubMed Central

2012-01-01

Background The importance of resting heart rate as a prognostic factor was described in several studies. An elevated heart rate is an independent risk factor for adverse cardiovascular events and total mortality in patients with coronary artery disease, chronic heart failure, and the general population. Also heart rate is elevated in the Multi Organ Dysfunction Syndrome (MODS) and the mortality due to MODS is highly correlated with inadequate sinus tachycardia. To evaluate the value of resting heart rate in predicting mortality in patients with traumatic brain injury along scoring systems like Acute Physiology and Chronic Health Evaluation(APACHE II), Sequential Organ Failure Assessment (SOFA) and Glasgow Coma Score (GCS). Method By analyzing data which was collected from an open labeled randomized clinical trial that compared the different means of osmotherapy (mannitol vs bolus or infusion hypertonic saline), heart rate, GCS, APACHE II and SOFA score were measured at baseline and daily for 7 days up to 60 days and the relationship between elevated heart rate and mortality during the first 7 days and 60th day were assessed. Results After adjustments for confounding factors, although there was no difference in mean heart rate between either groups of alive and expired patients, however, we have found a relative correlation between 60th day mortality rate and resting heart rate (P=0.07). Conclusion Heart rate can be a prognostic factor for estimating mortality rate in brain injury patients along with APACHE II and SOFA scores in patients with brain injury. PMID:23351393

Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243.

PubMed

Dutca, Laura M; Stasheff, Steven F; Hedberg-Buenz, Adam; Rudd, Danielle S; Batra, Nikhil; Blodi, Frederick R; Yorek, Matthew S; Yin, Terry; Shankar, Malini; Herlein, Judith A; Naidoo, Jacinth; Morlock, Lorraine; Williams, Noelle; Kardon, Randy H; Anderson, Michael G; Pieper, Andrew A; Harper, Matthew M

2014-12-02

Traumatic brain injury (TBI) frequently leads to chronic visual dysfunction. The purpose of this study was to investigate the effect of TBI on retinal ganglion cells (RGCs), and to test whether treatment with the novel neuroprotective compound P7C3-S243 could prevent in vivo functional deficits in the visual system. Blast-mediated TBI was modeled using an enclosed over-pressure blast chamber. The RGC physiology was evaluated using a multielectrode array and pattern electroretinogram (PERG). Histological analysis of RGC dendritic field and cell number were evaluated at the end of the study. Visual outcome measures also were evaluated based on treatment of mice with P7C3-S243 or vehicle control. We show that deficits in neutral position PERG after blast-mediated TBI occur in a temporally bimodal fashion, with temporary recovery 4 weeks after injury followed by chronically persistent dysfunction 12 weeks later. This later time point is associated with development of dendritic abnormalities and irreversible death of RGCs. We also demonstrate that ongoing pathologic processes during the temporary recovery latent period (including abnormalities of RGC physiology) lead to future dysfunction of the visual system. We report that modification of PERG to provocative postural tilt testing elicits changes in PERG measurements that correlate with a key in vitro measures of damage: the spontaneous and light-evoked activity of RGCs. Treatment with P7C3-S243 immediately after injury and throughout the temporary recovery latent period protects mice from developing chronic visual system dysfunction. Provocative PERG testing serves as a noninvasive test in the living organism to identify early damage to the visual system, which may reflect corresponding damage in the brain that is not otherwise detectable by noninvasive means. This provides the basis for developing an earlier diagnostic test to identify patients at risk for developing chronic CNS and visual system damage after TBI at an earlier stage when treatments may be more effective in preventing these sequelae. In addition, treatment with the neuroprotective agent P7C3-S243 after TBI protects from visual system dysfunction after TBI. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Early Detection of Subclinical Visual Damage After Blast-Mediated TBI Enables Prevention of Chronic Visual Deficit by Treatment With P7C3-S243

PubMed Central

Dutca, Laura M.; Stasheff, Steven F.; Hedberg-Buenz, Adam; Rudd, Danielle S.; Batra, Nikhil; Blodi, Frederick R.; Yorek, Matthew S.; Yin, Terry; Shankar, Malini; Herlein, Judith A.; Naidoo, Jacinth; Morlock, Lorraine; Williams, Noelle; Kardon, Randy H.; Anderson, Michael G.; Pieper, Andrew A.; Harper, Matthew M.

2014-01-01

Purpose. Traumatic brain injury (TBI) frequently leads to chronic visual dysfunction. The purpose of this study was to investigate the effect of TBI on retinal ganglion cells (RGCs), and to test whether treatment with the novel neuroprotective compound P7C3-S243 could prevent in vivo functional deficits in the visual system. Methods. Blast-mediated TBI was modeled using an enclosed over-pressure blast chamber. The RGC physiology was evaluated using a multielectrode array and pattern electroretinogram (PERG). Histological analysis of RGC dendritic field and cell number were evaluated at the end of the study. Visual outcome measures also were evaluated based on treatment of mice with P7C3-S243 or vehicle control. Results. We show that deficits in neutral position PERG after blast-mediated TBI occur in a temporally bimodal fashion, with temporary recovery 4 weeks after injury followed by chronically persistent dysfunction 12 weeks later. This later time point is associated with development of dendritic abnormalities and irreversible death of RGCs. We also demonstrate that ongoing pathologic processes during the temporary recovery latent period (including abnormalities of RGC physiology) lead to future dysfunction of the visual system. We report that modification of PERG to provocative postural tilt testing elicits changes in PERG measurements that correlate with a key in vitro measures of damage: the spontaneous and light-evoked activity of RGCs. Treatment with P7C3-S243 immediately after injury and throughout the temporary recovery latent period protects mice from developing chronic visual system dysfunction. Conclusions. Provocative PERG testing serves as a noninvasive test in the living organism to identify early damage to the visual system, which may reflect corresponding damage in the brain that is not otherwise detectable by noninvasive means. This provides the basis for developing an earlier diagnostic test to identify patients at risk for developing chronic CNS and visual system damage after TBI at an earlier stage when treatments may be more effective in preventing these sequelae. In addition, treatment with the neuroprotective agent P7C3-S243 after TBI protects from visual system dysfunction after TBI. PMID:25468886

Direct peritoneal resuscitation improves inflammation, liver blood flow, and pulmonary edema in a rat model of acute brain death.

PubMed

Smith, Jason W; Ghazi, Cameron A; Cain, Brandon C; Hurt, Ryan T; Garrison, R Neal; Matheson, Paul J

2014-07-01

Brain death in organ donors alters central hemodynamic performance, impairs physiology, exaggerates inflammation, and causes end-organ microcirculatory dysfunction and hypoxia. A new treatment, direct peritoneal resuscitation (DPR), might improve these derangements in acute brain death (ABD). We studied a standardized rodent model of brain death with matched controls to assess the efficacy of DPR as a resuscitation strategy after ABD. Anesthetized Sprague-Dawley rats were randomized as follows: ABD (supradural balloon inflation) with minimal IV fluid (IVF; 2 mL/h, n = 12); ABD + adequate IVF (5 mL/h, n = 12); ABD with aggressive IVF (goal: mean arterial pressure [MAP] >80 mmHg, n = 15); or ABD + IVF + DPR (goal: MAP >80 mmHg, n = 12). Ventilation support, IVF, and DPR were started at loss of reflexes, and MAP, heart rate, and effective hepatic blood flow were recorded. High IVF and DPR prevented mortality (0%) compared with low IVF (81.8%) or mid IVF (16.7%). Effective hepatic blood flow was decreased in low and mid IVF (2.8 ± 0.3 mL/min/g body weight and 4.0 ± 0.5 mL/min/g body weight, respectively) vs baseline, but was stable in high IVF (6.2 ± 0.5 mL/min/g body weight; NS) or improved with DPR (8.6 ± 0.7 mL/min/g body weight). The high-IVF group had significant organ edema, which was prevented in the DPR group. The mid-IVF and low-IVF groups had higher serum markers of organ injury compared with high-IVF or DPR groups. The high-IVF group had elevated inflammatory cytokines compared with the DPR group. Direct peritoneal resuscitation improved survival and effective hepatic blood flow, required less IVF to stabilize blood pressure, prevented organ edema, and normalized fluid electrolyte balance compared with IVF-alone groups. Direct peritoneal resuscitation in animals reduced inflammatory response after ABD compared with IVF-alone controls. These data suggest a potential role for DPR in organ donors to stabilize donors and possibly increase the number of organs suitable for transplantation per donor. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Neural Mechanisms Underlying Lower Urinary Tract Dysfunction

PubMed Central

Ogawa, Teruyuki; Miyazato, Minoru; Kitta, Takeya; Furuta, Akira; Chancellor, Michael B.; Tyagi, Pradeep

2014-01-01

This article summarizes anatomical, neurophysiological, and pharmacological studies in humans and animals to provide insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract and alterations in these mechanisms in lower urinary tract dysfunction. The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Therefore, injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce lower urinary tract dysfunction, leading to lower urinary tract symptoms, including both storage and voiding symptoms, and pelvic pain. Neuroplasticity underlying pathological changes in lower urinary tract function is discussed. PMID:24578802

Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation.

PubMed

Wang, Janice C; Bindokas, Vytautas P; Skinner, Matthew; Emrick, Todd; Marks, Jeremy D

2017-10-01

Global brain ischemia can lead to widespread neuronal death and poor neurologic outcomes in patients. Despite detailed understanding of the cellular and molecular mechanisms mediating neuronal death following focal and global brain hypoxia-ischemia, treatments to reduce ischemia-induced brain injury remain elusive. One pathway central to neuronal death following global brain ischemia is mitochondrial dysfunction, one consequence of which is the cascade of intracellular events leading to mitochondrial outer membrane permeabilization. A novel approach to rescuing injured neurons from death involves targeting cellular membranes using a class of synthetic molecules called Pluronics. Pluronics are triblock copolymers of hydrophilic poly[ethylene oxide] (PEO) and hydrophobic poly[propylene oxide] (PPO). Evidence is accumulating to suggest that hydrophilic Pluronics rescue injured neurons from death following substrate deprivation by preventing mitochondrial dysfunction. Here, we will review current understanding of the nature of interaction of Pluronic molecules with biological membranes and the efficacy of F-68, an 80% hydrophilic Pluronic, in rescuing neurons from injury. We will review data indicating that F-68 reduces mitochondrial dysfunction and mitochondria-dependent death pathways in a model of neuronal injury in vitro, and present new evidence that F-68 acts directly on mitochondria to inhibit mitochondrial outer membrane permeabilization. Finally, we will present results of a pilot, proof-of-principle study suggesting that F-68 is effective in reducing hippocampal injury induced by transient global ischemia in vivo. By targeting mitochondrial dysfunction, F-68 and other Pluronic molecules constitute an exciting new approach to rescuing neurons from acute injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

Postoperative Structural Brain Changes and Cognitive Dysfunction in Patients with Breast Cancer.

PubMed

Sato, Chiho; Sekiguchi, Atsushi; Kawai, Masaaki; Kotozaki, Yuka; Nouchi, Rui; Tada, Hiroshi; Takeuchi, Hikaru; Ishida, Takanori; Taki, Yasuyuki; Kawashima, Ryuta; Ohuchi, Noriaki

2015-01-01

The primary purpose of this study was to clarify the influence of the early response to surgery on brain structure and cognitive function in patients with breast cancer. It was hypothesized that the structure of the thalamus would change during the early response after surgery due to the effects of anesthesia and would represent one aspect of an intermediate phenotype of postoperative cognitive dysfunction (POCD). We examined 32 postmenopausal females with breast cancer and 20 age-matched controls. We assessed their cognitive function (attention, memory, and executive function), and performed brain structural MRI 1.5 ± 0.5 days before and 5.6 ± 1.2 days after surgery. We found a significant interaction between regional grey matter volume (rGMV) in the thalamus (P < 0.05, familywise error (FWE), small volume correction (SVC)) and one attention domain subtest (P = 0.001, Bonferroni correction) after surgery in the patient group compared with the control group. Furthermore, the changes in attention were significantly associated with sevoflurane anesthetic dose (r2 = 0.247, β = ‒0.471, P = 0.032) and marginally associated with rGMV changes in the thalamus (P = 0.07, FWE, SVC) in the Pt group. Our findings suggest that alterations in brain structure, particularly in the thalamus, may occur shortly after surgery and may be associated with attentional dysfunction. This early postoperative response to anesthesia may represent an intermediate phenotype of POCD. It was assumed that patients experiencing other risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments, would develop clinical POCD with broad and multiple types of cognitive dysfunction.

Cognitive Visual Dysfunctions in Preterm Children with Periventricular Leukomalacia

ERIC Educational Resources Information Center

Fazzi, Elisa; Bova, Stefania; Giovenzana, Alessia; Signorini, Sabrina; Uggetti, Carla; Bianchi, Paolo

2009-01-01

Aim: Cognitive visual dysfunctions (CVDs) reflect an impairment of the capacity to process visual information. The question of whether CVDs might be classifiable according to the nature and distribution of the underlying brain damage is an intriguing one in child neuropsychology. Method: We studied 22 children born preterm (12 males, 10 females;…

Prevalence of hypothalamo pituitary dysfunction in patients of traumatic brain injury

PubMed Central

Hari Kumar, K. V. S.; Swamy, M. N.; Khan, M. A.

2016-01-01

Background: Traumatic brain injury (TBI) is common in young soldiers of armed forces leading to significant morbidity and mortality. We studied the prevalence of hypopituitarism following TBI and its association with trauma severity. Materials and Methods: We conducted a 12-month prospective study of 56 TBI patients for the presence of hormonal dysfunction. Hormonal parameters were estimated during the early phase (0–10 days posttraumatically) and after 6 and 12 months. Dynamic testing was done when required, and the results were analyzed by appropriate statistical methods. Results: Hormonal dysfunction was seen in 39 of the 56 (70%) patients at initial assessment. Persisting pituitary deficiencies are seen in 7 and 8 patients at the end of 6 months and 12 months, respectively. Hypogonadotropic hypogonadism, hypothyroidism, and growth hormone deficiency are the most common diagnoses. Initial severe TBI and plurihormonal involvement predicted the long-term hypopituitarism. Conclusion: Early hypopituitarism was common in severe TBI, but recovers in majority. Evaluation for the occult pituitary dysfunction is required during the rehabilitation of TBI patients. PMID:27867878

Heparin-Binding Protein Measurement Improves the Prediction of Severe Infection With Organ Dysfunction in the Emergency Department

PubMed Central

Arnold, Ryan; Boyd, John H.; Zindovic, Marko; Zindovic, Igor; Lange, Anna; Paulsson, Magnus; Nyberg, Patrik; Russell, James A.; Pritchard, David; Christensson, Bertil; Åkesson, Per

2015-01-01

Objectives: Early identification of patients with infection and at risk of developing severe disease with organ dysfunction remains a difficult challenge. We aimed to evaluate and validate the heparin-binding protein, a neutrophil-derived mediator of vascular leakage, as a prognostic biomarker for risk of progression to severe sepsis with circulatory failure in a multicenter setting. Design: A prospective international multicenter cohort study. Setting: Seven different emergency departments in Sweden, Canada, and the United States. Patients: Adult patients with a suspected infection and at least one of three clinical systemic inflammatory response syndrome criteria (excluding leukocyte count). Intervention: None. Measurements and Main Results: Plasma levels of heparin-binding protein, procalcitonin, C-reactive protein, lactate, and leukocyte count were determined at admission and 12–24 hours after admission in 759 emergency department patients with suspected infection. Patients were defined depending on the presence of infection and organ dysfunction. Plasma samples from 104 emergency department patients with suspected sepsis collected at an independent center were used to validate the results. Of the 674 patients diagnosed with an infection, 487 did not have organ dysfunction at enrollment. Of these 487 patients, 141 (29%) developed organ dysfunction within the 72-hour study period; 78.0% of the latter patients had an elevated plasma heparin-binding protein level (> 30 ng/mL) prior to development of organ dysfunction (median, 10.5 hr). Compared with other biomarkers, heparin-binding protein was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve = 0.80). The performance of heparin-binding protein was confirmed in the validation cohort. Conclusion: In patients presenting at the emergency department, heparin-binding protein is an early indicator of infection-related organ dysfunction and a strong predictor of disease progression to severe sepsis within 72 hours. PMID:26468696

Function and Dysfunction of Prefrontal Brain Circuitry in Alcoholic Korsakoff’s Syndrome

PubMed Central

Oscar-Berman, Marlene

2013-01-01

The signature symptom of alcohol-induced persisting amnestic disorder, more commonly referred to as alcoholic Korsakoff’s syndrome (KS), is anterograde amnesia, or memory loss for recent events, and until the mid 20th Century, the putative brain damage was considered to be in diencephalic and medial temporal lobe structures. Overall intelligence, as measured by standardized IQ tests, usually remains intact. Preservation of IQ occurs because memories formed before the onset of prolonged heavy drinking — the types of information and abilities tapped by intelligence tests — remain relatively well preserved compared with memories recently acquired. However, clinical and experimental evidence has shown that neurobehavioral dysfunction in alcoholic patients with KS does include nonmnemonic abilities, and further brain damage involves extensive frontal and limbic circuitries. Among the abnormalities are confabulation, disruption of elements of executive functioning and cognitive control, and emotional impairments. Here, we discuss the relationship between neurobehavioral impairments in KS and alcoholism-related brain damage. More specifically, we examine the role of damage to prefrontal brain systems in the neuropsychological profile of alcoholic KS. PMID:22538385

A greater focus on metals in biomedicine and neuroscience is needed.

PubMed

White, Anthony R

2016-11-05

Metals have many essential functions in the brain and a large body of evidence supports important roles for altered metal stasis in many brain disorders. However, despite this evidence, acceptance of metals as key mediators of brain dysfunction is largely lacking in mainstream biomedicine. This editorial will outline the possible reasons for this and suggest potential means to improve the acceptance of metals as central players in brain disease.

Frequency-specific alterations in functional connectivity in treatment-resistant and -sensitive major depressive disorder.

PubMed

He, Zongling; Cui, Qian; Zheng, Junjie; Duan, Xujun; Pang, Yajing; Gao, Qing; Han, Shaoqiang; Long, Zhiliang; Wang, Yifeng; Li, Jiao; Wang, Xiao; Zhao, Jingping; Chen, Huafu

2016-11-01

Major depressive disorder (MDD) may involve alterations in brain functional connectivity in multiple neural circuits and present large-scale network dysfunction. Patients with treatment-resistant depression (TRD) and treatment-sensitive depression (TSD) show different responses to antidepressants and aberrant brain functions. This study aims to investigate functional connectivity patterns of TRD and TSD at the whole brain resting state. Seventeen patients with TRD, 17 patients with TSD, and 17 healthy controls matched with age, gender, and years of education were recruited in this study. The brain was divided using an automated anatomical labeling atlas into 90 regions of interest, which were used to construct the entire brain functional networks. An analysis method called network-based statistic was used to explore the dysconnected subnetworks of TRD and TSD at different frequency bands. At resting state, TSD and TRD present characteristic patterns of network dysfunction at special frequency bands. The dysconnected subnetwork of TSD mainly lies in the fronto-parietal top-down control network. Moreover, the abnormal neural circuits of TRD are extensive and complex. These circuits not only depend on the abnormal affective network but also involve other networks, including salience network, auditory network, visual network, and language processing cortex. Our findings reflect that the pathological mechanism of TSD may refer to impairment in cognitive control, whereas TRD mainly triggers the dysfunction of emotion processing and affective cognition. This study reveals that differences in brain functional connectivity at resting state reflect distinct pathophysiological mechanisms in TSD and TRD. These findings may be helpful in differentiating two types of MDD and predicting treatment responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

PubMed

Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

2016-12-01

Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats.

PubMed

Sa-Nguanmoo, Piangkwan; Tanajak, Pongpan; Kerdphoo, Sasiwan; Jaiwongkam, Thidarat; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-10-15

Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Event-Related Oscillations in Alcoholism Research: A Review

PubMed Central

Pandey, Ashwini K; Kamarajan, Chella; Rangaswamy, Madhavi; Porjesz, Bernice

2013-01-01

Alcohol dependence is characterized as a multi-factorial disorder caused by a complex interaction between genetic and environmental liabilities across development. A variety of neurocognitive deficits/dysfunctions involving impairments in different brain regions and/or neural circuitries have been associated with chronic alcoholism, as well as with a predisposition to develop alcoholism. Several neurobiological and neurobehavioral approaches and methods of analyses have been used to understand the nature of these neurocognitive impairments/deficits in alcoholism. In the present review, we have examined relatively novel methods of analyses of the brain signals that are collectively referred to as event-related oscillations (EROs) and show promise to further our understanding of human brain dynamics while performing various tasks. These new measures of dynamic brain processes have exquisite temporal resolution and allow the study of neural networks underlying responses to sensory and cognitive events, thus providing a closer link to the physiology underlying them. Here, we have reviewed EROs in the study of alcoholism, their usefulness in understanding dynamical brain functions/dysfunctions associated with alcoholism as well as their utility as effective endophenotypes to identify and understand genes associated with both brain oscillations and alcoholism. PMID:24273686

Evidence of Cognitive Dysfunction after Soccer Playing with Ball Heading Using a Novel Tablet-Based Approach

PubMed Central

Lin, Angela H.; Patel, Saumil S.; Sereno, Anne B.

2013-01-01

Does frequent head-to-ball contact cause cognitive dysfunctions and brain injury to soccer players? An iPad-based experiment was designed to examine the impact of ball-heading among high school female soccer players. We examined both direct, stimulus-driven, or reflexive point responses (Pro-Point) as well as indirect, goal-driven, or voluntary point responses (Anti-Point), thought to require cognitive functions in the frontal lobe. The results show that soccer players were significantly slower than controls in the Anti-Point task but displayed no difference in Pro-Point latencies, indicating a disruption specific to voluntary responses. These findings suggest that even subconcussive blows in soccer can result in cognitive function changes that are consistent with mild traumatic brain injury of the frontal lobes. There is great clinical and practical potential of a tablet-based application for quick detection and monitoring of cognitive dysfunction. PMID:23460843

Application of the Multicontextual Approach in Promoting Learning and Transfer of Strategy Use in an Individual with TBI and Executive Dysfunction.

PubMed

Toglia, Joan; Goverover, Yael; Johnston, Mark V; Dain, Barry

2011-01-01

The multicontext approach addresses strategy use and self-monitoring skills within activities and contexts that are systematically varied to facilitate transfer of learning. This article illustrates the application of the multicontext approach by presenting a case study of an adult who is 5 years post-traumatic brain injury with executive dysfunction and limited awareness. A single case study design with repeated pre-post measures was used. Methods to monitor strategy generation and specific awareness within intervention are described. Findings suggest improved functional performance and generalization of use of an external strategy despite absence of changes in general self-awareness of deficits. This case describes the multicontext intervention process and provides clinical suggestions for working with individuals with serious deficits in awareness and executive dysfunction following traumatic brain injury. Copyright 2011, SLACK Incorporated.

Dietary Capsaicin Protects Cardiometabolic Organs from Dysfunction

PubMed Central

Sun, Fang; Xiong, Shiqiang; Zhu, Zhiming

2016-01-01

Chili peppers have a long history of use for flavoring, coloring, and preserving food, as well as for medical purposes. The increased use of chili peppers in food is very popular worldwide. Capsaicin is the major pungent bioactivator in chili peppers. The beneficial effects of capsaicin on cardiovascular function and metabolic regulation have been validated in experimental and population studies. The receptor for capsaicin is called the transient receptor potential vanilloid subtype 1 (TRPV1). TRPV1 is ubiquitously distributed in the brain, sensory nerves, dorsal root ganglia, bladder, gut, and blood vessels. Activation of TRPV1 leads to increased intracellular calcium signaling and, subsequently, various physiological effects. TRPV1 is well known for its prominent roles in inflammation, oxidation stress, and pain sensation. Recently, TRPV1 was found to play critical roles in cardiovascular function and metabolic homeostasis. Experimental studies demonstrated that activation of TRPV1 by capsaicin could ameliorate obesity, diabetes, and hypertension. Additionally, TRPV1 activation preserved the function of cardiometabolic organs. Furthermore, population studies also confirmed the beneficial effects of capsaicin on human health. The habitual consumption of spicy foods was inversely associated with both total and certain causes of specific mortality after adjustment for other known or potential risk factors. The enjoyment of spicy flavors in food was associated with a lower prevalence of obesity, type 2 diabetes, and cardiovascular diseases. These results suggest that capsaicin and TRPV1 may be potential targets for the management of cardiometabolic vascular diseases and their related target organs dysfunction. PMID:27120617

Epilepsy and brain tumors

PubMed Central

ENGLOT, DARIO J.; CHANG, EDWARD F.; VECHT, CHARLES J.

2016-01-01

Seizures are common in patients with brain tumors, and epilepsy can significantly impact patient quality of life. Therefore, a thorough understanding of rates and predictors of seizures, and the likelihood of seizure freedom after resection, is critical in the treatment of brain tumors. Among all tumor types, seizures are most common with glioneuronal tumors (70–80%), particularly in patients with frontotemporal or insular lesions. Seizures are also common in individuals with glioma, with the highest rates of epilepsy (60–75%) observed in patients with low-grade gliomas located in superficial cortical or insular regions. Approximately 20–50% of patients with meningioma and 20–35% of those with brain metastases also suffer from seizures. After tumor resection, approximately 60–90% are rendered seizure-free, with most favorable seizure outcomes seen in individuals with glioneuronal tumors. Gross total resection, earlier surgical therapy, and a lack of generalized seizures are common predictors of a favorable seizure outcome. With regard to anticonvulsant medication selection, evidence-based guidelines for the treatment of focal epilepsy should be followed, and individual patient factors should also be considered, including patient age, sex, organ dysfunction, comorbidity, or cotherapy. As concomitant chemotherapy commonly forms an essential part of glioma treatment, enzyme-inducing anticonvulsants should be avoided when possible. Seizure freedom is the ultimate goal in the treatment of brain tumor patients with epilepsy, given the adverse effects of seizures on quality of life. PMID:26948360

Creativity, brain, and art: biological and neurological considerations.

PubMed

Zaidel, Dahlia W

2014-01-01

Creativity is commonly thought of as a positive advance for society that transcends the status quo knowledge. Humans display an inordinate capacity for it in a broad range of activities, with art being only one. Most work on creativity's neural substrates measures general creativity, and that is done with laboratory tasks, whereas specific creativity in art is gleaned from acquired brain damage, largely in observing established visual artists, and some in visual de novo artists (became artists after the damage). The verb "to create" has been erroneously equated with creativity; creativity, in the classic sense, does not appear to be enhanced following brain damage, regardless of etiology. The turning to communication through art in lieu of language deficits reflects a biological survival strategy. Creativity in art, and in other domains, is most likely dependent on intact and healthy knowledge and semantic conceptual systems, which are represented in several pathways in the cortex. It is adversely affected when these systems are dysfunctional, for congenital reasons (savant autism) or because of acquired brain damage (stroke, dementia, Parkinson's), whereas inherent artistic talent and skill appear less affected. Clues to the neural substrates of general creativity and specific art creativity can be gleaned from considering that art is produced spontaneously mainly by humans, that there are unique neuroanatomical and neurofunctional organizations in the human brain, and that there are biological antecedents of innovation in animals.

Creativity, brain, and art: biological and neurological considerations

PubMed Central

Zaidel, Dahlia W.

2014-01-01

Creativity is commonly thought of as a positive advance for society that transcends the status quo knowledge. Humans display an inordinate capacity for it in a broad range of activities, with art being only one. Most work on creativity’s neural substrates measures general creativity, and that is done with laboratory tasks, whereas specific creativity in art is gleaned from acquired brain damage, largely in observing established visual artists, and some in visual de novo artists (became artists after the damage). The verb “to create” has been erroneously equated with creativity; creativity, in the classic sense, does not appear to be enhanced following brain damage, regardless of etiology. The turning to communication through art in lieu of language deficits reflects a biological survival strategy. Creativity in art, and in other domains, is most likely dependent on intact and healthy knowledge and semantic conceptual systems, which are represented in several pathways in the cortex. It is adversely affected when these systems are dysfunctional, for congenital reasons (savant autism) or because of acquired brain damage (stroke, dementia, Parkinson’s), whereas inherent artistic talent and skill appear less affected. Clues to the neural substrates of general creativity and specific art creativity can be gleaned from considering that art is produced spontaneously mainly by humans, that there are unique neuroanatomical and neurofunctional organizations in the human brain, and that there are biological antecedents of innovation in animals. PMID:24917807

Cognitive control dysfunction in emotion dysregulation and psychopathology of major depression (MD): Evidence from transcranial brain stimulation of the dorsolateral prefrontal cortex (DLPFC).

PubMed

Salehinejad, Mohammad Ali; Ghanavai, Elham; Rostami, Reza; Nejati, Vahid

2017-03-01

Previous studies showed that MD is associated with a variety of cognitive deficits and executive dysfunctions which can persist even in remitted states. However, the role of cognitive impairments in MD psychopathology and treatment is not fully understood. This article aims to discuss how executive functions central components (e.g., Working memory and attention) mediate MD psychopathology considering the role of dorsolateral prefrontal cortex (dLPFC) and present findings of a brain stimulation experiment to support this notion. The effect of transcranial direct current stimulation (tDCS) of the dLPFC on enhancing cognitive control functions was investigated. Twenty-four patients with MD (Experimental group=12, Control group=12) received 10 sessions of tDCS (2mA for 30min) over 10 consecutive days. The experimental group received active stimulation and the control group received sham stimulation. Participant's performance on cognitive functions (PAL, SRM, RVP and CRT from CANTAB) and their depression scores were assessed before and after tDCS. Results showed that brain stimulation of the dLPFC improved executive dysfunction in patients and a significant improvement on depression scores was also observed suggesting that cognitive control dysfunction may be a mediator in emotional dysregulation and psychopathology of MD. No follow-up investigation was done in this study which does not allow to infer long-term effect of tDCS. Low-focality of tDCS might have stimulated adjacent areas too. Cognitive components, namely cognitive control dysfunction, play role in MD psychopathology as they are involved in emotion dysregulation in MD. The amount of contribution of cognitive components in MD psychopathology is however, an open question. tDCS can be used as an intervention to improve cognitive dysfunction in MD. Copyright © 2017 Elsevier B.V. All rights reserved.

Spatial Working Memory Impairment in Patients with Non-neuropsychiatric Systemic Lupus Erythematosus: A Blood-oxygen-level Dependent Functional Magnetic Resonance Imaging Study.

PubMed

Zhu, Chun-Min; Ma, Ye; Xie, Lei; Huang, Jin-Zhuang; Sun, Zong-Bo; Duan, Shou-Xing; Lin, Zhi-Rong; Yin, Jing-Jing; Le, Hong-Bo; Sun, Dan-Miao; Xu, Wen-Can; Ma, Shu-Hua

2017-02-01

Using ethology and functional magnetic resonance imaging (fMRI) to explore mild cognitive dysfunction and spatial working memory (WM) impairment in patients with systemic lupus erythematosus (SLE) without overt neuropsychiatric symptoms (non-NPSLE) and to study whether any clinical biomarkers could serve as predictors of brain dysfunction in this disease. Eighteen non-NPSLE patients and 18 matched subjects were all tested using the Montreal cognitive assessment scale test and scanned using blood-oxygen-level dependent fMRI while performing the n-back task to investigate the activation intensity of some cognition-related areas. Ethology results showed that non-NPSLE patients had mild cognitive dysfunction and memory dysfunction (p < 0.05). The fMRI scan confirmed a neural network consisting of bilateral dorsolateral prefrontal cortex (DLPFC), premotor area, parietal lobe, and supplementary motor area (SMA)/anterior cingulate cortex (ACC) that was activated during the n-back task, with right hemisphere dominance. However, only the right SMA/ACC showed a load effect in the non-NPSLE group; the activation intensity of most WM-related brain areas for the non-NPSLE group was lower than for the control group under 3 memory loads. Further, we found that the activation intensity of some cognition-related areas, including the bilateral caudate nucleus/insula and hippocampus/parahippocampal gyrus were lower than the control group under the memory loads. An inverse correlation existed between individual activation intensity and disease duration. Non-NPSLE-related brain damage with right DLPFC-posterior parietal lobe and parahippocampal gyrus default network causes impairment of spatial WM and mild cognitive dysfunction. Patients with longer disease duration would be expected to exhibit increased central nervous system damage.

Diffuse traumatic brain injury affects chronic corticosterone function in the rat.

PubMed

Rowe, Rachel K; Rumney, Benjamin M; May, Hazel G; Permana, Paska; Adelson, P David; Harman, S Mitchell; Lifshitz, Jonathan; Thomas, Theresa C

2016-07-01

As many as 20-55% of patients with a history of traumatic brain injury (TBI) experience chronic endocrine dysfunction, leading to impaired quality of life, impaired rehabilitation efforts and lowered life expectancy. Endocrine dysfunction after TBI is thought to result from acceleration-deceleration forces to the brain within the skull, creating enduring hypothalamic and pituitary neuropathology, and subsequent hypothalamic-pituitary endocrine (HPE) dysfunction. These experiments were designed to test the hypothesis that a single diffuse TBI results in chronic dysfunction of corticosterone (CORT), a glucocorticoid released in response to stress and testosterone. We used a rodent model of diffuse TBI induced by midline fluid percussion injury (mFPI). At 2months postinjury compared with uninjured control animals, circulating levels of CORT were evaluated at rest, under restraint stress and in response to dexamethasone, a synthetic glucocorticoid commonly used to test HPE axis regulation. Testosterone was evaluated at rest. Further, we assessed changes in injury-induced neuron morphology (Golgi stain), neuropathology (silver stain) and activated astrocytes (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Resting plasma CORT levels were decreased at 2months postinjury and there was a blunted CORT increase in response to restraint induced stress. No changes in testosterone were measured. These changes in CORT were observed concomitantly with altered complexity of neuron processes in the PVN over time, devoid of neuropathology or astrocytosis. Results provide evidence that a single moderate diffuse TBI leads to changes in CORT function, which can contribute to the persistence of symptoms related to endocrine dysfunction. Future experiments aim to evaluate additional HP-related hormones and endocrine circuit pathology following diffuse TBI. © 2016 The authors.

Diffuse traumatic brain injury affects chronic corticosterone function in the rat

PubMed Central

Rowe, Rachel K; Rumney, Benjamin M; May, Hazel G; Permana, Paska; Adelson, P David; Harman, S Mitchell; Lifshitz, Jonathan

2016-01-01

As many as 20–55% of patients with a history of traumatic brain injury (TBI) experience chronic endocrine dysfunction, leading to impaired quality of life, impaired rehabilitation efforts and lowered life expectancy. Endocrine dysfunction after TBI is thought to result from acceleration–deceleration forces to the brain within the skull, creating enduring hypothalamic and pituitary neuropathology, and subsequent hypothalamic–pituitary endocrine (HPE) dysfunction. These experiments were designed to test the hypothesis that a single diffuse TBI results in chronic dysfunction of corticosterone (CORT), a glucocorticoid released in response to stress and testosterone. We used a rodent model of diffuse TBI induced by midline fluid percussion injury (mFPI). At 2months postinjury compared with uninjured control animals, circulating levels of CORT were evaluated at rest, under restraint stress and in response to dexamethasone, a synthetic glucocorticoid commonly used to test HPE axis regulation. Testosterone was evaluated at rest. Further, we assessed changes in injury-induced neuron morphology (Golgi stain), neuropathology (silver stain) and activated astrocytes (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Resting plasma CORT levels were decreased at 2months postinjury and there was a blunted CORT increase in response to restraint induced stress. No changes in testosterone were measured. These changes in CORT were observed concomitantly with altered complexity of neuron processes in the PVN over time, devoid of neuropathology or astrocytosis. Results provide evidence that a single moderate diffuse TBI leads to changes in CORT function, which can contribute to the persistence of symptoms related to endocrine dysfunction. Future experiments aim to evaluate additional HP-related hormones and endocrine circuit pathology following diffuse TBI. PMID:27317610

LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease.

PubMed

Rothaug, Michelle; Stroobants, Stijn; Schweizer, Michaela; Peters, Judith; Zunke, Friederike; Allerding, Mirka; D'Hooge, Rudi; Saftig, Paul; Blanz, Judith

2015-01-31

The Lysosomal Associated Membrane Protein type-2 (LAMP-2) is an abundant lysosomal membrane protein with an important role in immunity, macroautophagy (MA) and chaperone-mediated autophagy (CMA). Mutations within the Lamp2 gene cause Danon disease, an X-linked lysosomal storage disorder characterized by (cardio)myopathy and intellectual dysfunction. The pathological hallmark of this disease is an accumulation of glycogen and autophagic vacuoles in cardiac and skeletal muscle that, along with the myopathy, is also present in LAMP-2-deficient mice. Intellectual dysfunction observed in the human disease suggests a pivotal role of LAMP-2 within brain. LAMP-2A, one specific LAMP-2 isoform, was proposed to be important for the lysosomal degradation of selective proteins involved in neurodegenerative diseases such as Huntington's and Parkinson's disease. To elucidate the neuronal function of LAMP-2 we analyzed knockout mice for neuropathological changes, MA and steady-state levels of CMA substrates. The absence of LAMP-2 in murine brain led to inflammation and abnormal behavior, including motor deficits and impaired learning. The latter abnormality points to hippocampal dysfunction caused by altered lysosomal activity, distinct accumulation of p62-positive aggregates, autophagic vacuoles and lipid storage within hippocampal neurons and their presynaptic terminals. The absence of LAMP-2 did not apparently affect MA or steady-state levels of selected CMA substrates in brain or neuroblastoma cells under physiological and prolonged starvation conditions. Our data contribute to the understanding of intellectual dysfunction observed in Danon disease patients and highlight the role of LAMP-2 within the central nervous system, particularly the hippocampus.

The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

PubMed Central

Weber, Daniel J.; Allette, Yohance M.; Wilkes, David S.

2015-01-01

Abstract Significance: Deceased patients who have suffered severe traumatic brain injury (TBI) are the largest source of organs for lung transplantation. However, due to severely compromised pulmonary lung function, only one-third of these patients are eligible organ donors, with far fewer capable of donating lungs (∼20%). As a result of this organ scarcity, understanding and controlling the pulmonary pathophysiology of potential donors are key to improving the health and long-term success of transplanted lungs. Recent Advances: Although the exact mechanism by which TBI produces pulmonary pathophysiology remains unclear, it may be related to the release of damage-associated molecular patterns (DAMPs) from the injured tissue. These heterogeneous, endogenous host molecules can be rapidly released from damaged or dying cells and mediate sterile inflammation following trauma. In this review, we highlight the interaction of the DAMP, high-mobility group box protein 1 (HMGB1) with the receptor for advanced glycation end-products (RAGE), and toll-like receptor 4 (TLR4). Critical Issues: Recently published studies are reviewed, implicating the release of HMGB1 as producing marked changes in pulmonary inflammation and physiology following trauma, followed by an overview of the experimental evidence demonstrating the benefits of blocking the HMGB1-RAGE axis. Future Directions: Targeting the HMGB1 signaling axis may increase the number of lungs available for transplantation and improve long-term benefits for organ recipient patient outcomes. Antioxid. Redox Signal. 23, 1316–1328. PMID:25751601

[Immune dysfunction and cognitive deficit in stress and physiological aging. Part II: New approaches to cognitive disorder prevention and treatment ].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

Long-term stress as well as physiological aging result in similar immunological and hormonal disturbances including hypothalamic-pituitary-adrenal) axis depletion, aberrant immune response (regulatory T-cells, Tregs, and T(h17)-lymphocyte accumulation) and decreased dehydroepian-drosterone synthesis both in the brain and in the adrenal glands. Since the main mechanisms of inflammation control, "prompt" (stress hormones) and "delayed" (Tregs), are broken, serum cytokine levels increase and become sufficient for blood-brain-barrier disruption. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Structural and functional alterations of blood-brain-barrier as well as stress- (or age-) induced neuroinflammation promote influx of bone marrow derived dendritic cells and lymphocyte effectors into the brain parenchyma. Thereafter, mass intrusion ofpro-inflammatory mediators and immune cells having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets: 1) reduction of excessive Treg accumulation; 2) supporting hypothalamic-pituitary-adrenal axis and inflammatory reaction attenuation; 3) recovery of dehydroepiandrosterone level; 4) improvement of blood-brain-barrier function.

Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults.

PubMed

Krahulik, David; Zapletalova, Jirina; Frysak, Zdenek; Vaverka, Miroslav

2010-09-01

Traumatic brain injury (TBI) is a major cause of serious morbidity and mortality. The incidence is 100-500/100,000 inhabitants/year. Chronic pituitary dysfunction is increasingly recognized after TBI. To define the incidence of endocrine dysfunction and risk factors, the authors describe a prospectively assessed group of patients in whom they documented hormonal functions, early diagnosis, and treatment of neuroendocrine dysfunction after TBI. Patients aged 18-65 years were prospectively observed from the time of injury to 1 year postinjury; the Glasgow Coma Scale score ranged from 3 to 14. Patients underwent evaluation of hormonal function at the time of injury and at 3, 6, and 12 months postinjury. Magnetic resonance imaging was also conducted at 1 year postinjury. During the study period, 89 patients were observed. The mean age of the patients was 36 years, there were 23 women, and the median Glasgow Coma Scale score was 7. Nineteen patients (21%) had primary hormonal dysfunction. Major deficits included growth hormone dysfunction, hypogonadism, and diabetes insipidus. Patients in whom the deficiency was major had a worse Glasgow Outcome Scale score, and MR imaging demonstrated empty sella syndrome more often than in patients without a deficit. To the authors' knowledge, this is the third largest study of its kind worldwide. The incidence of chronic hypopituitarism after TBI was higher than the authors expected. After TBI, patients are usually observed on the neurological and rehabilitative wards, and endocrine dysfunction can be overlooked. This dysfunction can be life threatening and other clinical symptoms can worsen the neurological deficit, extend the duration of physiotherapy, and lead to mental illness. The authors recommend routine pituitary hormone testing after moderate or severe TBI within 6 months and 1 year of injury.

Early life stress induces attention-deficit hyperactivity disorder (ADHD)-like behavioral and brain metabolic dysfunctions: functional imaging of methylphenidate treatment in a novel rodent model.

PubMed

Bock, J; Breuer, S; Poeggel, G; Braun, K

2017-03-01

In a novel animal model Octodon degus we tested the hypothesis that, in addition to genetic predisposition, early life stress (ELS) contributes to the etiology of attention-deficit hyperactivity disorder-like behavioral symptoms and the associated brain functional deficits. Since previous neurochemical observations revealed that early life stress impairs dopaminergic functions, we predicted that these symptoms can be normalized by treatment with methylphenidate. In line with our hypothesis, the behavioral analysis revealed that repeated ELS induced locomotor hyperactivity and reduced attention towards an emotionally relevant acoustic stimulus. Functional imaging using ( 14 C)-2-fluoro-deoxyglucose-autoradiography revealed that the behavioral symptoms are paralleled by metabolic hypoactivity of prefrontal, mesolimbic and subcortical brain areas. Finally, the pharmacological intervention provided further evidence that the behavioral and metabolic dysfunctions are due to impaired dopaminergic neurotransmission. Elevating dopamine in ELS animals by methylphenidate normalized locomotor hyperactivity and attention-deficit and ameliorated brain metabolic hypoactivity in a dose-dependent manner.

A milk-based wolfberry preparation prevents prenatal stress-induced cognitive impairment of offspring rats, and inhibits oxidative damage and mitochondrial dysfunction in vitro.

PubMed

Feng, Zhihui; Jia, Haiqun; Li, Xuesen; Bai, Zhuanli; Liu, Zhongbo; Sun, Lijuan; Zhu, Zhongliang; Bucheli, Peter; Ballèvre, Olivier; Wang, Junkuan; Liu, Jiankang

2010-05-01

Lycium barbarum (Fructus Lycii, Wolfberry, or Gouqi) belongs to the Solanaceae. The red-colored fruits of L. barbarum have been used for a long time as an ingredient in Chinese cuisine and brewing, and also in traditional Chinese herbal medicine for improving health. However, its effects on cognitive function have not been well studied. In the present study, prevention of a milk-based wolfberry preparation (WP) on cognitive dysfunction was tested in a prenatal stress model with rats and the antioxidant mechanism was tested by in vitro experiments. We found that prenatal stress caused a significant decrease in cognitive function (Morris water maze test) in female offspring. Pretreatment of the mother rats with WP significantly prevented the prenatal stress-induced cognitive dysfunction. In vitro studies showed that WP dose-dependently scavenged hydroxyl and superoxide radicals (determined by an electron spin resonance spectrometric assay), and inhibited FeCl(2)/ascorbic acid-induced dysfunction in brain tissue and tissue mitochondria, including increases in reactive oxygen species and lipid peroxidation and decreases in the activities of complex I, complex II, and glutamate cysteine ligase. These results suggest that dietary supplementation with WP may be an effective strategy for preventing the brain oxidative mitochondrial damage and cognitive dysfunction associated with prenatal stress.

Cingulate, Frontal and Parietal Cortical Dysfunction in Attention-Deficit/Hyperactivity Disorder

PubMed Central

Bush, George

2011-01-01

Functional and structural neuroimaging have identified abnormalities of the brain that are likely to contribute to the neuropathophysiology of attention-deficit/hyperactivity disorder (ADHD). In particular, hypofunction of the brain regions comprising the cingulo-frontal-parietal (CFP) cognitive-attention network have been consistently observed across studies. These are major components of neural systems that are relevant to ADHD, including cognitive/attention networks, motor systems and reward/feedback-based processing systems. Moreover, these areas interact with other brain circuits that have been implicated in ADHD, such as the “default mode” resting state network. ADHD imaging data related to CFP network dysfunction will be selectively highlighted here to help facilitate its integration with the other information presented in this special issue. Together, these reviews will help shed light on the neurobiology of ADHD. PMID:21489409

A Magnetoencephalographic (MEG) Study of Gulf War Illness (GWI).

PubMed

Engdahl, Brian E; James, Lisa M; Miller, Ryan D; Leuthold, Arthur C; Lewis, Scott M; Carpenter, Adam F; Georgopoulos, Apostolos P

2016-10-01

Gulf War Illness (GWI) has affected many Gulf War veterans. It involves several organs, most notably the brain. Neurological-cognitive-mood-related symptoms frequently dominate and are at the root of chronic ill-health and disability in GWI. Here we investigated the neural mechanisms underlying brain dysfunction in GWI in the absence of mental health disorders. Eighty-six veterans completed diagnostic interviews to establish the presence of GWI and assess mental health status. Participants diagnosed with GWI met both Center for Disease Control and Kansas criteria. We studied 46 healthy controls and 40 veterans with GWI without mental illness. They all underwent a resting-state magnetoencephalographic (MEG) scan to assess brain communication based on synchronous neural interactions (SNI; Georgopoulos et al., 2007). We found substantial differences in SNI between control and GWI groups centered on the cerebellum and frontal cortex. In addition, using the maxima and minima of SNI per sensor as predictors, we successfully classified 94.2% of the 86 participants (95% sensitivity, 93.5% specificity). These findings document distinct differences in brain function between control and GWI in the absence of mental health comorbidities, differences that are excellent predictors of GWI. U.S. Department of Veterans Affairs and University of Minnesota. Published by Elsevier B.V.

Stratified active screening: where neurotechnology meets public health.

PubMed

Valdés, Pedro; Obrador-Fragoso, Adianez

2007-10-01

Nearly one quarter of the global burden of disease stems from neurological, psychiatric and neurodevelopmental disorders due to malformations or dysfunctions of the central nervous system.[1] Such neuropsychiatric conditions influence quality of life worldwide, causing one third of years lost due to disability (YDL).[2] Ranging from congenital conditions to dementias of the elderly, these disorders appear throughout the life cycle and also account for a substantial proportion of mortality. Recent advances in neuroimaging and neuroinformatics have opened the way for early identification of dysfunctional brain networks, providing essential information for the early detection, proper diagnosis, treatment selection, and follow-up of people with disabilities due to brain disorders.

Stratified active screening: where neurotechnology meets public health.

PubMed

Valdés, Pedro; Obrador-Fragoso, Adianez

2008-10-01

Nearly one quarter of the global burden of disease stems from neurological, psychiatric and neurodevelopmental disorders due to malformations or dysfunctions of the central nervous system.[1] Such neuropsychiatric conditions influence quality of life worldwide, causing one third of years lost due to disability (YDL).[2] Ranging from congenital conditions to dementias of the elderly, these disorders appear throughout the life cycle and also account for a substantial proportion of mortality. Recent advances in neuroimaging and neuroinformatics have opened the way for early identification of dysfunctional brain networks, providing essential information for the early detection, proper diagnosis, treatment selection, and follow-up of people with disabilities due to brain disorders.

Stratified active screening: where neurotechnology meets public health.

PubMed

Valdés, Pedro; Obrador-Fragoso, Adianez

2009-01-01

Nearly one quarter of the global burden of disease stems from neurological, psychiatric and neurodevelopmental disorders due to malformations or dysfunctions of the central nervous system.[1] Such neuropsychiatric conditions influence quality of life worldwide, causing one third of years lost due to disability (YDL).[2] Ranging from congenital conditions to dementias of the elderly, these disorders appear throughout the life cycle and also account for a substantial proportion of mortality. Recent advances in neuroimaging and neuroinformatics have opened the way for early identification of dysfunctional brain networks, providing essential information for the early detection, proper diagnosis, treatment selection, and follow-up of people with disabilities due to brain disorders.

Pituitary dysfunction following traumatic brain injury: clinical perspectives

PubMed Central

Tanriverdi, Fatih; Kelestimur, Fahrettin

2015-01-01

Traumatic brain injury (TBI) is a well recognized public health problem worldwide. TBI has previously been considered as a rare cause of hypopituitarism, but an increased prevalence of neuroendocrine dysfunction in patients with TBI has been reported during the last 15 years in most of the retrospective and prospective studies. Based on data in the current literature, approximately 15%–20% of TBI patients develop chronic hypopituitarism, which clearly suggests that TBI-induced hypopituitarism is frequent in contrast with previous assumptions. This review summarizes the current data on TBI-induced hypopituitarism and briefly discusses some clinical perspectives on post-traumatic anterior pituitary hormone deficiency. PMID:26251600

MicroRNAs in neuronal function and dysfunction

PubMed Central

Im, Heh-In; Kenny, Paul J.

2012-01-01

MicroRNAs (miRNAs) are small noncoding RNA transcripts expressed throughout the brain that can regulate neuronal gene expression at the post-transcriptional level. Here, we provide an overview of the role for miRNAs in brain development and function, and review evidence suggesting that dysfunction in miRNA signaling contributes to neurodevelopment disorders such as Rett and fragile X syndromes, as well as complex behavioral disorders including schizophrenia, depression and drug addiction. A better understanding of how miRNAs influence the development of neuropsychiatric disorders may reveal fundamental insights into the causes of these devastating illnesses and offer novel targets for therapeutic development. PMID:22436491

[Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

PubMed

Ichikawa, Hiroo

2016-02-01

Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.

Cortical GABAergic neurons are more severely impaired by alkalosis than acidosis

PubMed Central

2013-01-01

Background Acid–base imbalance in various metabolic disturbances leads to human brain dysfunction. Compared with acidosis, the patients suffered from alkalosis demonstrate more severe neurological signs that are difficultly corrected. We hypothesize a causative process that the nerve cells in the brain are more vulnerable to alkalosis than acidosis. Methods The vulnerability of GABAergic neurons to alkalosis versus acidosis was compared by analyzing their functional changes in response to the extracellular high pH and low pH. The neuronal and synaptic functions were recorded by whole-cell recordings in the cortical slices. Results The elevation or attenuation of extracellular pH impaired these GABAergic neurons in terms of their capability to produce spikes, their responsiveness to excitatory synaptic inputs and their outputs via inhibitory synapses. Importantly, the dysfunction of these active properties appeared severer in alkalosis than acidosis. Conclusions The severer impairment of cortical GABAergic neurons in alkalosis patients leads to more critical neural excitotoxicity, so that alkalosis-induced brain dysfunction is difficultly corrected, compared to acidosis. The vulnerability of cortical GABAergic neurons to high pH is likely a basis of severe clinical outcomes in alkalosis versus acidosis. PMID:24314112

Is There Chronic Brain Damage in Retired NFL Players? Neuroradiology, Neuropsychology, and Neurology Examinations of 45 Retired Players

PubMed Central

Casson, Ira R.; Viano, David C.; Haacke, E. Mark; Kou, Zhifeng; LeStrange, Danielle G.

2014-01-01

Background: Neuropathology and surveys of retired National Football League (NFL) players suggest that chronic brain damage is a frequent result of a career in football. There is limited information on the neurological statuses of living retired players. This study aimed to fill the gap in knowledge by conducting in-depth neurological examinations of 30- to 60-year-old retired NFL players. Hypothesis: In-depth neurological examinations of 30- to 60-year-old retired players are unlikely to detect objective clinical abnormalities in the majority of subjects. Study Design: A day-long medical examination was conducted on 45 retired NFL players, including state-of-the-art magnetic resonance imaging (MRI; susceptibility weighted imaging [SWI], diffusion tensor imaging [DTI]), comprehensive neuropsychological and neurological examinations, interviews, blood tests, and APOE (apolipoprotein E) genotyping. Level of Evidence: Level 3. Methods: Participants’ histories focused on neurological and depression symptoms, exposure to football, and other factors that could affect brain function. The neurological examination included Mini-Mental State Examination (MMSE) evaluation of cognitive function and a comprehensive search for signs of dysarthria, pyramidal system dysfunction, extrapyramidal system dysfunction, and cerebellar dysfunction. The Beck Depression Inventory (BDI) and Patient Health Questionnaire (PHQ) measured depression. Neuropsychological tests included pen-and-paper and ImPACT evaluation of cognitive function. Anatomical examination SWI and DTI MRI searched for brain injuries. The results were statistically analyzed for associations with markers of exposure to football and related factors, such as body mass index (BMI), ethanol use, and APOE4 status. Results: The retired players’ ages averaged 45.6 ± 8.9 years (range, 30-60 years), and they had 6.8 ± 3.2 years (maximum, 14 years) of NFL play. They reported 6.9 ± 6.2 concussions (maximum, 25) in the NFL. The majority of retired players had normal clinical mental status and central nervous system (CNS) neurological examinations. Four players (9%) had microbleeds in brain parenchyma identified in SWI, and 3 (7%) had a large cavum septum pellucidum with brain atrophy. The number of concussions/dings was associated with abnormal results in SWI and DTI. Neuropsychological testing revealed isolated impairments in 11 players (24%), but none had dementia. Nine players (20%) endorsed symptoms of moderate or severe depression on the BDI and/or met criteria for depression on PHQ; however, none had dementia, dysarthria, parkinsonism, or cerebellar dysfunction. The number of football-related concussions was associated with isolated abnormalities on the clinical neurological examination, suggesting CNS dysfunction. The APOE4 allele was present in 38% of the players, a larger number than would be expected in the general male population (23%-26%). Conclusion: MRI lesions and neuropsychological impairments were found in some players; however, the majority of retired NFL players had no clinical signs of chronic brain damage. Clinical Relevance: These results need to be reconciled with the prevailing view that a career in football frequently results in chronic brain damage. PMID:25177413

Cardio-renal syndromes: a systematic approach for consensus definition and classification.

PubMed

Ronco, Claudio; Ronco, Federico

2012-03-01

The "Cardio-Renal Syndrome" (CRS) is a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The general definition has been expanded to five subtypes reflecting the primacy of organ dysfunction and the time-frame of the syndrome: CRS type I: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. CRS type II: chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction. CRS type III: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. CRS type IV: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. CRS type V: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. Different pathophysiological mechanisms are involved in the combined dysfunction of heart and kidney in these five types of the syndrome.

Lactate and the Lactate-to-Pyruvate Molar Ratio Cannot Be Used as Independent Biomarkers for Monitoring Brain Energetic Metabolism: A Microdialysis Study in Patients with Traumatic Brain Injuries

PubMed Central

Sahuquillo, Juan; Merino, Maria-Angels; Sánchez-Guerrero, Angela; Arikan, Fuat; Vidal-Jorge, Marian; Martínez-Valverde, Tamara; Rey, Anna; Riveiro, Marilyn; Poca, Maria-Antonia

2014-01-01

Background For decades, lactate has been considered an excellent biomarker for oxygen limitation and therefore of organ ischemia. The aim of the present study was to evaluate the frequency of increased brain lactate levels and the LP ratio (LPR) in a cohort of patients with severe or moderate traumatic brain injury (TBI) subjected to brain microdialysis monitoring to analyze the agreement between these two biomarkers and to indicate brain energy metabolism dysfunction. Methods Forty-six patients with an admission Glasgow coma scale score of ≤13 after resuscitation admitted to a dedicated 10-bed Neurotraumatology Intensive Care Unit were included, and 5305 verified samples of good microdialysis data were analyzed. Results Lactate levels were above 2.5 mmol/L in 56.9% of the samples. The relationships between lactate and the LPR could not be adequately modeled by any linear or non-linear model. Neither Cohen’s kappa nor Gwet’s statistic showed an acceptable agreement between both biomarkers to classify the samples in regard to normal or abnormal metabolism. The dataset was divided into four patterns defined by the lactate concentrations and the LPR. A potential interpretation for these patterns is suggested and discussed. Pattern 4 (low pyruvate levels) was found in 10.7% of the samples and was characterized by a significantly low concentration of brain glucose compared with the other groups. Conclusions Our study shows that metabolic abnormalities are frequent in the macroscopically normal brain in patients with traumatic brain injuries and a very poor agreement between lactate and the LPR when classifying metabolism. The concentration of lactate in the dialysates must be interpreted while taking into consideration the LPR to distinguish between anaerobic metabolism and aerobic hyperglycolysis. PMID:25025772

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia

PubMed Central

LaRosa, Domenic A.; Ellery, Stacey J.; Walker, David W.; Dickinson, Hayley

2017-01-01

Birth asphyxia is a significant global health problem, responsible for ~1.2 million neonatal deaths each year worldwide. Those who survive often suffer from a range of health issues including brain damage—manifesting as cerebral palsy (CP)—respiratory insufficiency, cardiovascular collapse, and renal dysfunction, to name a few. Although the majority of research is directed toward reducing the brain injury that results from intrapartum birth asphyxia, the multi-organ injury observed in surviving neonates is of equal importance. Despite the advent of hypothermia therapy for the treatment of hypoxic–ischemic encephalopathy (HIE), treatment options following asphyxia at birth remain limited, particularly in low-resource settings where the incidence of birth asphyxia is highest. Furthermore, although cooling of the neonate results in improved neurological outcomes for a small proportion of treated infants, it does not provide any benefit to the other organ systems affected by asphyxia at birth. The aim of this review is to summarize the current knowledge of the multi-organ effects of intrapartum asphyxia, with particular reference to the findings from our laboratory using the precocial spiny mouse to model birth asphyxia. Furthermore, we reviewed the current treatments available for neonates who have undergone intrapartum asphyxia, and highlight the emergence of maternal dietary creatine supplementation as a preventative therapy, which has been shown to provide multi-organ protection from birth asphyxia-induced injury in our preclinical studies. This cheap and effective nutritional supplement may be the key to reducing birth asphyxia-induced death and disability, particularly in low-resource settings where current treatments are unavailable. PMID:28261573

Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat.

PubMed

Ferris, Craig F; Morrison, Thomas R; Iriah, Sade; Malmberg, Samantha; Kulkarni, Praveen; Hartner, Jochen C; Trivedi, Malav

2018-01-01

Genetic models of Parkinson's disease (PD) coupled with advanced imaging techniques can elucidate neurobiological disease progression, and can help identify early biomarkers before clinical signs emerge. PTEN-induced putative kinase 1 (PINK1) helps protect neurons from mitochondrial dysfunction, and a mutation in the associated gene is a risk factor for recessive familial PD. The PINK1 knockout (KO) rat is a novel model for familial PD that has not been neuroradiologically characterized for alterations in brain structure/function, alongside behavior, prior to 4 months of age. To identify biomarkers of presymptomatic PD in the PINK1 -/- rat at 3 months using magnetic resonance imaging techniques. At postnatal weeks 12-13; one month earlier than previously reported signs of motor and cognitive dysfunction, this study combined imaging modalities, including assessment of quantitative anisotropy across 171 individual brain areas using an annotated MRI rat brain atlas to identify sites of gray matter alteration between wild-type and PINK1 -/- rats. The olfactory system, hypothalamus, thalamus, nucleus accumbens, and cerebellum showed differences in anisotropy between experimental groups. Molecular analyses revealed reduced levels of glutathione, ATP, and elevated oxidative stress in the substantia nigra, striatum and deep cerebellar nuclei. Mitochondrial genes encoding proteins in Complex IV, along with mRNA levels associated with mitochondrial function and genes involved in glutathione synthesis were reduced. Differences in brain structure did not align with any cognitive or motor impairment. These data reveal early markers, and highlight novel brain regions involved in the pathology of PD in the PINK1 -/- rat before behavioral dysfunction occurs.

Acute allograft failure in thoracic organ transplantation.

PubMed

Jahania, M S; Mullett, T W; Sanchez, J A; Narayan, P; Lasley, R D; Mentzer, R M

2000-01-01

Thoracic organ transplantation is an effective form of treatment for end-stage heart and lung disease. Despite major advances in the field, transplant patients remain at risk for acute allograft dysfunction, a major cause of early and late mortality. The most common causes of allograft failure include primary graft failure secondary to inadequate heart and lung preservation during cold storage, cellular rejection, and various donor-recipient-related factors. During cold storage and early reperfusion, heart and lung allografts are vulnerable to intracellular calcium overload, acidosis, cell swelling, injury mediated by reactive oxygen species, and the inflammatory response. Brain death itself is associated with a reduction in myocardial contractility, and recipient-related factors such as preexisting pulmonary hypertension can lead to acute right heart failure and the pulmonary reimplantation response. The development of new methods to prevent or treat these various causes of acute graft failure could lead to a marked improvement in short- and long-term survival of patients undergoing thoracic organ transplantation.

Dietary choline requirements of women: effects of estrogen and genetic variation123

PubMed Central

Fischer, Leslie M; da Costa, Kerry-Ann; Kwock, Lester; Galanko, Joseph

2010-01-01

Background: Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. Objective: The objective was to determine whether the risk of low choline–related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Design: Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. Results: A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Conclusions: Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546. PMID:20861172

Dietary choline requirements of women: effects of estrogen and genetic variation.

PubMed

Fischer, Leslie M; da Costa, Kerry-Ann; Kwock, Lester; Galanko, Joseph; Zeisel, Steven H

2010-11-01

Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. The objective was to determine whether the risk of low choline-related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546.

Histone Deacetylase Inhibitor Trichostatin A Ameliorated Endotoxin-Induced Neuroinflammation and Cognitive Dysfunction

PubMed Central

Chen, Yeong-Chang; Wei, Tsui-Shan; Sun, Ding-Ping; Wang, Jhi-Joung; Yeh, Ching-Hua

2015-01-01

Excessive production of cytokines by microglia may cause cognitive dysfunction and long-lasting behavioral changes. Activating the peripheral innate immune system stimulates cytokine secretion in the central nervous system, which modulates cognitive function. Histone deacetylases (HDACs) modulate cytokine synthesis and release. Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective. We investigated whether TSA reduces lipopolysaccharide- (LPS-) induced neuroinflammation and cognitive dysfunction. ICR mice were first intraperitoneally (i.p.) injected with vehicle or TSA (0.3 mg/kg). One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg). We analyzed the food and water intake, body weight loss, and sucrose preference of the injected mice and then determined the microglia activation and inflammatory cytokine expression in the brains of LPS-treated mice and LPS-treated BV-2 microglial cells. In the TSA-pretreated mice, microglial activation was lower, anhedonia did not occur, and LPS-induced cognitive dysfunction (anorexia, weight loss, and social withdrawal) was attenuated. Moreover, mRNA expression of HDAC2, HDAC5, indoleamine 2,3-dioxygenase (IDO), TNF-α, MCP-1, and IL-1β in the brain of LPS-challenged mice and in the LPS-treated BV-2 microglial cells was lower. TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression. PMID:26273133

Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain.

PubMed

Li, Ben; Chen, Minjun; Guo, Lin; Yun, Yang; Li, Guangke; Sang, Nan

2017-01-01

Sulfur dioxide (SO 2 ) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. However, there are currently no effective medications targeting the harmful outcomes from chemical inhalation. Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction. Here, we indicated that endogenous 2-AG protected against neuroinflammation in response to SO 2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS). In addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO 2 inhalation by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors. Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO 2 inhalation. Copyright © 2016. Published by Elsevier B.V.

Rehabilitation of Executive Functions in Patients with Chronic Acquired Brain Injury with Goal Management Training, External Cuing, and Emotional Regulation: A Randomized Controlled Trial.

PubMed

Tornås, Sveinung; Løvstad, Marianne; Solbakk, Anne-Kristin; Evans, Jonathan; Endestad, Tor; Hol, Per Kristian; Schanke, Anne-Kristine; Stubberud, Jan

2016-04-01

Executive dysfunction is a common consequence of acquired brain injury (ABI), causing significant disability in daily life. This randomized controlled trial investigated the efficacy of Goal Management Training (GMT) in improving executive functioning in patients with chronic ABI. Seventy patients with a verified ABI and executive dysfunction were randomly allocated to GMT (n=33) or a psycho-educative active control condition, Brain Health Workshop (BHW) (n=37). In addition, all participants received external cueing by text messages. Neuropsychological tests and self-reported questionnaires of executive functioning were administered pre-intervention, immediately after intervention, and at 6 months follow-up. Assessors were blinded to group allocation. Questionnaire measures indicated significant improvement of everyday executive functioning in the GMT group, with effects lasting at least 6 months post-treatment. Both groups improved on the majority of the applied neuropsychological tests. However, improved performance on tests demanding executive attention was most prominent in the GMT group. The results indicate that GMT combined with external cueing is an effective metacognitive strategy training method, ameliorating executive dysfunction in daily life for patients with chronic ABI. The strongest effects were seen on self-report measures of executive functions 6 months post-treatment, suggesting that strategies learned in GMT were applied and consolidated in everyday life after the end of training. Furthermore, these findings show that executive dysfunction can be improved years after the ABI.

Post-Concussion Tools to Assist with Assessment, Treatment, and Return to Duty

DTIC Science & Technology

2014-12-01

cognitively engaged in a challenging mental task. 15. SUBJECT TERMS Dizziness, balance dysfunction, vestibular, sway, instability, falls, physiotherapy ...test battery for monitoring treatment during the physiotherapy and 3) development of an enhanced program of rehabilitation. 2. KEYWORDS...Dizziness, balance dysfunction, vestibular, sway, instability, falls, physiotherapy , tactile cueing, vibrotactile, tactors, mild traumatic brain injury, mTBI

Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives

PubMed Central

Javed, Zeeshan; Qamar, Unaiza; Sathyapalan, Thozhukat

2015-01-01

There is an increasing deliberation regarding hypopituitarism following traumatic brain injury (TBI) and recent data have suggested that pituitary dysfunction is very common among survivors of patients having moderate-severe TBI which may evolve or resolve over time. Due to high prevalence of pituitary dysfunction after moderate-severe TBI and its association with increased morbidity and poor recovery and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences. The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible primary and secondary causes. Results of recent studies focusing on the incidence of hypopituitarism in the acute and chronic phases after TBI are varied in terms of severity and time of occurrence. Although the literature available does not show consistent values and there is difference in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI and patients should be carefully monitored. The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function up to 1 year after TBI. In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation. PMID:26693424

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

PubMed Central

Mittal, Anubhav; Hickey, Anthony JR; Chai, Chau C; Loveday, Benjamin PT; Thompson, Nichola; Dare, Anna; Delahunt, Brett; Cooper, Garth JS; Windsor, John A; Phillips, Anthony RJ

2011-01-01

Introduction Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. Methods Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n = 8), saline control; Group 2 (n = 6), caerulein-induced mild acute pancreatitis; Group 3 (n = 7) sham surgical controls; and Group 4 (n = 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. Results Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. Conclusions The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis. PMID:21492333

Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves.

PubMed

Everaert, K; de Waard, W I Q; Van Hoof, T; Kiekens, C; Mulliez, T; D'herde, C

2010-03-01

Review article. The neuroanatomy and physiology of psychogenic erection, cholinergic versus adrenergic innervation of emission and the predictability of outcome of vibration and electroejaculation require a review and synthesis. University Hospital Belgium. We reviewed the literature with PubMed 1973-2008. Erection, emission and ejaculation are separate phenomena and have different innervations. It is important to realize, which are the afferents and efferents and where the motor neuron of the end organ is located. When interpreting a specific lesion it is important to understand if postsynaptic fibres are intact or not. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. For vibratory-evoked ejaculation, the reflex arch must be complete; for electroejaculation, the postsynaptic neurons (paravertebral ganglia) must be intact. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. In neurogenic disease, a good knowledge of neuroanatomy and physiology makes understanding of sexual dysfunction possible and predictable. The minimal requirement for the success of penile vibration is a preserved reflex arch and the minimal requirement for the success of electroejaculation is the existence of intact post-ganglionic fibres.

Non-Alcoholic Fatty Liver Disease: The Emerging Burden in Cardiometabolic and Renal Diseases.

PubMed

Han, Eugene; Lee, Yong Ho

2017-12-01

As the number of individuals with non-alcoholic fatty liver disease (NAFLD) has increased, the influence of NAFLD on other metabolic diseases has been highlighted. Accumulating epidemiologic evidence indicates that NAFLD not only affects the liver but also increases the risk of extra-hepatic diseases such as type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, hypertension, cardiovascular or cerebrovascular diseases, and chronic kidney disease. Non-alcoholic steatohepatitis, an advanced type of NAFLD, can aggravate these inter-organ relationships and lead to poorer outcomes. NAFLD induces insulin resistance and exacerbates systemic chronic inflammation and oxidative stress, which leads to organ dysfunction in extra-hepatic tissues. Although more research is needed to identify the pathophysiological mechanisms and causal relationship between NAFLD and cardiometabolic and renal diseases, screening for heart, brain, and kidney diseases, risk assessment for diabetes, and a multidisciplinary approach for managing these patients should be highly encouraged. Copyright © 2017 Korean Diabetes Association.

Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task.

PubMed

Tamura, Makoto; Spellman, Timothy J; Rosen, Andrew M; Gogos, Joseph A; Gordon, Joshua A

2017-12-19

Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta-prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty.

Nanotechnology Based Theranostic Approaches in Alzheimer's Disease Management: Current Status and Future Perspective.

PubMed

Ahmad, Javed; Akhter, Sohail; Rizwanullah, Md; Khan, Mohammad Ahmed; Pigeon, Lucie; Addo, Richard T; Greig, Nigel H; Midoux, Patrick; Pichon, Chantal; Kamal, Mohammad Amjad

2017-01-01

Alzheimer's disease (AD), a cognitive dysfunction/dementia state amongst the elders is characterized by irreversible neurodegeneration due to varied pathophysiology. Up till now, anti-AD drugs having different pharmacology have been developed and used in clinic. Yet, these medications are not curative and only lowering the AD associated symptoms. Improvement in treatment outcome required drug targeting across the blood-brain barrier (BBB) to the central nervous system (CNS) in optimal therapeutic concentration. Nanotechnology based diagnostic tools, drug carriers and theranostics offer highly sensitive molecular detection, effective drug targeting and their combination. Over the past decade, significant works have been done in this area and we have seen very remarkable outocome in AD therapy. Various nanoparticles from organic and inorganic nanomaterial category have successfully been investigated against AD. This paper discussed the role of nanoparticles in early detection of AD, effective drug targeting to brain and theranostic (diagnosis and therapy) approaches in AD's management. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Neuroimaging correlates of language network impairment and reorganization in temporal lobe epilepsy

PubMed Central

Balter, S.; Lin, G.; Leyden, K.M.; Paul, B.M.; McDonald, C.R.

2016-01-01

Advanced, noninvasive imaging has revolutionized our understanding of language networks in the brain and is reshaping our approach to the presurgical evaluation of patients with epilepsy. Functional magnetic resonance imaging (fMRI) has had the greatest impact, unveiling the complexity of language organization and reorganization in patients with epilepsy both pre- and postoperatively, while volumetric MRI and diffusion tensor imaging have led to a greater appreciation of structural and microstructural correlates of language dysfunction in different epilepsy syndromes. In this article, we review recent literature describing how unimodal and multimodal imaging has advanced our knowledge of language networks and their plasticity in epilepsy, with a focus on the most frequently studied epilepsy syndrome in adults, temporal lobe epilepsy (TLE). We also describe how new analytic techniques (i.e., graph theory) are leading to a refined characterization of abnormal brain connectivity, and how subject-specific imaging profiles combined with clinical data may enhance the prediction of both seizure and language outcomes following surgical interventions. PMID:27393391

A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.

PubMed

Sripetchwandee, Jirapas; Wongjaikam, Suwakon; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2016-09-22

Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

ADHD- and Medication-Related Brain Activation Effects in Concordantly Affected Parent-Child Dyads with ADHD

ERIC Educational Resources Information Center

Epstein, Jeffery N.; Casey, B. J.; Tonev, Simon T.; Davidson, Matthew C.; Reiss, Allan L.; Garrett, Amy; Hinshaw, Stephen P.; Greenhill, Laurence L.; Glover, Gary; Shafritz, Keith M.; Vitolo, Alan; Kotler, Lisa A.; Jarrett, Matthew A.; Spicer, Julie

2007-01-01

Background: Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological…

To the Cloud! A Grassroots Proposal to Accelerate Brain Science Discovery

PubMed Central

Vogelstein, Joshua T.; Mensh, Brett; Hausser, Michael; Spruston, Nelson; Evans, Alan; Kording, Konrad; Amunts, Katrin; Ebell, Christoph; Muller, Jeff; Telefont, Martin; Hill, Sean; Koushika, Sandhya P.; Cali, Corrado; Valdés-Sosa, Pedro Antonio; Littlewood, Peter; Koch, Christof; Saalfeld, Stephan; Kepecs, Adam; Peng, Hanchuan; Halchenko, Yaroslav O.; Kiar, Gregory; Poo, Mu-Ming; Poline, Jean-Baptiste; Milham, Michael P.; Schaffer, Alyssa Picchini; Gidron, Rafi; Okano, Hideyuki; Calhoun, Vince D; Chun, Miyoung; Kleissas, Dean M.; Vogelstein, R. Jacob; Perlman, Eric; Burns, Randal; Huganir, Richard; Miller, Michael I.

2018-01-01

The revolution in neuroscientific data acquisition is creating an analysis challenge. We propose leveraging cloud-computing technologies to enable large-scale neurodata storing, exploring, analyzing, and modeling. This utility will empower scientists globally to generate and test theories of brain function and dysfunction. PMID:27810005

Developmental Hypothyroidism Reduces the Expression of Activity-Dependent Plasticity Genes in Denate Gyrus of the Adult Following Long Term Potentiation

EPA Science Inventory

Disruption of thyroid hormone (TH) is a known effect of environmental contaminants. Neurotrophins including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been implicated in brain dysfunction resulting from severe developmental TH insufficiency. Neuro...

Risk of Erectile Dysfunction in Transfusion-naive Thalassemia Men

PubMed Central

Chen, Yu-Guang; Lin, Te-Yu; Lin, Cheng-Li; Dai, Ming-Shen; Ho, Ching-Liang; Kao, Chia-Hung

2015-01-01

Abstract Based on the mechanism of pathophysiology, thalassemia major or transfusion-dependent thalassemia patients may have an increased risk of developing organic erectile dysfunction resulting from hypogonadism. However, there have been few studies investigating the association between erectile dysfunction and transfusion-naive thalassemia populations. We constructed a population-based cohort study to elucidate the association between transfusion-naive thalassemia populations and organic erectile dysfunction This nationwide population-based cohort study involved analyzing data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified men with transfusion-naive thalassemia and selected a comparison cohort that was frequency-matched with these according to age, and year of diagnosis thalassemia at a ratio of 1 thalassemia man to 4 control men. We analyzed the risks for transfusion-naive thalassemia men and organic erectile dysfunction by using Cox proportional hazards regression models. In this study, 588 transfusion-naive thalassemia men and 2337 controls were included. Total 12 patients were identified within the thalassaemia group and 10 within the control group. The overall risks for developing organic erectile dysfunction were 4.56-fold in patients with transfusion-naive thalassemia men compared with the comparison cohort after we adjusted for age and comorbidities. Our long-term cohort study results showed that in transfusion-naive thalassemia men, there was a higher risk for the development of organic erectile dysfunction, particularly in those patients with comorbidities. PMID:25837766

Risk of erectile dysfunction in transfusion-naive thalassemia men: a nationwide population-based retrospective cohort study.

PubMed

Chen, Yu-Guang; Lin, Te-Yu; Lin, Cheng-Li; Dai, Ming-Shen; Ho, Ching-Liang; Kao, Chia-Hung

2015-04-01

Based on the mechanism of pathophysiology, thalassemia major or transfusion-dependent thalassemia patients may have an increased risk of developing organic erectile dysfunction resulting from hypogonadism. However, there have been few studies investigating the association between erectile dysfunction and transfusion-naive thalassemia populations. We constructed a population-based cohort study to elucidate the association between transfusion-naive thalassemia populations and organic erectile dysfunction. This nationwide population-based cohort study involved analyzing data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified men with transfusion-naive thalassemia and selected a comparison cohort that was frequency-matched with these according to age, and year of diagnosis thalassemia at a ratio of 1 thalassemia man to 4 control men. We analyzed the risks for transfusion-naive thalassemia men and organic erectile dysfunction by using Cox proportional hazards regression models. In this study, 588 transfusion-naive thalassemia men and 2337 controls were included. Total 12 patients were identified within the thalassaemia group and 10 within the control group. The overall risks for developing organic erectile dysfunction were 4.56-fold in patients with transfusion-naive thalassemia men compared with the comparison cohort after we adjusted for age and comorbidities. Our long-term cohort study results showed that in transfusion-naive thalassemia men, there was a higher risk for the development of organic erectile dysfunction, particularly in those patients with comorbidities.

[Dysfunctional workplace organization and mobbing. 4 representative cases].

PubMed

Albini, Elisa; Benedetti, Laura; Giordano, S; Punzi, Silvia; Cassitto, Maria Grazia

2003-01-01

Stress and psychological harassment at work are increasing worldwide, according to International Agencies (European Community, NIOSH) and to most authors. To describe typical working situations responsible for distress and mobbing, with the aim of early diagnosis and effectiveness of therapy and rehabilitation. Four cases are reported as representative of dysfunctional organization producing distress and pathology or inducing mobbing behavior or mobbing without clear organization responsibilities. In all cases dysfunctional organization appeared to have played a significant role even though not always a direct one. Also, common characteristics were highlighted in the three cases where mobbing was recognized.

Timing of light exposure affects mood and brain circuits

PubMed Central

Bedrosian, T A; Nelson, R J

2017-01-01

Temporal organization of physiology is critical for human health. In the past, humans experienced predictable periods of daily light and dark driven by the solar day, which allowed for entrainment of intrinsic circadian rhythms to the environmental light–dark cycles. Since the adoption of electric light, however, pervasive exposure to nighttime lighting has blurred the boundaries of day and night, making it more difficult to synchronize biological processes. Many systems are under circadian control, including sleep–wake behavior, hormone secretion, cellular function and gene expression. Circadian disruption by nighttime light perturbs those processes and is associated with increasing incidence of certain cancers, metabolic dysfunction and mood disorders. This review focuses on the role of artificial light at night in mood regulation, including mechanisms through which aberrant light exposure affects the brain. Converging evidence suggests that circadian disruption alters the function of brain regions involved in emotion and mood regulation. This occurs through direct neural input from the clock or indirect effects, including altered neuroplasticity, neurotransmission and clock gene expression. Recently, the aberrant light exposure has been recognized for its health effects. This review summarizes the evidence linking aberrant light exposure to mood. PMID:28140399

Mechanisms of CNS invasion and damage by parasites.

PubMed

Kristensson, Krister; Masocha, Willias; Bentivoglio, Marina

2013-01-01

Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection. Copyright © 2013 Elsevier B.V. All rights reserved.

Articulatory rehearsal in verbal working memory: a possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder.

PubMed

Gruber, Oliver; Gruber, Eva; Falkai, Peter

2006-09-11

Recent fMRI studies have identified brain systems underlying different components of working memory in healthy individuals. The aim of this study was to compare the functional integrity of these neural networks in terms of behavioural performance in patients with schizophrenia, schizoaffective disorder and healthy controls. In order to detect specific working memory deficits based on dysfunctions of underlying brain circuits we used the same verbal and visuospatial Sternberg item-recognition tasks as in previous neuroimaging studies. Clinical and performance data from matched groups consisting of 14 subjects each were statistically analyzed. Schizophrenic patients exhibited pronounced impairments of both verbal and visuospatial working memory, whereas verbal working memory performance was preserved in schizoaffective patients. The findings provide first evidence that dysfunction of a brain system subserving articulatory rehearsal could represent a biological marker which differentiates between schizophrenia and schizoaffective disorder.

Clinical review: Neuromonitoring - an update

PubMed Central

2013-01-01

Critically ill patients are frequently at risk of neurological dysfunction as a result of primary neurological conditions or secondary insults. Determining which aspects of brain function are affected and how best to manage the neurological dysfunction can often be difficult and is complicated by the limited information that can be gained from clinical examination in such patients and the effects of therapies, notably sedation, on neurological function. Methods to measure and monitor brain function have evolved considerably in recent years and now play an important role in the evaluation and management of patients with brain injury. Importantly, no single technique is ideal for all patients and different variables will need to be monitored in different patients; in many patients, a combination of monitoring techniques will be needed. Although clinical studies support the physiologic feasibility and biologic plausibility of management based on information from various monitors, data supporting this concept from randomized trials are still required. PMID:23320763

A cognitive neuroscience perspective on psychopathy: evidence for paralimbic system dysfunction.

PubMed

Kiehl, Kent A

2006-06-15

Psychopathy is a complex personality disorder that includes interpersonal and affective traits such as glibness, lack of empathy, guilt or remorse, shallow affect, and irresponsibility, and behavioral characteristics such as impulsivity, poor behavioral control, and promiscuity. Much is known about the assessment of psychopathy; however, relatively little is understood about the relevant brain disturbances. The present review integrates data from studies of behavioral and cognitive changes associated with focal brain lesions or insults and results from psychophysiology, cognitive psychology and cognitive and affective neuroscience in health and psychopathy. The review illustrates that the brain regions implicated in psychopathy include the orbital frontal cortex, insula, anterior and posterior cingulate, amygdala, parahippocampal gyrus, and anterior superior temporal gyrus. The relevant functional neuroanatomy of psychopathy thus includes limbic and paralimbic structures that may be collectively termed 'the paralimbic system'. The paralimbic system dysfunction model of psychopathy is discussed as it relates to the extant literature on psychopathy.

Parkinson's: a syndrome rather than a disease?

PubMed

Titova, Nataliya; Padmakumar, C; Lewis, Simon J G; Chaudhuri, K Ray

2017-08-01

Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder. The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease.

An uncommon case of random fire-setting behavior associated with Todd paralysis: a case report.

PubMed

Kanehisa, Masayuki; Morinaga, Katsuhiko; Kohno, Hisae; Maruyama, Yoshihiro; Ninomiya, Taiga; Ishitobi, Yoshinobu; Tanaka, Yoshihiro; Tsuru, Jusen; Hanada, Hiroaki; Yoshikawa, Tomoya; Akiyoshi, Jotaro

2012-08-31

The association between fire-setting behavior and psychiatric or medical disorders remains poorly understood. Although a link between fire-setting behavior and various organic brain disorders has been established, associations between fire setting and focal brain lesions have not yet been reported. Here, we describe the case of a 24-year-old first time arsonist who suffered Todd's paralysis prior to the onset of a bizarre and random fire-setting behavior. A case of a 24-year-old man with a sudden onset of a bizarre and random fire-setting behavior is reported. The man, who had been arrested on felony arson charges, complained of difficulties concentrating and of recent memory disturbances with leg weakness. A video-EEG recording demonstrated a close relationship between the focal motor impairment and a clear-cut epileptic ictal discharge involving the bilateral motor cortical areas. The SPECT result was statistically analyzed by comparing with standard SPECT images obtained from our institute (easy Z-score imaging system; eZIS). eZIS revealed hypoperfusion in cingulate cortex, basal ganglia and hyperperfusion in frontal cortex,. A neuropsychological test battery revealed lower than normal scores for executive function, attention, and memory, consistent with frontal lobe dysfunction. The fire-setting behavior and Todd's paralysis, together with an unremarkable performance on tests measuring executive function fifteen months prior, suggested a causal relationship between this organic brain lesion and the fire-setting behavior. The case describes a rare and as yet unreported association between random, impulse-driven fire-setting behavior and damage to the brain and suggests a disconnection of frontal lobe structures as a possible pathogenic mechanism.

P-glycoprotein (Mdr1a/1b) and breast cancer resistance protein (Bcrp) decrease the uptake of hydrophobic alkyl triphenylphosphonium cations by the brain

PubMed Central

Porteous, Carolyn M.; Menon, David K.; Aigbirhio, Franklin I.; Smith, Robin A.J.; Murphy, Michael P.

2013-01-01

Background Mitochondrial dysfunction contributes to degenerative neurological disorders, consequently there is a need for mitochondria-targeted therapies that are effective within the brain. One approach to deliver pharmacophores is by conjugation to the lipophilic triphenylphosphonium (TPP) cation that accumulates in mitochondria driven by the membrane potential. While this approach has delivered TPP-conjugated compounds to the brain, the amounts taken up are lower than by other organs. Methods To discover why uptake of hydrophobic TPP compounds by the brain is relatively poor, we assessed the role of the P-glycoprotein (Mdr1a/b) and breast cancer resistance protein (Bcrp) ATP binding cassette (ABC) transporters, which drive the efflux of lipophilic compounds from the brain thereby restricting the uptake of lipophilic drugs. We used a triple transgenic mouse model lacking two isoforms of P-glycoprotein (Mdr1a/1b) and the Bcrp. Results There was a significant increase in the uptake into the brain of two hydrophobic TPP compounds, MitoQ and MitoF, in the triple transgenics following intra venous (IV) administration compared to control mice. Greater amounts of the hydrophobic TPP compounds were also retained in the liver of transgenic mice compared to controls. The uptake into the heart, white fat, muscle and kidneys was comparable between the transgenic mice and controls. Conclusion Efflux of hydrophobic TPP compounds by ABC transporters contributes to their lowered uptake into the brain and liver. General significance These findings suggest that strategies to bypass ABC transporters in the BBB will enhance delivery of mitochondria-targeted antioxidants, probes and pharmacophores to the brain. PMID:23454352

Energy Metabolism and Inflammation in Brain Aging and Alzheimer’s Disease

PubMed Central

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-01-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies. PMID:27154981

Alterations in blood-brain barrier function following acute hypertension: comparison of the blood-to-brain transfer of horseradish peroxidase with that of alpha-aminisobutyric acid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellison, M.D.B.

The blood-brain barrier (BBB) selectively restricts the blood-to-brain passage of many solutes owing to unique properties of cerebrovascular endothelial cell membranes. To date, experimental study of the BBB has been accomplished primarily through the use of two different methodological approaches. Morphological studies have mostly employed large molecular weight (MW) tracers to detect morphological alterations underlying increased permeability. Physiological studies, employing smaller, more physiologic tracers have successfully described, quantitatively, certain functional aspects of blood-to-brain transfer. The current work attempts to merge these two approaches and to consider barrier function/dysfunction from both a morphological and a functional perspective. Specifically, the study comparesmore » in rats, following acute hypertension, the cerebrovascular passage of /sup 14/C-alpha-aminoisobutyric acid (AIB) and that of horseradish peroxidase (HRP). The blood-to-brain passage of AIB and HRP were compared following acute hypertension, with regard to both the distributions of the tracer extravasation patterns and the magnitude of tracer extravasation. The results of this study suggest that traditional morphological barrier studies alone do not reveal all aspects of altered barrier status and that multiple mechanisms underlying increased BBB permeability may operate simultaneously during BBB dysfunction.« less

New Treatment Strategies of Depression: Based on Mechanisms Related to Neuroplasticity

PubMed Central

Lane, Hsien-Yuan

2017-01-01

Major depressive disorder is a severe and complex mental disorder. Impaired neurotransmission and disrupted signalling pathways may influence neuroplasticity, which is involved in the brain dysfunction in depression. Traditional neurobiological theories of depression, such as monoamine hypothesis, cannot fully explain the whole picture of depressive disorders. In this review, we discussed new treatment directions of depression, including modulation of glutamatergic system and noninvasive brain stimulation. Dysfunction of glutamatergic neurotransmission plays an important role in the pathophysiology of depression. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has rapid and lasting antidepressive effects in previous studies. In addition to ketamine, other glutamatergic modulators, such as sarcosine, also show potential antidepressant effect in animal models or clinical trials. Noninvasive brain stimulation is another new treatment strategy beyond pharmacotherapy. Growing evidence has demonstrated that superficial brain stimulations, such as transcranial magnetic stimulation, transcranial direct current stimulation, cranial electrotherapy stimulation, and magnetic seizure therapy, can improve depressive symptoms. The antidepressive effect of these brain stimulations may be through modulating neuroplasticity. In conclusion, drugs that modulate neurotransmission via NMDA receptor and noninvasive brain stimulation may provide new directions of treatment for depression. Furthermore, exploring the underlying mechanisms will help in developing novel therapies for depression in the future. PMID:28491480

Neurosurgery of the future: Deep brain stimulations and manipulations.

PubMed

Nicolaidis, Stylianos

2017-04-01

Important advances are afoot in the field of neurosurgery-particularly in the realms of deep brain stimulation (DBS), deep brain manipulation (DBM), and the newly introduced refinement "closed-loop" deep brain stimulation (CLDBS). Use of closed-loop technology will make both DBS and DBM more precise as procedures and will broaden their indications. CLDBS utilizes as feedback a variety of sources of electrophysiological and neurochemical afferent information about the function of the brain structures to be treated or studied. The efferent actions will be either electric, i.e. the classic excitatory or inhibitory ones, or micro-injection of such things as neural proteins and transmitters, neural grafts, implants of pluripotent stem cells or mesenchymal stem cells, and some variants of gene therapy. The pathologies to be treated, beside Parkinson's disease and movement disorders, include repair of neural tissues, neurodegenerative pathologies, psychiatric and behavioral dysfunctions, i.e. schizophrenia in its various guises, bipolar disorders, obesity, anorexia, drug addiction, and alcoholism. The possibility of using these new modalities to treat a number of cognitive dysfunctions is also under consideration. Because the DBS-CLDBS technology brings about a cross-fertilization between scientific investigation and surgical practice, it will also contribute to an enhanced understanding of brain function. Copyright © 2017. Published by Elsevier Inc.

Cerebral Visual Impairment: Which Perceptive Visual Dysfunctions Can Be Expected in Children with Brain Damage? A Systematic Review

ERIC Educational Resources Information Center

Boot, F. H.; Pel, J. J. M.; van der Steen, J.; Evenhuis, H. M.

2010-01-01

The current definition of Cerebral Visual Impairment (CVI) includes all visual dysfunctions caused by damage to, or malfunctioning of, the retrochiasmatic visual pathways in the absence of damage to the anterior visual pathways or any major ocular disease. CVI is diagnosed by exclusion and the existence of many different causes and symptoms make…

Regional Brain Dysfunction Associated with Semantic Errors in Comprehension.

PubMed

Shahid, Hinna; Sebastian, Rajani; Tippett, Donna C; Saxena, Sadhvi; Wright, Amy; Hanayik, Taylor; Breining, Bonnie; Bonilha, Leonardo; Fridriksson, Julius; Rorden, Chris; Hillis, Argye E

2018-02-01

Here we illustrate how investigation of individuals acutely after stroke, before structure/function reorganization through recovery or rehabilitation, can be helpful in answering questions about the role of specific brain regions in language functions. Although there is converging evidence from a variety of sources that the left posterior-superior temporal gyrus plays some role in spoken word comprehension, its precise role in this function has not been established. We hypothesized that this region is essential for distinguishing between semantically related words, because it is critical for linking the spoken word to the complete semantic representation. We tested this hypothesis in 127 individuals with 48 hours of acute ischemic stroke, before the opportunity for reorganization or recovery. We identified tissue dysfunction (acute infarct and/or hypoperfusion) in gray and white matter parcels of the left hemisphere, and we evaluated the association between rate of semantic errors in a word-picture verification tasks and extent of tissue dysfunction in each region. We found that after correcting for lesion volume and multiple comparisons, the rate of semantic errors correlated with the extent of tissue dysfunction in left posterior-superior temporal gyrus and retrolenticular white matter. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies

PubMed Central

Venkat, Poornima; Chopp, Michael; Zacharek, Alex; Cui, Chengcheng; Zhang, Li; Li, Qingjiang; Lu, Mei; Zhang, Talan; Liu, Amy; Chen, Jieli

2016-01-01

We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia (VaD) using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p<0.05) cognitive decline that worsens with age starting at 2 weeks, which persists until at least 6 weeks after MMI. RB rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 (AQP-4) expression around blood vessels. MMI induced glymphatic dysfunction with delayed cerebrospinal fluid (CSF) penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases AQP-4 and induces glymphatic dysfunction which may play an important role in MMI induced axonal/WM damage and cognitive deficits. PMID:27940353

White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies.

PubMed

Venkat, Poornima; Chopp, Michael; Zacharek, Alex; Cui, Chengcheng; Zhang, Li; Li, Qingjiang; Lu, Mei; Zhang, Talan; Liu, Amy; Chen, Jieli

2017-02-01

We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p < 0.05) cognitive decline that worsens with age starting at 2 weeks, which persists until at least 6 weeks after MMI. RB rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age-matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 expression around blood vessels. MMI-induced glymphatic dysfunction with delayed cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases Aquaporin-4 and induces glymphatic dysfunction which may play an important role in MMI-induced axonal/WM damage and cognitive deficits. Copyright © 2016 Elsevier Inc. All rights reserved.

Cognitive Impairment in Folate-Deficient Rats Corresponds to Depleted Brain Phosphatidylcholine and Is Prevented by Dietary Methionine without Lowering Plasma Homocysteine12

PubMed Central

Troen, Aron M.; Chao, Wei-Hsun; Crivello, Natalia A.; D'Anci, Kristen E.; Shukitt-Hale, Barbara; Smith, Don E.; Selhub, Jacob; Rosenberg, Irwin H.

2008-01-01

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction. PMID:19022979

[The Influence of the Functioning of Brain Regulatory Systems onto the Voluntary Regulation of Cognitive Performance in Children. Report 2. Neuropsychological and Electrophysiological Assessment of Brain Regulatory Functions in Children Aged 10-12 with Learning Difficulties].

PubMed

Semenova, O A; Machinskaya, R I

2015-01-01

A total number of 172 children aged 10-12 were electrophysiologically and neuropsychologically assessed in order to analyze the influence of the functioning of brain regulatory systems onto the voluntary regulation of cognitive performance during the preteen years. EEG patterns associated with the nonoptimal functioning of brain regulatory systems, particularly fronto-thalamic, limbic and fronto-striatal structures were significantly more often observed in children with learning and behavioral difficulties, as compared to the control group. Neuropsychological assessment showed that the nonoptimal functioning of different brain regulatory systems specifically affect the voluntary regulation of cognitive performance. Children with EEG patterns of fronto-thalamic nonoptimal functioning demonstrated poor voluntary regulation such as impulsiveness and difficulties in continuing the same algorithms. Children with EEG patterns of limbic nonoptimal functioning showed a less pronounced executive dysfunction manifested only in poor switching between program units within a task. Children with EEG patterns of fronto-striatal nonoptimal functioning struggled with such executive dysfunctions as motor and tactile perseverations and emotional-motivational deviations such as poor motivation and communicative skills.

Brainstem auditory-evoked potentials as an objective tool for evaluating hearing dysfunction in traumatic brain injury.

PubMed

Lew, Henry L; Lee, Eun Ha; Miyoshi, Yasushi; Chang, Douglas G; Date, Elaine S; Jerger, James F

2004-03-01

Because of the violent nature of traumatic brain injury, traumatic brain injury patients are susceptible to various types of trauma involving the auditory system. We report a case of a 55-yr-old man who presented with communication problems after traumatic brain injury. Initial results from behavioral audiometry and Weber/Rinne tests were not reliable because of poor cooperation. He was transferred to our service for inpatient rehabilitation, where review of the initial head computed tomographic scan showed only left temporal bone fracture. Brainstem auditory-evoked potential was then performed to evaluate his hearing function. The results showed bilateral absence of auditory-evoked responses, which strongly suggested bilateral deafness. This finding led to a follow-up computed tomographic scan, with focus on bilateral temporal bones. A subtle transverse fracture of the right temporal bone was then detected, in addition to the left temporal bone fracture previously identified. Like children with hearing impairment, traumatic brain injury patients may not be able to verbalize their auditory deficits in a timely manner. If hearing loss is suspected in a patient who is unable to participate in traditional behavioral audiometric testing, brainstem auditory-evoked potential may be an option for evaluating hearing dysfunction.

Should general anaesthesia be avoided in the elderly?

PubMed Central

Strøm, C.; Rasmussen, L. S.; Sieber, F. E.

2016-01-01

Summary Surgery and anaesthesia exert comparatively greater adverse effects on the elderly than on the younger brain, manifest by the higher prevalence of postoperative delirium and cognitive dysfunction. Postoperative delirium and cognitive dysfunction delay rehabilitation, and are associated with increases in morbidity and mortality among elderly surgical patients. We review the aetiology of postoperative delirium and cognitive dysfunction in the elderly with a particular focus on anaesthesia and sedation, discuss methods of diagnosing and monitoring postoperative cognitive decline, and describe the treatment strategies by which such decline may be prevented. PMID:24303859

What Gene Mutations Affect Serotonin in Mice?

PubMed

Tenpenny, Richard C; Commons, Kathryn G

2017-05-17

Although serotonin neurotransmission has been implicated in several neurodevelopmental and psychological disorders, the factors that drive dysfunction of the serotonin system are poorly understood. Current research regarding the serotonin system revolves around its dysfunction in neuropsychiatric disorders, but there is no database collating genetic mutations that result in serotonin abnormalities. To bridge this gap, we developed a list of genes in mice that, when perturbed, result in altered levels of serotonin either in brain or blood. Due to the intrinsic limitations of search, the current list should be considered a preliminary subset of all relevant cases. Nevertheless, it offered an opportunity to gain insight into what types of genes have the potential to impact serotonin by using gene ontology (GO). This analysis found that genes associated with monoamine metabolism were more often associated with increases in brain serotonin than decreases. Speculatively, this could be because several pathways (and therefore many genes) are responsible for the clearance and metabolism of serotonin whereas only one pathway (and therefore fewer genes) is directly involved in the synthesis of serotonin. Another contributor could be cross talk between monoamine systems such as dopamine. In contrast, genes that were associated with decreases in brain serotonin were more likely linked to a developmental process. Sensitivity of serotonin neurons to developmental perturbations could be due to their complicated neuroanatomy or possibly they may be negatively regulated by dysfunction of their innervation targets. Thus, these observations suggest hypotheses regarding the mechanisms underlying the vulnerability of brain serotonin neurotransmission.

Is cerebral glucose metabolism related to blood-brain barrier dysfunction and intrathecal IgG synthesis in Alzheimer disease?: A 18F-FDG PET/CT study.

PubMed

Chiaravalloti, Agostino; Fiorentini, Alessandro; Ursini, Francesco; Martorana, Alessandro; Koch, Giacomo; Belli, Lorena; Toniolo, Sofia; Di Pietro, Barbara; Motta, Caterina; Schillaci, Orazio

2016-09-01

The aim of this study was to investigate the relationships between blood-brain barrier (BBB) dysfunction, intrathecal IgG synthesis, and brain glucose consumption as detectable by means of serum/cerebrospinal fluid (CSF) albumin index (Qalb) and IgG index [(CSF IgG/serum IgG) × Serum albumin/CSF albumin)] and 2-deoxy-2-(F) fluoro-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in a selected population affected by Alzheimer disease (AD). The study included 134 newly diagnosed AD patients according to the NINCDS-ADRDA criteria. The mean (±SD) age of the patients was 70 (±6) years; 60 were male and 64 were female. Mini mental State Examination was equal to 18.9 (±7.2). All patients underwent a CSF assay and magnetic resonance before F-FDG PET scanning. The relationships were evaluated by means of statistical parametric mapping (SPM8). We found a significant negative correlation between the increase of Qalb and F-FDG uptake in the Brodmann Area 42 and 22 that corresponds to the left superior temporal gyrus, with higher Qalb values being related to a reduced glucose consumption in these areas. No significant relationships have been found between brain glucose consumption and IgG index. The results of our study suggest that BBB dysfunction is related to reduction of cortical activity in the left temporal cortex in AD subjects.

Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice

PubMed Central

Hemmati, Ali Asghar; Ahangarpour, Akram

2018-01-01

The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30–35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice. PMID:29719448

Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice.

PubMed

Hemmati, Ali Asghar; Alboghobeish, Soheila; Ahangarpour, Akram

2018-05-01

The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30-35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice.

[Traumatic brain injury and anterior pituitary dysfunction. Regarding 33 cases: Evolution profile over a six-month period].

PubMed

Sanoussi, S; Ali, A; Laouali, H; Assoumane, I; Chaibou Maman, S; Baoua, M

2013-01-01

To measure anterior pituitary dysfunction in traumatic brain injury (TBI) and assess the correlations between this disorder, clinical signs and brain lesions. This was a prospective, longitudinal and analytic study conducted in the department of neurosurgery at the National Hospital of Niamey and the institute of radioisotopes of Niamey University between November 2009 and November 2010. All patients admitted for head trauma were included in the study. They were followed-up for 6 months and underwent clinical, hormonal and CT scan analysis. The hormonal studies targeted gonadotroph hormone, growth hormone (GH), corticotroph, lactotroph, and thyreotroph axes. Thirty-three patients were included in the study. The sex ratio was 15.4:1. The mean age was 28.21 years. Glasgow coma scale score was between 7 and 12 in 52% of cases, with brain contusions in 54.5% of cases. In the acute phase, hypogonadism was reported in 64% of cases, and growth hormone deficiency in 58% of cases. Hormonal follow-up at three months showed GH deficiency in 48% of cases with an elevated luteinizing hormone (LH) in 42% of cases. At sixth months, a rise in LH was observed in 55% with GH deficiency in 52% of cases. Surgical procedures were performed in 21% of cases. At 6 months a post-concussion syndrome was observed in 48.48% of cases. These pituitary dysfunctions are common and should be investigated into the management of TBI. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Deanol in minimal brain dysfunction.

PubMed

Lewis, J A; Lewis, B S

1977-12-01

The literature on minimal brain dysfunction is confused, confusing and controversial. The statements that the condition exists, needs treatment, and that treatment may be pharmacological, are more expressions of faith than accepted fact. We believe they are true (within limits not discussed in the article). Furthermore, there is evidence that some patients with MBD are hypo-aroused, while others are not. The role of deanol in the treatment of MBD is still unclear, because of the complexities of identifying appropriate patients in terms of levels of arousal, as well as identifying appropriate measures of response. There is sufficient support for an effect of deanol in the literature to justify further investigation. Further studies should attend to important methodological problems as discussed.

Individual responses to methylphenidate and caffeine in children with minimal brain dysfunction.

PubMed Central

Garfinkel, B. D.; Webster, C. D.; Sloman, L.

1975-01-01

Eight children with minimal brain dysfunction were studied for their individual responses to two stimulant medications--methylphenidate hydrochloride and caffeine citrate. Four types of behavioural responses were observed in the double-blind crossover experiment: four children responded favourably to both psychostimulants, one responded to methylphenidate alone and two responded to the placebo. The behaviour of one child deteriorated while he was taking methylphenidate and caffeine. In general, methylphenidate was superior to caffeine in diminishing hyperactive and aggressive behaviour. It is apparent that such stimulant medication exerts its therapeutic effects in these two areas primarily and would therefore be useful as one aspect of a complete treatment program for children with this syndrome. PMID:803184

Effects of fisetin on hyperhomocysteinemia-induced experimental endothelial dysfunction and vascular dementia.

PubMed

Hemanth Kumar, Boyina; Arun Reddy, Ravula; Mahesh Kumar, Jerald; Dinesh Kumar, B; Diwan, Prakash V

2017-01-01

This study was designed to investigate the effects of fisetin (FST) on hyperhomocysteinemia (HHcy)-induced experimental endothelial dysfunction (ED) and vascular dementia (VaD) in rats. Wistar rats were randomly divided into 8 groups: control, vehicle control, l-methionine, FST (5, 10, and 25 mg/kg, p.o.), FST-per se (25 mg/kg, p.o.), and donepezil (0.1 mg/kg, p.o.). l-Methionine administration (1.7 g/kg, p.o.) for 32 days induced HHcy. ED and VaD induced by HHcy were determined by vascular reactivity measurements, behavioral analysis using Morris water maze and Y-maze, along with a biochemical and histological evaluation of thoracic aorta and brain tissues. Administration of l-methionine developed behavioral deficits; triggered brain lipid peroxidation (LPO); compromised brain acetylcholinesterase activity (AChE); and reduced the levels of brain superoxide dismutase (SOD), brain catalase (CAT), brain reduced glutathione (GSH), and serum nitrite; and increased serum homocysteine and cholesterol levels. These effects were accompanied by decreased vascular NO bioavailability, marked intimal thickening of the aorta, and multiple necrotic foci in brain cortex. HHcy-induced alterations in the activities of SOD, CAT, GSH, AChE, LPO, behavioral deficits, ED, and histological aberrations were significantly attenuated by treatment with fisetin in a dose-dependent manner. Collectively, our results indicate that fisetin exerts endothelial and neuroprotective effects against HHcy-induced ED and VaD.

Ameliorative effects of oleanolic acid on fluoride induced metabolic and oxidative dysfunctions in rat brain: Experimental and biochemical studies.

PubMed

Sarkar, Chaitali; Pal, Sudipta; Das, Niranjan; Dinda, Biswanath

2014-04-01

Beneficial effects of oleanolic acid on fluoride-induced oxidative stress and certain metabolic dysfunctions were studied in four regions of rat brain. Male Wistar rats were treated with sodium fluoride at a dose of 20 mg/kg b.w./day (orally) for 30 days. Results indicate marked reduction in acidic, basic and neutral protein contents due to fluoride toxicity in cerebrum, cerebellum, pons and medulla. DNA, RNA contents significantly decreased in those regions after fluoride exposure. Activities of proteolytic enzymes (such as cathepsin, trypsin and pronase) were inhibited by fluoride, whereas transaminase enzyme (GOT and GPT) activities increased significantly in brain tissue. Fluoride appreciably elevated brain malondialdehyde level, free amino acid nitrogen, NO content and free OH radical generation. Additionally, fluoride perturbed GSH content and markedly reduced SOD, GPx, GR and CAT activities in brain tissues. Oral supplementation of oleanolic acid (a plant triterpenoid), at a dose of 5mg/kgb.w./day for last 14 days of fluoride treatment appreciably ameliorated fluoride-induced alteration of brain metabolic functions. Appreciable counteractive effects of oleanolic acid against fluoride-induced changes in protein and nucleic acid contents, proteolytic enzyme activities and other oxidative stress parameters indicate that oleanolic acid has potential antioxidative effects against fluoride-induced oxidative brain damage. Copyright © 2014 Elsevier Ltd. All rights reserved.

Altered brain structural networks in attention deficit/hyperactivity disorder children revealed by cortical thickness.

PubMed

Liu, Tian; Chen, Yanni; Li, Chenxi; Li, Youjun; Wang, Jue

2017-07-04

This study investigated the cortical thickness and topological features of human brain anatomical networks related to attention deficit/hyperactivity disorder. Data were collected from 40 attention deficit/hyperactivity disorder children and 40 normal control children. Interregional correlation matrices were established by calculating the correlations of cortical thickness between all pairs of cortical regions (68 regions) of the whole brain. Further thresholds were applied to create binary matrices to construct a series of undirected and unweighted graphs, and global, local, and nodal efficiencies were computed as a function of the network cost. These experimental results revealed abnormal cortical thickness and correlations in attention deficit/hyperactivity disorder, and showed that the brain structural networks of attention deficit/hyperactivity disorder subjects had inefficient small-world topological features. Furthermore, their topological properties were altered abnormally. In particular, decreased global efficiency combined with increased local efficiency in attention deficit/hyperactivity disorder children led to a disorder-related shift of the network topological structure toward regular networks. In addition, nodal efficiency, cortical thickness, and correlation analyses revealed that several brain regions were altered in attention deficit/hyperactivity disorder patients. These findings are in accordance with a hypothesis of dysfunctional integration and segregation of the brain in patients with attention deficit/hyperactivity disorder and provide further evidence of brain dysfunction in attention deficit/hyperactivity disorder patients by observing cortical thickness on magnetic resonance imaging.

Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies.

PubMed

Doctor, Allan; Zimmerman, Jerry; Agus, Michael; Rajasekaran, Surender; Bubeck Wardenburg, Juliane; Fortenberry, James; Zajicek, Anne; Mairson, Emma; Typpo, Katri

2017-03-01

To describe the state of the science, identify knowledge gaps, and offer potential future research questions regarding promising therapies for children with multiple organ dysfunction syndrome presented during the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Pediatric Multiple Organ Dysfunction Syndrome (March 26-27, 2015). Literature review, research data, and expert opinion. Not applicable. Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Summary of presentations and discussion supported and supplemented by relevant literature. Among critically ill children, multiple organ dysfunction syndrome is relatively common and associated with significant morbidity and mortality. For outcomes to improve, effective therapies aimed at preventing and treating this condition must be discovered and rigorously evaluated. In this article, a number of potential opportunities to enhance current care are highlighted including the need for a better understanding of the pharmacokinetics and pharmacodynamics of medications, the effect of early and optimized nutrition, and the impact of effective glucose control in the setting of multiple organ dysfunction syndrome. Additionally, a handful of the promising therapies either currently being implemented or developed are described. These include extracorporeal therapies, anticytokine therapies, antitoxin treatments, antioxidant approaches, and multiple forms of exogenous steroids. For the field to advance, promising therapies and other therapies must be assessed in rigorous manner and implemented accordingly.

Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8.

PubMed

Eckert, Gunter P; Schiborr, Christina; Hagl, Stephanie; Abdel-Kader, Reham; Müller, Walter E; Rimbach, Gerald; Frank, Jan

2013-04-01

The aging brain suffers mitochondrial dysfunction and a reduced availability of energy in the form of ATP, which in turn may cause or promote the decline in cognitive, sensory, and motor function observed with advancing age. There is a need for animal models that display some of the pathological features of human brain aging in order to study their prevention by e.g. dietary factors. We thus investigated the suitability of the fast-aging senescence-accelerated mouse-prone 8 (SAMP8) strain and its normally aging control senescence-accelerated mouse-resistant 1 (SAMR1) as a model for the age-dependent changes in mitochondrial function in the brain. To this end, 2-months old male SAMR1 (n=10) and SAMP8 mice (n=7) were fed a Western type diet (control groups) for 5months and one group of SAMP8 mice (n=6) was fed an identical diet fortified with 500mg curcumin per kg. Dissociated brain cells and brain tissue homogenates were analyzed for malondialdehyde, heme oxygenase-1 mRNA, mitochondrial membrane potential (MMP), ATP concentrations, protein levels of mitochondrial marker proteins for mitochondrial membranes (TIMM, TOMM), the mitochondrial permeability transition pore (ANT1, VDAC1, TSPO), respiration complexes, and fission and fusion (Fis, Opa1, Mfn1, Drp1). Dissociated brain cells isolated from SAMP8 mice showed significantly reduced MMP and ATP levels, probably due to significantly diminished complex V protein expression, and increased expression of TSPO. Fission and fusion marker proteins indicate enhanced mitochondrial fission in brains of SAMP8 mice. Treatment of SAMP8 mice with curcumin improved MMP and ATP and restored mitochondrial fusion, probably by up-regulating nuclear factor PGC1α protein expression. In conclusion, SAMP8 compared to SAMR1 mice are a suitable model to study age-dependent changes in mitochondrial function and curcumin emerges as a promising nutraceutical for the prevention of neurodegenerative diseases that are accompanied or caused by mitochondrial dysfunction. Copyright © 2013 Elsevier Ltd. All rights reserved.

A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice.

PubMed

Edut, S; Rubovitch, V; Rehavi, M; Schreiber, S; Pick, C G

2014-12-01

Driving under methylenedioxymethamphetamine (MDMA) influence increases the risk of being involved in a car accident, which in turn can lead to traumatic brain injury. The behavioral deficits after traumatic brain injury (TBI) are closely connected to dopamine pathway dysregulation. We have previously demonstrated in mice that low MDMA doses prior to mTBI can lead to better performances in cognitive tests. The purpose of this study was to assess in mice the changes in the dopamine system that occurs after both MDMA and minimal traumatic brain injury (mTBI). Experimental mTBI was induced using a concussive head trauma device. One hour before injury, animals were subjected to MDMA. Administration of MDMA before injury normalized the alterations in tyrosine hydroxylase (TH) levels that were observed in mTBI mice. This normalization was also able to lower the elevated dopamine receptor type 2 (D2) levels observed after mTBI. Brain-derived neurotrophic factor (BDNF) levels did not change following injury alone, but in mice subjected to MDMA and mTBI, significant elevations were observed. In the behavioral tests, haloperidol reversed the neuroprotection seen when MDMA was administered prior to injury. Altered catecholamine synthesis and high D2 receptor levels contribute to cognitive dysfunction, and strategies to normalize TH signaling and D2 levels may provide relief for the deficits observed after injury. Pretreatment with MDMA kept TH and D2 receptor at normal levels, allowing regular dopamine system activity. While the beneficial effect we observe was due to a dangerous recreational drug, understanding the alterations in dopamine and the mechanism of dysfunction at a cellular level can lead to legal therapies and potential candidates for clinical use.

Protective effects of phosphodiesterase-1 (PDE1) and ATP sensitive potassium (KATP) channel modulators against 3-nitropropionic acid induced behavioral and biochemical toxicities in experimental Huntington׳s disease.

PubMed

Gupta, Surbhi; Sharma, Bhupesh

2014-06-05

Huntington׳s disease (HD), a devastating neurodegenerative disorder, is characterized by weight loss, impairment of motor function, cognitive dysfunction, neuropsychiatric disturbances and striatal damage. Phosphodiesterase-1 (PDE1) has been implicated in various neurological diseases. Mitochondrial potassium channels in the brain take part in neuroprotection. This study has been structured to investigate the role of vinpocetine, a selective PDE1 inhibitor as well as nicorandil, selective ATP sensitive potassium (KATP) channel opener in 3-nitropropionic acid (3-NP) induced HD symptoms in rats. Systemic administration of 3-NP significantly, reduced body weight, impaired locomotion, grip strength and impaired cognition. 3-NP elicited marked oxidative stress in the brain (enhanced malondialdehyde-MDA, reduced glutathione-GSH content, superoxide dismutase-SOD and catalase-CAT), elevated brain acetylcholinesterase activity and inflammation (myeloperoxidase-MPO), with marked nitrosative stress (nitrite/nitrate) in the brain. 3-NP has also induced mitochondrial dysfunction (impaired mitochondrial NADH dehydrogenase-complex I, succinate dehydrogenase-complex II and cytochrome oxidase-complex IV) activities in the striatum of the rat. Tetrabenazine was used as a positive control. Treatment with vinpocetine, nicorandil and tetrabenazine ameliorated 3-NP induced reduction in body weight, impaired locomotion, grip strength and impaired cognition. Treatment with these drugs reduced brain striatum oxidative (MDA, GSH, SOD and CAT) and nitrosative (nitrite/nitrate) stress, acetylcholinesterase activity, inflammation and mitochondrial dysfunctions. These results indicate that vinpocetine, a selective PDE1 inhibitor and nicorandil, a KATP channel opener have attenuated 3-NP induced experimental HD. Hence, pharmacological modulation of PDE1 as well as KATP channels may be considered as potential research targets for mitigation of HD. Copyright © 2014 Elsevier B.V. All rights reserved.

The neurobiology and treatment of first-episode schizophrenia

PubMed Central

Kahn, R S; Sommer, I E

2015-01-01

It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years. At the time of diagnosis, patients with schizophrenia show decreased mean intracranial volume (ICV) as compared with healthy subjects. Since ICV is driven by brain growth, which reaches its maximum size at approximately 13 years of age, this finding suggests that brain development in patients with schizophrenia is stunted before that age. The smaller brain volume is expressed as decrements in both grey and white matter. After diagnosis, it is mainly the grey matter loss that progresses over time whereas white matter deficits are stable or may even improve over the course of the illness. To understand the possible causes of the brain changes in the first phase of schizophrenia, evidence from treatment studies, postmortem and neuroimaging investigations together with animal experiments needs to be incorporated. These data suggest that the pathophysiology of schizophrenia is multifactorial. Increased striatal dopamine synthesis is already evident before the time of diagnosis, starting during the at-risk mental state, and increases during the onset of frank psychosis. Cognitive impairment and negative symptoms may, in turn, result from other abnormalities, such as NMDA receptor hypofunction and low-grade inflammation of the brain. The latter two dysfunctions probably antedate increased dopamine synthesis by many years, reflecting the much earlier presence of cognitive and social dysfunction. Although correction of the hyperdopaminergic state with antipsychotic agents is generally effective in patients with a first-episode psychosis, the effects of treatments to correct NMDA receptor hypofunction or low-grade inflammation are (so far) rather modest at best. Improved efficacy of these interventions can be expected when they are applied at the onset of cognitive and social dysfunction, rather than at the onset of psychosis. PMID:25048005

Brain and Cognition Abnormalities in Long-Term Anabolic-Androgenic Steroid Users

PubMed Central

Kaufman, Marc J.; Janes, Amy C.; Hudson, James I.; Brennan, Brian P.; Kanayama, Gen; Kerrigan, Andrew R.; Jensen, J. Eric; Pope, Harrison G.

2015-01-01

Background Anabolic-androgenic steroid (AAS) use is associated with psychiatric symptoms including increased aggression as well as with cognitive dysfunction. The brain effects of long-term AAS use have not been assessed in humans. Methods This multimodal magnetic resonance imaging study of the brain compared 10 male weightlifters reporting long-term AAS use with 10 age-matched weightlifters reporting no AAS exposure. Participants were administered visuospatial memory tests and underwent neuroimaging. Brain volumetric analyses were performed; resting-state fMRI functional connectivity (rsFC) was evaluated using a region-of-interest analysis focused on the amygdala; and dorsal anterior cingulate cortex (dACC) metabolites were quantified by proton magnetic resonance spectroscopy (MRS). Results AAS users had larger right amygdala volumes than nonusers (P=0.002) and reduced rsFC between right amygdala and frontal, striatal, limbic, hippocampal, and visual cortical areas. Left amygdala volumes were slightly larger in AAS users (P=0.061) but few group differences were detected in left amygdala rsFC. AAS users also had lower dACC scyllo-inositol levels (P=0.004) and higher glutamine/glutamate ratios (P=0.028), possibly reflecting increased glutamate turnover. On a visuospatial cognitive task, AAS users performed more poorly than nonusers, with the difference approaching significance (P=0.053). Conclusions Long-term AAS use is associated with right amygdala enlargement and reduced right amygdala rsFC with brain areas involved in cognitive control and spatial memory, which could contribute to the psychiatric effects and cognitive dysfunction associated with AAS use. The MRS abnormalities we detected could reflect enhanced glutamate turnover and increased vulnerability to neurotoxic or neurodegenerative processes, which could contribute to AAS-associated cognitive dysfunction. PMID:25986964

Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice

PubMed Central

Wen, Jing; Chen, Chris; Stock, Ariel; Doerner, Jessica; Gulinello, Maria; Putterman, Chaim

2016-01-01

Fn14, the sole known signaling receptor for the TNF family member TWEAK, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. There is increasing recognition of the importance of the TWEAK/Fn14 pathway in autoimmune neurologic conditions, including experimental autoimmune encephalomyelitis and neuropsychiatric lupus. Previously, we had found that Fn14 knockout lupus-prone MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To investigate whether this improvement in disease is secondary to inhibition of TWEAK/Fn14 signaling within the CNS or the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular (ICV) injection of Fc-TWEAK or an isotype matched control protein to C57Bl6/J non-autoimmune mice. We found that Fc-TWEAK injected C57Bl6/J mice developed significant depression-like behavior and cognitive dysfunction. Inflammatory mediators associated with lupus brain disease, including CCL2, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased blood brain barrier (BBB) permeability, as demonstrated by increased IgG deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex and hippocampus. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive dysfunction by acting within the CNS to enhance production of inflammatory mediators, promote disruption of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS. PMID:26721417

Cocaine users with comorbid Cluster B personality disorders show dysfunctional brain activation and connectivity in the emotional regulation networks during negative emotion maintenance and reappraisal.

PubMed

Albein-Urios, Natalia; Verdejo-Román, Juan; Soriano-Mas, Carles; Asensio, Samuel; Martínez-González, José Miguel; Verdejo-García, Antonio

2013-12-01

Cocaine dependence often co-occurs with Cluster B personality disorders. Since both disorders are characterized by emotion regulation deficits, we predicted that cocaine comorbid patients would exhibit dysfunctional patterns of brain activation and connectivity during reappraisal of negative emotions. We recruited 18 cocaine users with comorbid Cluster B personality disorders, 17 cocaine users without comorbidities and 21 controls to be scanned using functional magnetic resonance imaging (fMRI) during performance on a reappraisal task in which they had to maintain or suppress the emotions induced by negative affective stimuli. We followed region of interest (ROI) and whole-brain approaches to investigate brain activations and connectivity associated with negative emotion experience and reappraisal. Results showed that cocaine users with comorbid personality disorders had reduced activation of the subgenual anterior cingulate cortex during negative emotion maintenance and increased activation of the lateral orbitofrontal cortex and the amygdala during reappraisal. Amygdala activation correlated with impulsivity and antisocial beliefs in the comorbid group. Connectivity analyses showed that in the cocaine comorbid group the subgenual cingulate was less efficiently connected with the amygdala and the fusiform gyri and more efficiently connected with the anterior insula during maintenance, whereas during reappraisal the left orbitofrontal cortex was more efficiently connected with the amygdala and the right orbitofrontal cortex was less efficiently connected with the dorsal striatum. We conclude that cocaine users with comorbid Cluster B personality disorders have distinctive patterns of brain activation and connectivity during maintenance and reappraisal of negative emotions, which correlate with impulsivity and dysfunctional beliefs. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: a double-blind trial using proton and lithium magnetic resonance spectroscopy.

PubMed

Lyoo, In Kyoon; Demopulos, Christina M; Hirashima, Fuyuki; Ahn, Kyung Heup; Renshaw, Perry F

2003-08-01

Oral choline administration has been reported to increase brain phosphatidylcholine levels. As phospholipid synthesis for maintaining membrane integrity in mammalian brain cells consumes approximately 10-15% of the total adenosine triphosphate (ATP) pool, an increased availability of brain choline may lead to an increase in ATP consumption. Given reports of genetic studies, which suggest mitochondrial dysfunction, and phosphorus (31P) magnetic resonance spectroscopy (MRS) studies, which report dysfunction in high-energy phosphate metabolism in patients with bipolar disorder, the current study is designed to evaluate the role of oral choline supplementation in modifying high-energy phosphate metabolism in subjects with bipolar disorder. Eight lithium-treated patients with DSM-IV bipolar disorder, rapid cycling type were randomly assigned to 50 mg/kg/day of choline bitartrate or placebo for 12 weeks. Brain purine, choline and lithium levels were assessed using 1H- and 7Li-MRS. Patients received four to six MRS scans, at baseline and weeks 2, 3, 5, 8, 10 and 12 of treatment (n = 40 scans). Patients were assessed using the Clinical Global Impression Scale (CGIS), the Young Mania Rating Scale (YRMS) and the Hamilton Depression Rating Scale (HDRS) at each MRS scan. There were no significant differences in change-from-baseline measures of CGIS, YMRS, and HDRS, brain choline/creatine ratios, and brain lithium levels over a 12-week assessment period between the choline and placebo groups or within each group. However, the choline treatment group showed a significant decrease in purine metabolite ratios from baseline (purine/n-acetyl aspartate: coef = -0.08, z = -2.17, df = 22, p = 0.030; purine/choline: coef = -0.12, z = -1.97, df = 22, p = 0.049) compared to the placebo group, controlling for brain lithium level changes. Brain lithium level change was not a significant predictor of purine ratios. The current study reports that oral choline supplementation resulted in a significant decrease in brain purine levels over a 12-week treatment period in lithium-treated patients with DSM-IV bipolar disorder, rapid-cycling type, which may be related to the anti-manic effects of adjuvant choline. This result is consistent with mitochondrial dysfunction in bipolar disorder inadequately meeting the demand for increased ATP production as exogenous oral choline administration increases membrane phospholipid synthesis.

High Prevalence of Chronic Pituitary and Target-Organ Hormone Abnormalities after Blast-Related Mild Traumatic Brain Injury

PubMed Central

Wilkinson, Charles W.; Pagulayan, Kathleen F.; Petrie, Eric C.; Mayer, Cynthia L.; Colasurdo, Elizabeth A.; Shofer, Jane B.; Hart, Kim L.; Hoff, David; Tarabochia, Matthew A.; Peskind, Elaine R.

2011-01-01

Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25–50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation. PMID:22347210

High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury.

PubMed

Wilkinson, Charles W; Pagulayan, Kathleen F; Petrie, Eric C; Mayer, Cynthia L; Colasurdo, Elizabeth A; Shofer, Jane B; Hart, Kim L; Hoff, David; Tarabochia, Matthew A; Peskind, Elaine R

2012-01-01

Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25-50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.

The TNF-α/NF-κB signaling pathway has a key role in methamphetamine–induced blood–brain barrier dysfunction

PubMed Central

Coelho-Santos, Vanessa; Leitão, Ricardo A; Cardoso, Filipa L; Palmela, Inês; Rito, Manuel; Barbosa, Marcos; Brito, Maria A; Fontes-Ribeiro, Carlos A; Silva, Ana P

2015-01-01

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction. PMID:25899299

[Hypopituitarism following traumatic brain injury: diagnostic and therapeutic issues].

PubMed

Lecoq, A-L; Chanson, P

2015-10-01

Traumatic Brain Injury (TBI) is a well-known public health problem worldwide and is a leading cause of death and disability, particularly in young adults. Besides neurological and psychiatric issues, pituitary dysfunction can also occur after TBI, in the acute or chronic phase. The exact prevalence of post-traumatic hypopituitarism is difficult to assess due to the wide heterogeneity of published studies and bias in interpretation of hormonal test results in this specific population. Predictive factors for hypopituitarism have been proposed and are helpful for the screening. The pathophysiology of pituitary dysfunction after TBI is not well understood but the vascular hypothesis is privileged. Activation of pituitary stem/progenitor cells is probably involved in the recovery of pituitary functions. Those cells also play a role in the induction of pituitary tumors, highlighting their crucial place in pituitary conditions. This review updates the current data related to anterior pituitary dysfunction after TBI and discusses the bias and difficulties encountered in its diagnosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome.

PubMed

Mitsumoto, H; Schwartzman, M J; Estes, M L; Chou, S M; La Franchise, E F; De Camilli, P; Solimena, M

1991-04-01

Two women with typical stiff-man syndrome (SMS) developed increasingly frequent attacks of muscle spasms with severe paroxysmal autonomic dysfunctions such as transient hyperpyrexia, diaphoresis, tachypnea, tachycardia, pupillary dilation, and arterial hypertension. Autoantibodies to GABA-ergic neurons were identified in the serum of both patients and in the cerebrospinal fluid of one. Both died suddenly and unexpectedly. General autopsy did not reveal the cause of death. Neuropathological studies revealed perivascular gliosis in the spinal cord and brain stem of one patient and lymphocytic perivascular infiltration in the spinal cord, brain stem, and basal ganglia of the other. The occurrence of a chronic inflammatory reaction in one of the two patients supports the idea that an autoimmune disease against GABA-ergic neurons may be involved in SMS. A review of the literature indicates that functional impairment in SMS is severe and prognosis is unpredictable because of the potential for sudden and unexpected death. Both muscular abnormalities and autonomic dysfunctions may result from autoimmunity directed against GABA-ergic neurons.

Brain Mitochondria, Aging, and Parkinson's Disease.

PubMed

Rango, Mario; Bresolin, Nereo

2018-05-11

This paper reconsiders the role of mitochondria in aging and in Parkinson's Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD.

F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline.

PubMed

Yan, Shijun; Du, Fang; Wu, Long; Zhang, Zhihua; Zhong, Changjia; Yu, Qing; Wang, Yongfu; Lue, Lih-Fen; Walker, Douglas G; Douglas, Justin T; Yan, Shirley ShiDu

2016-11-01

Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif -/- ) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca 2+ -induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca 2+ overload. Diabetes-induced elevation of CypD triggers enhancement of F 1 F 0 ATP synthase-CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F 1 F 0 ATP synthase-CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy. © 2016 by the American Diabetes Association.

A multilevel analysis of cognitive dysfunction and psychopathology associated with chromosome 22q11.2 deletion syndrome in children

PubMed Central

SIMON, TONY J.; BISH, JOEL P.; BEARDEN, CARRIE E.; DING, LIJUN; FERRANTE, SAMANTHA; NGUYEN, VY; GEE, JAMES C.; McDONALD–McGINN, DONNA M.; ZACKAI, ELAINE H.; EMANUEL, BEVERLY S.

2006-01-01

We present a multilevel approach to developing potential explanations of cognitive impairments and psychopathologies common to individuals with chromosome 22q11.2 deletion syndrome. Results presented support our hypothesis of posterior parietal dysfunction as a central determinant of characteristic visuospatial and numerical cognitive impairments. Converging data suggest that brain development anomalies, primarily tissue reductions in the posterior brain and changes to the corpus callosum, may affect parietal connectivity. Further findings indicate that dysfunction in “frontal” attention systems may explain some executive cognition impairments observed in affected children, and that there may be links between these domains of cognitive function and some of the serious psychiatric conditions, such as attention-deficit/hyperactivity disorder, autism, and schizophrenia, that have elevated incidence rates in the syndrome. Linking the neural structure and the cognitive processing levels in this way enabled us to develop an elaborate structure/function mapping hypothesis for the impairments that are observed. We show also, that in the case of the catechol-O-methyltransferase gene, a fairly direct relationship between gene expression, cognitive function, and psychopathology exists in the affected population. Beyond that, we introduce the idea that variation in other genes may further explain the phenotypic variation in cognitive function and possibly the anomalies in brain development. PMID:16262991

Detecting social-cognitive deficits after traumatic brain injury: An ALE meta-analysis of fMRI studies.

PubMed

Xiao, Hui; Jacobsen, Andre; Chen, Ziqian; Wang, Yang

2017-01-01

Traumatic brain injury (TBI) can result in significant social dysfunction, which is represented by impairment to social-cognitive abilities (i.e. social cognition, social attention/executive function and communication). This study is aimed to explore brain networks mediating the social dysfunction after TBI and its underlying mechanisms. We performed a quantitative meta-analysis using the activation likelihood estimation (ALE) approach on functional magnetic resonance imaging (fMRI) studies of social-cognitive abilities following TBI. Sixteen studies fulfilled the inclusion criteria resulting in a total of 190 patients with TBI and 206 controls enrolled in the ALE meta-analysis. The temporoparietal junction (TPJ) and the medial prefrontal cortex (mPFC) were the specific regions that social cognition predominantly engaged. The cingulate gyrus, frontal gyrus and inferior parietal lobule were the main regions related to social attention/executive functions. Communication dysfunction, especially related to language deficits, was found to show greater activation of the temporal gyrus and fusiform gyrus in TBI. The current ALE meta-analytic findings provide evidence that patients have significant social-cognitive disabilities following TBI. The relatively limited pool of literature and the varied fMRI results from published studies indicate that social-cognitive abilities following TBI is an area that would greatly benefit from further investigation.

Source localization of intermittent rhythmic delta activity in a patient with acute confusional migraine: cross-spectral analysis using standardized low-resolution brain electromagnetic tomography (sLORETA).

PubMed

Kim, Dae-Eun; Shin, Jung-Hyun; Kim, Young-Hoon; Eom, Tae-Hoon; Kim, Sung-Hun; Kim, Jung-Min

2016-01-01

Acute confusional migraine (ACM) shows typical electroencephalography (EEG) patterns of diffuse delta slowing and frontal intermittent rhythmic delta activity (FIRDA). The pathophysiology of ACM is still unclear but these patterns suggest neuronal dysfunction in specific brain areas. We performed source localization analysis of IRDA (in the frequency band of 1-3.5 Hz) to better understand the ACM mechanism. Typical IRDA EEG patterns were recorded in a patient with ACM during the acute stage. A second EEG was obtained after recovery from ACM. To identify source localization of IRDA, statistical non-parametric mapping using standardized low-resolution brain electromagnetic tomography was performed for the delta frequency band comparisons between ACM attack and non-attack periods. A difference in the current density maximum was found in the dorsal anterior cingulated cortex (ACC). The significant differences were widely distributed over the frontal, parietal, temporal and limbic lobe, paracentral lobule and insula and were predominant in the left hemisphere. Dorsal ACC dysfunction was demonstrated for the first time in a patient with ACM in this source localization analysis of IRDA. The ACC plays an important role in the frontal attentional control system and acute confusion. This dysfunction of the dorsal ACC might represent an important ACM pathophysiology.

Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives.

PubMed

Hovens, Iris B; Schoemaker, Regien G; van der Zee, Eddy A; Heineman, Erik; Izaks, Gerbrand J; van Leeuwen, Barbara L

2012-10-01

Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account. Copyright © 2012 Elsevier Inc. All rights reserved.

Post-Translational Incorporation of L-Phenylalanine into the C-Terminus of α-Tubulin as a Possible Cause of Neuronal Dysfunction.

PubMed

Ditamo, Yanina; Dentesano, Yanela M; Purro, Silvia A; Arce, Carlos A; Bisig, C Gastón

2016-12-01

α-Tubulin C-terminus undergoes post-translational, cyclic tyrosination/detyrosination, and L-Phenylalanine (Phe) can be incorporated in place of tyrosine. Using cultured mouse brain-derived cells and an antibody specific to Phe-tubulin, we showed that: (i) Phe incorporation into tubulin is reversible; (ii) such incorporation is not due to de novo synthesis; (iii) the proportion of modified tubulin is significant; (iv) Phe incorporation reduces cell proliferation without affecting cell viability; (v) the rate of neurite retraction declines as level of C-terminal Phe incorporation increases; (vi) this inhibitory effect of Phe on neurite retraction is blocked by the co-presence of tyrosine; (vii) microtubule dynamics is reduced when Phe-tubulin level in cells is high as a result of exogenous Phe addition and returns to normal values when Phe is removed; moreover, microtubule dynamics is also reduced when Phe-tubulin is expressed (plasmid transfection). It is known that Phe levels are greatly elevated in blood of phenylketonuria (PKU) patients. The molecular mechanism underlying the brain dysfunction characteristic of PKU is unknown. Beyond the differences between human and mouse cells, it is conceivable the possibility that Phe incorporation into tubulin is the first event (or among the initial events) in the molecular pathways leading to brain dysfunctions that characterize PKU.

Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

PubMed Central

Berggren, Kiersten L.; Chen, Jianfang; Fox, Julia; Miller, Jonathan; Dodds, Lindsay; Dugas, Bryan; Vargas, Liset; Lothian, Amber; McAllum, Erin; Volitakis, Irene; Roberts, Blaine; Bush, Ashley I.; Fox, Jonathan H.

2015-01-01

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. Iron supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD. PMID:25703232

Dysregulation of heart and brain specific micro-RNA in sudden infant death syndrome.

PubMed

Courts, Cornelius; Grabmüller, Melanie; Madea, Burkhard

2013-05-10

Channelopathic heart arrhythmias and dysfunctional autonomic regulation of respiration and arousal based on defects in the brainstem are assumed to be involved in the pathogenesis of SIDS. There is evidence that, apart from mutational alterations in associated genes, disruption of physiological processes and deficient responses to external stressors may be influenced by the dysregulation of organ specific micro-RNA expression. It is unknown, however, whether these small, non-coding regulatory RNA molecules are involved in any SIDS pathomechanism. In a case-control study of two series of fresh-frozen heart tissue (n=14) and formalin fixed, paraffin embedded brainstem tissue (n=11) from SIDS and respective control cases, differential expression of heart and brain specific miR-1/miR-133 and miR-124a/let-7b, respectively, was determined using quantitative PCR analysis. Our results show a significant upregulation of heart specific miR-1 and brainspecific let-7b in SIDS compared to control cases. This pilot study is first to analyze differential miRNA expression in SIDS. Our findings suggest that organ specific miRNA dysregulation may be associated with SIDS pathogenesis and establishes the feasibility of miRNA analysis in different kinds of preserved and archived SIDS tissues. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Thyroid Hormone-Dependent Formation of a Subcortical Band Heterotopia (SBH) in the Neonatal Brain is not Exacerbated Under Conditions of Low Dietary Iron (FeD)

EPA Science Inventory

Although the critical role of thyroid hormone (TH) in brain development is well established - severe deficiency producing significant neurological dysfunction - there is a paucity of data on neurological impairments that accompany modest degrees of TH disruption. Quantitative m...

Age-Related Impairments in Object-Place Associations Are Not Due to Hippocampal Dysfunction

PubMed Central

Hernandez, Abigail R.; Maurer, Andrew P.; Reasor, Jordan E.; Turner, Sean M.; Barthle, Sarah E.; Johnson, Sarah A.; Burke, Sara N.

2016-01-01

Age-associated cognitive decline can reduce an individual’s quality of life. As no single neurobiological deficit can account for the wide spectrum of behavioral impairments observed in old age, it is critical to develop an understanding of how interactions between different brain regions change over the life span. The performance of young and aged animals on behaviors that require the hippocampus and cortical regions to interact, however, has not been well characterized. Specifically, the ability to link a spatial location with specific features of a stimulus, such as object identity, relies on the hippocampus, perirhinal and prefrontal cortices. Although aging is associated with dysfunction in each of these brain regions, behavioral measures of functional change within the hippocampus, perirhinal and prefrontal cortices in individual animals are often not correlated. Thus, how dysfunction of a single brain region within this circuit, such as the hippocampus, impacts behaviors that require communication with the perirhinal and prefrontal cortices remains unknown. To address this question, young and aged rats were tested on the interregion dependent object-place paired association task, as well as a hippocampal-dependent test of spatial reference memory. This particular cohort of aged rats did not show deficits on the hippocampal-dependent task, but were significantly impaired at acquiring object-place associations relative to young. These data suggest that behaviors requiring functional connectivity across different regions of the memory network may be particularly sensitive to aging, and can be used to develop models that will clarify the impact of systems-level dysfunction in the elderly. PMID:26413723

Multiple White Matter Volume Reductions in Patients with Panic Disorder: Relationships between Orbitofrontal Gyrus Volume and Symptom Severity and Social Dysfunction

PubMed Central

Konishi, Jun; Asami, Takeshi; Hayano, Fumi; Yoshimi, Asuka; Hayasaka, Shunsuke; Fukushima, Hiroshi; Whitford, Thomas J.; Inoue, Tomio; Hirayasu, Yoshio

2014-01-01

Numerous brain regions are believed to be involved in the neuropathology of panic disorder (PD) including fronto-limbic regions, thalamus, brain stem, and cerebellum. However, while several previous studies have demonstrated volumetric gray matter reductions in these brain regions, there have been no studies evaluating volumetric white matter changes in the fiber bundles connecting these regions. In addition, although patients with PD typically exhibit social, interpersonal and occupational dysfunction, the neuropathologies underlying these dysfunctions remain unclear. A voxel-based morphometry study was conducted to evaluate differences in regional white matter volume between 40 patients with PD and 40 healthy control subjects (HC). Correlation analyses were performed between the regional white matter volumes and patients' scores on the Panic Disorder Severity Scale (PDSS) and the Global Assessment of Functioning (GAF). Patients with PD demonstrated significant volumetric reductions in widespread white matter regions including fronto-limbic, thalamo-cortical and cerebellar pathways (p<0.05, FDR corrected). Furthermore, there was a significant negative relationship between right orbitofrontal gyrus (OFG) white matter volume and the severity of patients' clinical symptoms, as assessed with the PDSS. A significant positive relationship was also observed between patients' right OFG volumes and their scores on the GAF. Our results suggest that volumetric reductions in widespread white matter regions may play an important role in the pathology of PD. In particular, our results suggest that structural white matter abnormalities in the right OFG may contribute to the social, personal and occupational dysfunction typically experienced by patients with PD. PMID:24663245

Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.

PubMed

Cotman, Carl W; Head, Elizabeth; Muggenburg, Bruce A; Zicker, S; Milgram, Norton W

2002-01-01

Animal models that simulate various aspects of human brain aging are an essential step in the development of interventions to manage cognitive dysfunction in the elderly. Over the past several years we have been studying cognition and neuropathology in the aged-canine (dog). Like humans, canines naturally accumulate deposits of beta-amyloid (Abeta) in the brain with age. Further, canines and humans share the same Abeta sequence and also first show deposits of the longer Abeta1-42 species followed by the deposition of Abeta1-40. Aged canines like humans also show increased oxidative damage. As a function of age, canines show impaired learning and memory on tasks similar to those used in aged primates and humans. The extent of Abeta deposition correlates with the severity of cognitive dysfunction in canines. To test the hypothesis that a cascade of mechanisms centered on oxidative damage and Abeta results in cognitive dysfunction we have evaluated the cognitive effects of an antioxidant diet in aged canines. The diet resulted in a significant improvement in the ability of aged but not young animals to acquire progressively more difficult learning tasks (e.g. oddity discrimination learning). The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies. Copyright 2002 Elsevier Science Inc.

Piracetam improves mitochondrial dysfunction following oxidative stress

PubMed Central

Keil, Uta; Scherping, Isabel; Hauptmann, Susanne; Schuessel, Katin; Eckert, Anne; Müller, Walter E

2005-01-01

Mitochondrial dysfunction including decrease of mitochondrial membrane potential and reduced ATP production represents a common final pathway of many conditions associated with oxidative stress, for example, hypoxia, hypoglycemia, and aging. Since the cognition-improving effects of the standard nootropic piracetam are usually more pronounced under such pathological conditions and young healthy animals usually benefit little by piracetam, the effect of piracetam on mitochondrial dysfunction following oxidative stress was investigated using PC12 cells and dissociated brain cells of animals treated with piracetam. Piracetam treatment at concentrations between 100 and 1000 μM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside (SNP) and serum deprivation. Under conditions of mild serum deprivation, piracetam (500 μM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. Piracetam treatment (100–500 mg kg−1 daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Moreover, the same treatment reduced antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in aged mouse brain only, which are elevated as an adaptive response to the increased oxidative stress with aging. In conclusion, therapeutically relevant in vitro and in vivo concentrations of piracetam are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of piracetam's beneficial effects in elderly patients. PMID:16284628

Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis.

PubMed

Li, H; Sun, J; Du, J; Wang, F; Fang, R; Yu, C; Xiong, J; Chen, W; Lu, Z; Liu, J

2018-05-01

Traumatic brain injury (TBI) is a common occurrence following gastrointestinal dysfunction. Recently, more and more attentions are being focused on gut microbiota in brain and behavior. Glucagon-like peptide-1 (GLP-1) is considered as a mediator that links the gut-brain axis. The aim of this study was to explore the neuroprotective effects of Clostridium butyricum (Cb) on brain damage in a mouse model of TBI. Male C57BL/6 mice were subjected to a model of TBI-induced by weight-drop impact head injury and were treated intragastrically with Cb. The cognitive deficits, brain water content, neuronal death, and blood-brain barrier (BBB) permeability were evaluated. The expression of tight junction (TJ) proteins, Bcl-2, Bax, GLP-1 receptor (GLP-1R), and phosphorylation of Akt (p-Akt) in the brain were also measured. Moreover, the intestinal barrier permeability, the expression of TJ protein and GLP-1, and IL-6 level in the intestine were detected. Cb treatment significantly improved neurological dysfunction, brain edema, neurodegeneration, and BBB impairment. Meanwhile, Cb treatment also significantly increased the expression of TJ proteins (occludin and zonula occluden-1), p-Akt and Bcl-2, but decreased expression of Bax. Moreover, Cb treatment exhibited more prominent effects on decreasing the levels of plasma d-lactate and colonic IL-6, upregulating expression of Occludin, and protecting intestinal barrier integrity. Furthermore, Cb-treated mice showed increased the secretion of intestinal GLP-1 and upregulated expression of cerebral GLP-1R. Our findings demonstrated the neuroprotective effect of Cb in TBI mice and the involved mechanisms were partially attributed to the elevating GLP-1 secretion through the gut-brain axis. © 2017 John Wiley & Sons Ltd.

Protection of cultured brain endothelial cells from cytokine-induced damage by α-melanocyte stimulating hormone.

PubMed

Harazin, András; Bocsik, Alexandra; Barna, Lilla; Kincses, András; Váradi, Judit; Fenyvesi, Ferenc; Tubak, Vilmos; Deli, Maria A; Vecsernyés, Miklós

2018-01-01

The blood-brain barrier (BBB), an interface between the systemic circulation and the nervous system, can be a target of cytokines in inflammatory conditions. Pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induce damage in brain endothelial cells and BBB dysfunction which contribute to neuronal injury. The neuroprotective effects of α-melanocyte stimulating hormone (α-MSH) were investigated in experimental models, but there are no data related to the BBB. Based on our recent study, in which α-MSH reduced barrier dysfunction in human intestinal epithelial cells induced by TNF-α and IL-1β, we hypothesized a protective effect of α-MSH on brain endothelial cells. We examined the effect of these two pro-inflammatory cytokines, and the neuropeptide α-MSH on a culture model of the BBB, primary rat brain endothelial cells co-cultured with rat brain pericytes and glial cells. We demonstrated the expression of melanocortin-1 receptor in isolated rat brain microvessels and cultured brain endothelial cells by RT-PCR and immunohistochemistry. TNF-α and IL-1β induced cell damage, measured by impedance and MTT assay, which was attenuated by α-MSH (1 and 10 pM). The peptide inhibited the cytokine-induced increase in brain endothelial permeability, and restored the morphological changes in cellular junctions visualized by immunostaining for claudin-5 and β-catenin. Elevated production of reactive oxygen species and the nuclear translocation of NF-κB were also reduced by α-MSH in brain endothelial cells stimulated by cytokines. We demonstrated for the first time the direct beneficial effect of α-MSH on cultured brain endothelial cells, indicating that this neurohormone may be protective at the BBB.

Protection of cultured brain endothelial cells from cytokine-induced damage by α-melanocyte stimulating hormone

PubMed Central

Barna, Lilla; Kincses, András; Váradi, Judit; Fenyvesi, Ferenc; Tubak, Vilmos

2018-01-01

The blood–brain barrier (BBB), an interface between the systemic circulation and the nervous system, can be a target of cytokines in inflammatory conditions. Pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induce damage in brain endothelial cells and BBB dysfunction which contribute to neuronal injury. The neuroprotective effects of α-melanocyte stimulating hormone (α-MSH) were investigated in experimental models, but there are no data related to the BBB. Based on our recent study, in which α-MSH reduced barrier dysfunction in human intestinal epithelial cells induced by TNF-α and IL-1β, we hypothesized a protective effect of α-MSH on brain endothelial cells. We examined the effect of these two pro-inflammatory cytokines, and the neuropeptide α-MSH on a culture model of the BBB, primary rat brain endothelial cells co-cultured with rat brain pericytes and glial cells. We demonstrated the expression of melanocortin-1 receptor in isolated rat brain microvessels and cultured brain endothelial cells by RT-PCR and immunohistochemistry. TNF-α and IL-1β induced cell damage, measured by impedance and MTT assay, which was attenuated by α-MSH (1 and 10 pM). The peptide inhibited the cytokine-induced increase in brain endothelial permeability, and restored the morphological changes in cellular junctions visualized by immunostaining for claudin-5 and β-catenin. Elevated production of reactive oxygen species and the nuclear translocation of NF-κB were also reduced by α-MSH in brain endothelial cells stimulated by cytokines. We demonstrated for the first time the direct beneficial effect of α-MSH on cultured brain endothelial cells, indicating that this neurohormone may be protective at the BBB. PMID:29780671

[Forensic application of brainstem auditory evoked potential in patients with brain concussion].

PubMed

Zheng, Xing-Bin; Li, Sheng-Yan; Huang, Si-Xing; Ma, Ke-Xin

2008-12-01

To investigate changes of brainstem auditory evoked potential (BAEP) in patients with brain concussion. Nineteen patients with brain concussion were studied with BAEP examination. The data was compared to the healthy persons reported in literatures. The abnormal rate of BAEP for patients with brain concussion was 89.5%. There was a statistically significant difference between the abnormal rate of patients and that of healthy persons (P<0.05). The abnormal rate of BAEP in the brainstem pathway for patients with brain concussion was 73.7%, indicating dysfunction of the brainstem in those patients. BAEP might be helpful in forensic diagnosis of brain concussion.

How cognitive neuroscience could be more biological—and what it might learn from clinical neuropsychology

PubMed Central

Frisch, Stefan

2014-01-01

Three widespread assumptions of Cognitive-affective Neuroscience are discussed: first, mental functions are assumed to be localized in circumscribed brain areas which can be exactly determined, at least in principle (localizationism). Second, this assumption is associated with the more general claim that these functions (and dysfunctions, such as in neurological or mental diseases) are somehow generated inside the brain (internalism). Third, these functions are seen to be “biological” in the sense that they can be decomposed and finally explained on the basis of elementary biological causes (i.e., genetic, molecular, neurophysiological etc.), causes that can be identified by experimental methods as the gold standard (isolationism). Clinical neuropsychology is widely assumed to support these tenets. However, by making reference to the ideas of Kurt Goldstein (1878–1965), one of its most important founders, I argue that none of these assumptions is sufficiently supported. From the perspective of a clinical-neuropsychological practitioner, assessing and treating brain damage sequelae reveals a quite different picture of the brain as well as of us “brain carriers”, making the organism (or person) in its specific environment the crucial reference point. This conclusion can be further elaborated: all experimental and clinical research on humans presupposes the notion of a situated, reflecting, and interacting subject, which precedes all kinds of scientific decomposition, however useful. These implications support the core assumptions of the embodiment approach to brain and mind, and, as I argue, Goldstein and his clinical-neuropsychological observations are part of its very origin, for both theoretical and historical reasons. PMID:25100981

Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway.

PubMed

Ugun-Klusek, Aslihan; Tatham, Michael H; Elkharaz, Jamal; Constantin-Teodosiu, Dumitru; Lawler, Karen; Mohamed, Hala; Paine, Simon M L; Anderson, Glen; John Mayer, R; Lowe, James; Ellen Billett, E; Bedford, Lynn

2017-01-05

The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated.

[Organ damage and cardiorenal syndrome in acute heart failure].

PubMed

Casado Cerrada, Jesús; Pérez Calvo, Juan Ignacio

2014-03-01

Heart failure is a complex syndrome that affects almost all organs and systems of the body. Signs and symptoms of organ dysfunction, in particular kidney dysfunction, may be accentuated or become evident for the first time during acute decompensation of heart failure. Cardiorenal syndrome has been defined as the simultaneous dysfunction of both the heart and the kidney, regardless of which of the two organs may have suffered the initial damage and regardless also of their previous functional status. Research into the mechanisms regulating the complex relationship between the two organs is prompting the search for new biomarkers to help physicians detect renal damage in subclinical stages. Hence, a preventive approach to renal dysfunction may be adopted in the clinical setting in the near future. This article provides a general overview of cardiorenal syndrome and an update of the physiopathological mechanisms involved. Special emphasis is placed on the role of visceral congestion as an emergent mechanism in this syndrome. Copyright © 2014 Elsevier España, S.L. All rights reserved.

Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer's Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET.

PubMed

Li, Xue-Yuan; Men, Wei-Wei; Zhu, Hua; Lei, Jian-Feng; Zuo, Fu-Xing; Wang, Zhan-Jing; Zhu, Zhao-Hui; Bao, Xin-Jie; Wang, Ren-Zhi

2016-10-18

Alzheimer's disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18 F-labed fluorodeoxyglucose ( 18 F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer's cognition after cognitive decline, at least in animals.

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by ß-amyloid peptide

PubMed Central

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, WE

2010-01-01

Background and purpose: β-Amyloid peptide (Aβ) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. Experimental approach: We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Aβ-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Aβ and on neurite outgrowth in PC12 cells were investigated. Key results: Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Aβ1-42. Similar protective effects against Aβ1-42 were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Aβ load was markedly diminished in the brain of those animals after treatment with piracetam. Aβ production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Aβ-induced mitochondrial dysfunction and Aβ-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Conclusion and implications: Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Aβ on brain function. This article is commented on by Moncada, pp. 217–219 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00706.x and to view related papers by Pravdic et al. and Puerta et al. visit http://dx.doi.org/10.1111/j.1476-5381.2010.00698.x and http://dx.doi.org/10.1111/j.1476-5381.2010.00663.x PMID:20218980

Minor Neurological Dysfunction in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

de Jong, Marianne; Punt, Marja; de Groot, Erik; Minderaa, Ruud B; Hadders-Algra, Mijna

2011-01-01

Aim: The aim of this study was to improve the understanding of brain function in children with autism spectrum disorder (ASD) in relation to minor neurological dysfunctions (MNDs). Method: We studied MNDs in 122 children (93 males, 29 females; mean age 8y 1mo, SD 2y 6mo) who, among a total cohort of 705 children (513 males, 192 females; mean age…

Minor Neurological Dysfunction in Children with Dyslexia

ERIC Educational Resources Information Center

Punt, Marja; de Jong, Marianne; de Groot, Erik; Hadders-Algra, Mijna

2010-01-01

Aim: To improve understanding of brain function in children with severe dyslexia in terms of minor neurological dysfunctions (MNDs). Method: One hundred and four children (81 males, 23 females; age range 7-12y; mean age 9y 7mo, SD 1y 2mo;) with severe dyslexia (the presence of a Full-scale IQ score of greater than or equal to 85, retardation in…

Nose-to-Brain Delivery of Peptide Drugs Enhanced by Coadministration of Cell-penetrating Peptides: Therapeutic Potential for Dementia.

PubMed

Kamei, Noriyasu

2017-01-01

Recent reports suggest that peptide drugs such as insulin have the potential to serve as therapeutics in neurodegenerative diseases such as Alzheimer's disease. However, the transport of these drugs to the therapeutic target, the brain, is significantly hindered by the blood-brain barrier (BBB). Intranasal administration appears to be an ideal solution for drug delivery to the brain, bypassing the BBB, however the entry of peptide drugs into neuronal and epithelial cells in the olfactory mucosa remains low. In this study, we therefore examined whether intranasal coadministration of cell-penetrating peptides (CPPs) could improve nose-to-brain drug transport. In both mice and rats, we found that direct transport of insulin into the brain was significantly facilitated when coadministered with amphipathic CPP penetratin, and eventually insulin reached the deeper regions of the brain such as the hippocampus. In the mouse line senescence-accelerated mouse prone-8 (SAMP8), spatial learning tests demonstrated that long-term intranasal coadministration of insulin with penetratin improved mild memory loss in the early stages of dementia. In contrast, the severe cognitive dysfunction in the aged SAMP8 mice was preserved despite intranasal coadministration of insulin with penetratin. The immunohistological examination of the hippocampus suggested that enhanced nose-to-brain delivery of insulin had a partial neuroprotective effect but unexpectedly increased amyloid β plaque deposition. In conclusion, intranasal coadministration of insulin with CPPs has the potential to serve as a therapeutic for mild cognitive dysfunction. To identify suitable pharmacotherapy for dementia with severe pathology, further studies of nose-to-brain delivery of molecularly appropriate biopharmaceuticals are necessary.

Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain.

PubMed

Siegel, Jennifer J; Chitwood, Raymond A; Ding, James M; Payne, Clayton; Taylor, William; Gray, Richard; Zemelman, Boris V; Johnston, Daniel

2017-08-02

Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein-protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain. SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC function. The results suggest that at least some FX-specific neurological defects can be rescued in the adult FX brain after development. Copyright © 2017 the authors 0270-6474/17/377305-13$15.00/0.

Concurrent Vision Dysfunctions in Convergence Insufficiency with Traumatic Brain Injury

PubMed Central

Alvarez, Tara L.; Kim, Eun H.; Vicci, Vincent R.; Dhar, Sunil K.; Biswal, Bharat B.; Barrett, A. M.

2012-01-01

Purpose This study assessed the prevalence of convergence insufficiency (CI) with and without simultaneous vision dysfunctions within the traumatic brain injury (TBI) sample population because although CI is commonly reported with TBI, the prevalence of concurrent visual dysfunctions with CI in TBI is unknown. Methods A retrospective analysis of 557 medical records from TBI civilian patients was conducted. Patients were all evaluated by a single optometrist. Visual acuity, oculomotor, binocular vision function, accommodation, visual fields, ocular health and vestibular function were assessed. Statistical comparisons between the CI and non-CI, as well as in-patient and out-patient subgroups, were conducted using chi-squared and Z-tests. Results Approximately 9% of the TBI sample had CI without the following simultaneous diagnoses: saccade or pursuit dysfunction; 3rd, 4th, or 6th nerve palsy; visual field deficit; visual spatial inattention/neglect; vestibular dysfunction or nystagmus. Photophobia with CI was observed in 16.3% (N=21/130) and vestibular dysfunction with CI was observed in 18.5% (N=24/130) of the CI subgroup. CI and cranial nerve palsies were common and yielded prevalence rates of 23.3% (N=130/557) and 26.9% (N=150/557), respectively, within the TBI sample. Accommodative dysfunction was common within the non-presbyopic TBI sample with a prevalence of 24.4% (N=76/314). Visual field deficits or unilateral visual spatial inattention/neglect were observed within 29.6% (N=80/270) of the TBI in-patient subgroup and were significantly more prevalent compared to the out-patient subgroup (p<0.001). Most TBI patients had visual acuities of 20/60 or better in the TBI sample (85%;N=473/557). Conclusions CI without simultaneous visual or vestibular dysfunctions was observed in about 9% of the visually symptomatic TBI civilian population studied. A thorough visual and vestibular examination is recommended for all TBI patients. PMID:23190716

Monitoring glutamate levels in the posterior cingulate cortex of thyroid dysfunction patients with TE-averaged PRESS at 3T.

PubMed

Zhang, Qiujuan; Bai, Zhilan; Gong, Yan; Liu, Xinxin; Dai, Xiaoqing; Wang, Shejiao; Liu, Feng

2015-07-01

Patients with thyroid dysfunction frequently have neuropsychiatric complaints such as lack of concentration, poor memory, depression, anxiety and mania, which suggest brain dysfunction. However, the underlying process of this dysfunction remains unclear. Recent studies of the glutamatergic system have offered important insight into the neuropsychiatric process. Thus, this study investigates changes in glutamate concentration in patients with thyroid dysfunction. It also clarifies whether Glu levels are related to thyroid hormones via proton magnetic resonance spectroscopy. 36 untreated patients with thyroid dysfunction (18 hyperthyroidism patients and 18 hypothyroidism patients) and 18 age- and gender-matched controls were included in this study. The posterior cingulate cortex was examined by MRS with TE-averaged PRESS at 3T. The intensity of glutamate, choline, N-acetylaspartate, and creatine was assessed using jMRUI v4.0 software. We found a significant difference among hyper-/hypo- and control groups in Glu (P=0.003) and Cho (P=0.015). The concentrations of glutamate increased (P=0.006) in the posterior cingulate cortex in patients with hypothyroidism and significantly decreased (P=0.002) in hyperthyroidism patients relative to controls. There were no difference in the concentrations of choline between hyperthyroidism patients and controls (P=0.679). Versus the hyperthyroidism group, the hypothyroidism group showed increased glutamate (P=0.018) and choline (P=0.001) in the posterior cingulate cortex. There was no significant difference in the concentrations of NAA or creatine across the three groups (P>0.05). The Glu level correlates with TT3 (P=0.000) and FT3 (P=0.022). The signal intensity of glutamate shows significant differences in the region of the posterior cingulate cortex in patients with thyroid dysfunction. This change indicates a potential role of glutamate in the brain dysfunction experience by patients with thyroid hormone disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Brain differences between persistent and remitted attention deficit hyperactivity disorder.

PubMed

Mattfeld, Aaron T; Gabrieli, John D E; Biederman, Joseph; Spencer, Thomas; Brown, Ariel; Kotte, Amelia; Kagan, Elana; Whitfield-Gabrieli, Susan

2014-09-01

Previous resting state studies examining the brain basis of attention deficit hyperactivity disorder have not distinguished between patients who persist versus those who remit from the diagnosis as adults. To characterize the neurobiological differences and similarities of persistence and remittance, we performed resting state functional magnetic resonance imaging in individuals who had been longitudinally and uniformly characterized as having or not having attention deficit hyperactivity disorder in childhood and again in adulthood (16 years after baseline assessment). Intrinsic functional brain organization was measured in patients who had a persistent diagnosis in childhood and adulthood (n = 13), in patients who met diagnosis in childhood but not in adulthood (n = 22), and in control participants who never had attention deficit hyperactivity disorder (n = 17). A positive functional correlation between posterior cingulate and medial prefrontal cortices, major components of the default-mode network, was reduced only in patients whose diagnosis persisted into adulthood. A negative functional correlation between medial and dorsolateral prefrontal cortices was reduced in both persistent and remitted patients. The neurobiological dissociation between the persistence and remittance of attention deficit hyperactivity disorder may provide a framework for the relation between the clinical diagnosis, which indicates the need for treatment, and additional deficits that are common, such as executive dysfunctions. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Glycemic extremes in youth with T1DM: the structural and functional integrity of the developing brain.

PubMed

Arbelaez, Ana Maria; Semenkovich, Katherine; Hershey, Tamara

2013-12-01

The adult brain accounts for a disproportionally large percentage of the body’s total energy consumption (1). However, during brain development,energy demand is even higher, reaching the adult rate by age 2 and increasing to nearly twice the adult rate by age 10, followed by gradual reduction toward adult levels in the next decade (1,2). The dramatic changes in brain metabolism occurring over the first two decades of life coincide with the initial proliferation and then pruning of synapses to adult levels.The brain derives its energy almost exclusively from glucose and is largely driven by neuronal signaling, biosynthesis, and neuroprotection (3–6).Glucose homeostasis in the body is tightly regulated by a series of hormones and physiologic responses. As a result, hypoglycemia and hyperglycemia are rare occurrences in normal individuals, but they occur commonly inpatients with type 1 diabetes mellitus (T1DM) due to a dysfunction of peripheral glucose-insulin-glucagon responses and non-physiologic doses of exogenous insulin, which imperfectly mimic normal physiology. These extremes can occur more frequently in children and adolescents with T1DM due to the inadequacies of insulin replacement therapy, events leading to the diagnosis [prolonged untreated hyperglycemia and diabetic ketoacidosis (DKA)], and to behavioral factors interfering with optimal treatment. When faced with fluctuations in glucose supply the metabolism of the body and brain change dramatically, largely to conserve resources and, at a cost to other organs, to preserve brain function (7). However,if the normal physiological mechanisms that prevent these severe glucose fluctuations and maintain homeostasis are impaired, neuronal function and potentially viability can be affected (8–11).

Early Immune Function and Duration of Organ Dysfunction in Critically Ill Septic Children.

PubMed

Muszynski, Jennifer A; Nofziger, Ryan; Moore-Clingenpeel, Melissa; Greathouse, Kristin; Anglim, Larissa; Steele, Lisa; Hensley, Josey; Hanson-Huber, Lisa; Nateri, Jyotsna; Ramilo, Octavio; Hall, Mark W

2018-02-22

Late immune suppression is associated with nosocomial infection and mortality in septic adults and children. Relationships between early immune suppression and outcomes in septic children remain unclear. Prospective observational study to test the hypothesis that early innate and adaptive immune suppression are associated with longer duration of organ dysfunction in children with severe sepsis/septic shock. Methods, Measurements and Main Results: Children aged < 18 years meeting consensus criteria for severe sepsis or septic shock were sampled within 48 hours of sepsis onset. Healthy controls were sampled once. Innate immune function was quantified by whole blood ex vivo lipopolysaccharide-induced TNFα production capacity. Adaptive immune function was quantified by ex vivo phytohemagglutinin-induced IFNγ production capacity. 102 septic children and 35 healthy children were enrolled. Compared to healthy children, septic children demonstrated lower LPS-induced TNFα production (p < 0.0001) and lower PHA-induced IFNγ production (p<0.0001). Among septic children, early innate and adaptive immune suppression were associated with greater number of days with multiple organ dysfunction (MODS) and greater number of days with any organ dysfunction. On multivariable analyses, early innate immune suppression remained independently associated with increased MODS days [aRR 1.2 (1.03, 1.5)] and organ dysfunction days [aRR 1.2 (1.1, 1.3)]. Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early suppression of both innate and adaptive immunity are associated with longer duration of organ dysfunction and may be useful markers to guide investigations of immunomodulatory therapies in septic children.

Protocolized Treatment Is Associated With Decreased Organ Dysfunction in Pediatric Severe Sepsis.

PubMed

Balamuth, Fran; Weiss, Scott L; Fitzgerald, Julie C; Hayes, Katie; Centkowski, Sierra; Chilutti, Marianne; Grundmeier, Robert W; Lavelle, Jane; Alpern, Elizabeth R

2016-09-01

To determine whether treatment with a protocolized sepsis guideline in the emergency department was associated with a lower burden of organ dysfunction by hospital day 2 compared to nonprotocolized usual care in pediatric patients with severe sepsis. Retrospective cohort study. Tertiary care children's hospital from January 1, 2012, to March 31, 2014. Patients older than 56 days old and younger than 18 years old with international consensus defined severe sepsis and who required PICU admission within 24 hours of emergency department arrival were included. The exposure was the use of a protocolized emergency department sepsis guideline. The primary outcome was complete resolution of organ dysfunction by hospital day 2. One hundred eighty nine subjects were identified during the study period. Of these, 121 (64%) were treated with the protocolized emergency department guideline and 68 were not. There were no significant differences between the groups in age, sex, race, number of comorbid conditions, emergency department triage level, or organ dysfunction on arrival to the emergency department. Patients treated with protocolized emergency department care were more likely to be free of organ dysfunction on hospital day 2 after controlling for sex, comorbid condition, indwelling central venous catheter, Pediatric Index of Mortality-2 score, and timing of antibiotics and IV fluids (adjusted odds ratio, 4.2; 95% CI, 1.7-10.4). Use of a protocolized emergency department sepsis guideline was independently associated with resolution of organ dysfunction by hospital day 2 compared to nonprotocolized usual care. These data indicate that morbidity outcomes in children can be improved with the use of protocolized care.

Seeing more clearly through the fog of encephalopathy.

PubMed

Kaplan, Peter W; Sutter, Raoul

2013-10-01

Patients with acute confusional states (often referred to as encephalopathy or delirium) pose diagnostic and management challenges for treating physicians. Encephalopathy is associated with a high morbidity and mortality rate, and the diagnosis rests on clinical grounds but may also be supported by the finding of electroencephalographic (EEG) evidence for diffuse cerebral dysfunction. The myriad cerebral transmitter and metabolic disruptions are generated by systemic organ system failures, principal among which are those of the liver, kidneys, lungs, heart, and endocrine system, along with the effects of exogenous toxins and medications. In most cases, several of these organ failures together contribute to the confusional state, frequently in the context of a diffuse cerebral atrophy that affects the aging brain. This special issue of the Journal of Clinical Neurophysiology is dedicated to exploring the electrophysiology of these conditions. It reviews the pathophysiology, psychiatric manifestations, clinical and imaging correlations of the many causes and types of encephalopathy. A literature review of the EEG abnormalities in the various types of encephalopathy provides an overview that ranges from paraneoplastic causes, through organ system failures, postcardiorespiratory arrest, to postoperative delirium. The issue is supplemented by tables of relevant clinical correlations, graphs, Venn diagrams, and the use of mathematical modeling used to explain how defects in the neuronal interplay might generate the EEG patterns seen in encephalopathy. We hope that this assembly will act as a springboard for further discussion and investigation into the EEG underpinnings, clinical correlations, diagnosis. and prognostication of these common and morbid disturbances of brain function.

TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders.

PubMed

Pascual, María; Montesinos, Jorge; Montagud-Romero, Sandra; Forteza, Jerónimo; Rodríguez-Arias, Marta; Miñarro, José; Guerri, Consuelo

2017-07-24

Inflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents. We hypothesize that by activating the TLR4 response, maternal alcohol consumption during pregnancy triggers the release of cytokines and chemokines in both the maternal sera and brains of fetuses/offspring, which impairs brain ontogeny and causes cognitive dysfunction. WT and TLR4-KO female mice treated with or without 10% ethanol in the drinking water during gestation and lactation were used. Cytokine/chemokine levels were determined by ELISA in the amniotic fluid, maternal serum, and cerebral cortex, as well as in the offspring cerebral cortex. Microglial and neuronal markers (evaluated by western blotting), myelin proteins (immunohistochemical and western blotting) and synaptic parameters (western blotting and electron microscopy) were assessed in the cortices of the WT and TLR4-KO pups on PND 0, 20, and 66. Behavioral tests (elevated plus maze and passive avoidance) were performed in the WT and TLR4-KO mice on PND 66 exposed or not to ethanol. We show that alcohol intake during gestation and lactation increases the levels of several cytokines/chemokines (IL-1β, IL-17, MIP-1α, and fractalkine) in the maternal sera, amniotic fluid, and brains of fetuses and offspring. The upregulation of cytokines/chemokines is associated with an increase in activated microglia markers (CD11b and MHC-II), and with a reduction in some synaptic (synaptotagmin, synapsin IIa) and myelin (MBP, PLP) proteins in the brains of offspring on days 0, 20, and 66 (long-term effects). These changes are associated with long-term behavioral impairments, in the 66-day-old alcohol-exposed pups. TLR4-deficient mice are protected against ethanol-induced cytokine/chemokine production in alcohol-treated dams and offspring, along with synaptic and myelin alterations, and the log-term behavioral dysfunction induced by ethanol in offspring. These results suggest that the immune system activation, through the TLR4 response, might play an important role in the neurodevelopmental defects in FASD.

Persistent, severe hypoglycemia-induced organic brain syndrome with neurological sequelae: a case report.

PubMed

Xu, Changqing; Yogaratnam, Jegan; Lua, Regina; Naik, Sandeep; Khoo, Chai Ling; Pillai, Santhia Sasidaran; Sim, Kang

2011-01-01

Hypoglycemia is a biochemical abnormality and often the rate-limiting step in the treatment of both type 1 and type 2 diabetes mellitus. Left uncorrected and prolonged, hypoglycemia can result in neuronal dysfunction and death, with deficits ranging from measurable cognitive impairments to aberrant behavior, seizures and coma. In this case report, hypoglycemia resulted in severe and persistent neurological (slurred speech and gait abnormalities), cognitive (inattention, disorientation and memory deficits) and behavioral manifestations (verbal hostility and irritability). It highlights the potentially severe neuropsychiatric sequelae following hypoglycemia and is timely for clinicians to be reminded that hypoglycemia prevention needs to be more of a focus of diabetes care in general. Copyright © 2011 Elsevier Inc. All rights reserved.

Central insulin and leptin-mediated autonomic control of glucose homeostasis

PubMed Central

Marino, Joseph S.; Xu, Yong; Hill, Jennifer W.

2016-01-01

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. PMID:21489811

Central insulin and leptin-mediated autonomic control of glucose homeostasis.

PubMed

Marino, Joseph S; Xu, Yong; Hill, Jennifer W

2011-07-01

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

A Review of Wearable Sensor Systems for Monitoring Body Movements of Neonates

PubMed Central

Chen, Hongyu; Xue, Mengru; Mei, Zhenning; Bambang Oetomo, Sidarto; Chen, Wei

2016-01-01

Characteristics of physical movements are indicative of infants’ neuro-motor development and brain dysfunction. For instance, infant seizure, a clinical signal of brain dysfunction, could be identified and predicted by monitoring its physical movements. With the advance of wearable sensor technology, including the miniaturization of sensors, and the increasing broad application of micro- and nanotechnology, and smart fabrics in wearable sensor systems, it is now possible to collect, store, and process multimodal signal data of infant movements in a more efficient, more comfortable, and non-intrusive way. This review aims to depict the state-of-the-art of wearable sensor systems for infant movement monitoring. We also discuss its clinical significance and the aspect of system design. PMID:27983664

Functional network dysfunction in anxiety and anxiety disorders

PubMed Central

Sylvester, C.M.; Corbetta, M.; Raichle, M.E.; Rodebaugh, T.; Schlaggar, B.L.; Sheline, Y.I.; Zorumski, C.F.; Lenze, E.J.

2012-01-01

A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. Here, we propose that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies. PMID:22658924

The mirror neuron system and the consequences of its dysfunction.

PubMed

Iacoboni, Marco; Dapretto, Mirella

2006-12-01

The discovery of premotor and parietal cells known as mirror neurons in the macaque brain that fire not only when the animal is in action, but also when it observes others carrying out the same actions provides a plausible neurophysiological mechanism for a variety of important social behaviours, from imitation to empathy. Recent data also show that dysfunction of the mirror neuron system in humans might be a core deficit in autism, a socially isolating condition. Here, we review the neurophysiology of the mirror neuron system and its role in social cognition and discuss the clinical implications of mirror neuron dysfunction.

The Churchill School: An Alternative to Drug Treatment for Hyperactive Children.

ERIC Educational Resources Information Center

Krippner, Stanley

This paper is a discussion of The Churchill School, founded in 1972 as an alternative approach to serving the educational needs of children diagnosed as hyperactive, hyperkinetic, brain damaged, neurologically impaired, or suffering from minimal brain dysfunction. The school has a student body of 65, ranging between 6 and 13 years of age. The…

Atypical Brain Activation during Simple & Complex Levels of Processing in Adult ADHD: An fMRI Study

ERIC Educational Resources Information Center

Hale, T. Sigi; Bookheimer, Susan; McGough, James J.; Phillips, Joseph M.; McCracken, James T.

2007-01-01

Objective: Executive dysfunction in ADHD is well supported. However, recent studies suggest that more fundamental impairments may be contributing. We assessed brain function in adults with ADHD during simple and complex forms of processing. Method: We used functional magnetic resonance imaging with forward and backward digit spans to investigate…

EEG Delta Band as a Marker of Brain Damage in Aphasic Patients after Recovery of Language

ERIC Educational Resources Information Center

Spironelli, Chiara; Angrilli, Alessandro

2009-01-01

In this study spectral delta percentage was used to assess both brain dysfunction/inhibition and functional linguistic impairment during different phases of word processing. To this aim, EEG delta amplitude was measured in 17 chronic non-fluent aphasic patients while engaged in three linguistic tasks: Orthographic, Phonological and Semantic.…

The diagnosis and management of progressive dysfunction of health care organizations.

PubMed

Chervenak, Frank A; McCullough, Laurence B

2005-04-01

This paper presents an ethically justified approach to the diagnosis and management of progressive dysfunction of health care organizational cultures. We explain the concept of professional integrity in terms of the ethical concept of the cofiduciary responsibility of physicians and health care organizations. We identify the ethical features of a healthy health care organization and the spectrum of progressive dysfunction of organizational cultures from cynical through wonderland and Kafkaesque to postmodern. Physicians should respond to cynical health care organizations by creating moral enclaves of professional integrity for the main purpose of confrontation and reform, to wonderland organizations by strengthening moral enclaves for the main purpose of resisting self-deception, to Kafkaesque organizations by strengthening moral enclaves still further for the main purpose of defending professional integrity (adopting a Machiavellian appearance of virtue as necessary), and to postmodern organizations by creating moral fortresses and, should these fail, quitting.

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia.

PubMed

Nakagawa, Yutaka; Chiba, Kenji

2016-09-01

Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

miR-98 and let-7g* protect the blood–brain barrier under neuroinflammatory conditions

PubMed Central

Rom, Slava; Dykstra, Holly; Zuluaga-Ramirez, Viviana; Reichenbach, Nancy L; Persidsky, Yuri

2015-01-01

Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood–brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier ‘leakiness' in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation. PMID:26126865

Integration of transcriptomic and cytoarchitectonic data implicates a role for MAOA and TAC1 in the limbic-cortical network.

PubMed

Bludau, Sebastian; Mühleisen, Thomas W; Eickhoff, Simon B; Hawrylycz, Michael J; Cichon, Sven; Amunts, Katrin

2018-06-01

Decoding the chain from genes to cognition requires detailed insights how areas with specific gene activities and microanatomical architectures contribute to brain function and dysfunction. The Allen Human Brain Atlas contains regional gene expression data, while the JuBrain Atlas offers three-dimensional cytoarchitectonic maps reflecting interindividual variability. To date, an integrated framework that combines the analytical benefits of both scientific platforms towards a multi-level brain atlas of adult humans was not available. We have, therefore, developed JuGEx, a new method for integrating tissue transcriptome and cytoarchitectonic segregation. We investigated differential gene expression in two JuBrain areas of the frontal pole that we have structurally and functionally characterized in previous studies. Our results show a significant upregulation of MAOA and TAC1 in the medial area frontopolaris which is a node in the limbic-cortical network and known to be susceptible for gray matter loss and behavioral dysfunction in patients with depression. The MAOA gene encodes an enzyme which is involved in the catabolism of dopamine, norepinephrine, serotonin, and other monoaminergic neurotransmitters. The TAC1 locus generates hormones that play a role in neuron excitations and behavioral responses. Overall, JuGEx provides a new tool for the scientific community that empowers research from basic, cognitive and clinical neuroscience in brain regions and disease models with regard to gene expression.

miR-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions.

PubMed

Rom, Slava; Dykstra, Holly; Zuluaga-Ramirez, Viviana; Reichenbach, Nancy L; Persidsky, Yuri

2015-12-01

Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier 'leakiness' in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.

Menopause-related brain activation patterns during visual sexual arousal in menopausal women: An fMRI pilot study using time-course analysis.

PubMed

Kim, Gwang-Won; Jeong, Gwang-Woo

2017-02-20

The aging process and menopausal transition are important factors in sexual dysfunction of menopausal women. No neuroimaging study has assessed the age- and menopause-related changes on brain activation areas associated with sexual arousal in menopausal women. The purpose of this study was to evaluate the time course of regional brain activity associated with sexual arousal evoked by visual stimulation in premenopausal and menopausal women, and further to assess the effect of menopause on the brain areas associated with sexual arousal in menopausal women using functional magnetic resonance imaging (fMRI). Thirty volunteers consisting of 15 premenopausal and 15 menopausal women underwent the fMRI. For the activation condition, volunteers viewed sexually arousing visual stimulation. The brain areas with significantly higher activation in premenopausal women compared with menopausal women included the thalamus, amygdala, and anterior cingulate cortex (ACC) using analysis of covariance adjusting for age (p<0.005). Blood-oxygen-level-dependent signal changes in the amygdala while viewing erotic video were positively correlated with estrogen levels in the two groups. Our findings suggest that reduced brain activity of the thalamus, amygdala, and ACC in menopausal women may be associated with menopause-related decrease in sexual arousal. These findings might help elucidate the neural mechanisms associated with sexual dysfunction in menopausal women. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Energy metabolism and inflammation in brain aging and Alzheimer's disease.

PubMed

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-11-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer's disease. As important cellular sources of H 2 O 2 , mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer's disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer's disease. Interaction of these systems is reviewed based on basic research and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

A biopsychological review of gambling disorder

PubMed Central

Quintero, Gabriel C

2017-01-01

The present review is an overview of previous experimental work on biopsychological aspects of gambling disorder. It includes the topics 1) gambling disorder from the neuroimaging and electroencephalography (EEG) perspective, 2) cognitive, executive functioning, and neuropsychological aspects of gambling disorder, and 3) rodent models of gambling disorder. Penalties and losses in gambling can differ in terms of brain activity. Also, specific patterns of brain activity, brain anatomical traits, EEG responses, and cognitive and executive performance can discriminate pathological gamblers from nonpathological gamblers. Also, pathological gamblers can display dysfunction in such brain areas as the insula, frontal lobe, and orbitofrontal cortex. Pathological gambling is a heterogeneous disorder that can vary depending on the severity of cognition, the style of gambling (strategic or not), the prospect of recovery, proneness to relapse, and proneness to treatment withdrawal. Finally, based on rodent models of gambling, the appropriateness of gambling decision is influenced by the presence of cues, the activity of dopamine receptors, and the activity of some brain areas (infralimbic, prelimbic, or rostral agranular insular cortex). Pathological gamblers differed in terms of frontoparietal brain activation compared to nonpathological gamblers (if winning or losing a game). Pathological gamblers had dysfunctional EEG activity. The severity of gambling was linked to the magnification and content of cognitive distortions. The insula was fundamental in the distortion of cognitions linked to result analysis during gambling activity. PMID:28096672

Cognitive dysfunction in patients with brain metastases: influences on caregiver resilience and coping.

PubMed

Saria, Marlon Garzo; Courchesne, Natasia; Evangelista, Lorraine; Carter, Joshua; MacManus, Daniel A; Gorman, Mary Kay; Nyamathi, Adeline M; Phillips, Linda R; Piccioni, David; Kesari, Santosh; Maliski, Sally

2017-04-01

Neurologic deficits that may be manifested as cognitive impairment contribute to the challenges faced by caregivers of patients with brain metastases. To better address their needs, we examined how caregivers respond to these challenges and explore the relationship between the patient's cognitive impairment and caregiver resilience and coping. We conducted a descriptive, cross-sectional study using self-reported data from 56 caregivers of patients with brain metastases. Study participants from a comprehensive cancer center were asked to complete a series of instruments that measured their perception of the patient's cognitive dysfunction (revised memory and behavior problems checklist, RMBC), their own personal resilience (Resilience Scale, RS), and their utilization of a broad range of coping responses (COPE inventory and Emotional-Approach Coping scale). Caregivers reported that memory-related problems occurred more frequently in the patients they cared for compared to depression and disruptive behavior (mean scores 3.52 vs 2.34 vs. 1.32, respectively). Coping strategies most frequently used by caregivers were acceptance (3.28), planning (3.08), and positive reinterpretation and growth (2.95). Most caregivers scored moderate to high on the RS (77%). The coping strategy acceptance correlated significantly with the memory and disruptive behavior subscales of the RMBC. Given the protective effect of problem-focused coping and the high rate of caregivers utilizing less effective coping strategies in instances of worsening cognitive dysfunction, healthcare professionals need to systematically assess the coping strategies of caregivers and deliver a more personalized approach to enhance effective coping among caregivers of patients with brain metastases.

Neuroprotective effect of selective DPP-4 inhibitor in experimental vascular dementia.

PubMed

Jain, Swati; Sharma, Bhupesh

2015-12-01

Vascular risk factors are associated with a higher incidence of dementia. Diabetes mellitus is considered as a main risk factor for Alzheimer's disease and vascular dementia. Both forms of dementia are posing greater risk to the world population and are increasing at a faster rate. In the past we have reported the induction of vascular dementia by experimental diabetes. This study investigates the role of vildagliptin, a dipeptidyl peptidase-4 inhibitor in the pharmacological interdiction of pancreatectomy diabetes induced vascular endothelial dysfunction and subsequent vascular dementia in rats. Attentional set shifting and Morris water-maze test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. Pancreatectomy diabetes rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with increase in brain inflammation, oxidative stress and calcium. Administration of vildagliptin has significantly attenuated pancreatectomy induced impairment of learning, memory, endothelial function, blood brain barrier permeability and biochemical parameters. It may be concluded that vildagliptin, a dipeptidyl peptidase-4 inhibitor may be considered as potential pharmacological agents for the management of pancreatectomy induced endothelial dysfunction and subsequent vascular dementia. The selective modulators of dipeptidyl peptidase-4 may further be explored for their possible benefits in vascular dementia. Copyright © 2015 Elsevier Inc. All rights reserved.

Whole-brain functional connectivity identification of functional dyspepsia.

PubMed

Nan, Jiaofen; Liu, Jixin; Li, Guoying; Xiong, Shiwei; Yan, Xuemei; Yin, Qing; Zeng, Fang; von Deneen, Karen M; Liang, Fanrong; Gong, Qiyong; Qin, Wei; Tian, Jie

2013-01-01

Recent neuroimaging studies have shown local brain aberrations in functional dyspepsia (FD) patients, yet little attention has been paid to the whole-brain resting-state functional network abnormalities. The purpose of this study was to investigate whether FD disrupts the patterns of whole-brain networks and the abnormal functional connectivity could reflect the severity of the disease. The dysfunctional interactions between brain regions at rest were investigated in FD patients as compared with 40 age- and gender- matched healthy controls. Multivariate pattern analysis was used to evaluate the discriminative power of our results for classifying patients from controls. In our findings, the abnormal brain functional connections were mainly situated within or across the limbic/paralimbic system, the prefrontal cortex, the tempo-parietal areas and the visual cortex. About 96% of the subjects among the original dataset were correctly classified by a leave one-out cross-validation approach, and 88% accuracy was also validated in a replication dataset. The classification features were significantly associated with the patients' dyspepsia symptoms, the self-rating depression scale and self-rating anxiety scale, but it was not correlated with duration of FD patients (p>0.05). Our results may indicate the effectiveness of the altered brain functional connections reflecting the disease pathophysiology underling FD. These dysfunctional connections may be the epiphenomena or causative agents of FD, which may be affected by clinical severity and its related emotional dimension of the disease rather than the clinical course.

Bioactivation of organic nitrates and the mechanism of nitrate tolerance.

PubMed

Klemenska, Emila; Beresewicz, Andrzej

2009-01-01

Organic nitrates, such as nitroglycerin, are commonly used in the therapy of cardiovascular disease. Long-term therapy with these drugs, however, results in the rapid development of nitrate tolerance, limiting their hemodynamic and anti-ischemic efficacy. In addition, nitrate tolerance is associated with the expression of potentially deleterious modifications such as increased oxidative stress, endothelial dysfunction, and sympathetic activation. In this review we discuss current concepts regarding the mechanisms of organic nitrate bioactivation, nitrate tolerance, and nitrate-mediated oxidative stress and endothelial dysfunction. We also examine how hydralazine may prevent nitrate tolerance and related endothelial dysfunction.

Sociosexual and Communication Deficits after Traumatic Injury to the Developing Murine Brain

PubMed Central

Semple, Bridgette D.; Noble-Haeusslein, Linda J.; Jun Kwon, Yong; Sam, Pingdewinde N.; Gibson, A. Matt; Grissom, Sarah; Brown, Sienna; Adahman, Zahra; Hollingsworth, Christopher A.; Kwakye, Alexander; Gimlin, Kayleen; Wilde, Elisabeth A.; Hanten, Gerri; Levin, Harvey S.; Schenk, A. Katrin

2014-01-01

Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intruder paradigm at adulthood. These outcomes were complemented by assays of urine scent marking and ultrasonic vocalizations as indices of social communication. We provide evidence of sociosexual deficits after brain injury at p21, which manifest as reduced mounting behavior and scent marking towards an unfamiliar female at adulthood. In contrast, with the exception of the loss of social recognition in a three-chamber social approach task, mice that received TBI at adolescence were remarkably resilient to social deficits at adulthood. Increased emission of ultrasonic vocalizations (USVs) as well as preferential emission of high frequency USVs after injury was dependent upon both the stimulus and prior social experience. Contrary to the hypothesis that changes in white matter volume may underlie social dysfunction, injury at both p21 and p35 resulted in a similar degree of atrophy of the corpus callosum by adulthood. However, loss of hippocampal tissue was greater after p21 compared to p35 injury, suggesting that a longer period of lesion progression or differences in the kinetics of secondary pathogenesis after p21 injury may contribute to observed behavioral differences. Together, these findings indicate vulnerability of the developing brain to social dysfunction, and suggest that a younger age-at-insult results in poorer social and sociosexual outcomes. PMID:25106033

Organizational topology of brain and its relationship to ADHD in adolescents with d-transposition of the great arteries.

PubMed

Schmithorst, Vincent J; Panigrahy, Ashok; Gaynor, J William; Watson, Christopher G; Lee, Vince; Bellinger, David C; Rivkin, Michael J; Newburger, Jane W

2016-08-01

Little is currently known about the impact of congenital heart disease (CHD) on the organization of large-scale brain networks in relation to neurobehavioral outcome. We investigated whether CHD might impact ADHD symptoms via changes in brain structural network topology in a cohort of adolescents with d-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and referent subjects. We also explored whether these effects might be modified by apolipoprotein E (APOE) genotype, as the APOE ε2 allele has been associated with worse neurodevelopmental outcomes after repair of d-TGA in infancy. We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 47 d-TGA adolescents and 29 healthy referents to construct measures of structural topology at the global and regional levels. We developed statistical mediation models revealing the respective contributions of d-TGA, APOE genotype, and structural network topology on ADHD outcome as measured by the Connors ADHD/DSM-IV Scales (CADS). Changes in overall network connectivity, integration, and segregation mediated worse ADHD outcomes in d-TGA patients compared to healthy referents; these changes were predominantly in the left and right intrahemispheric regional subnetworks. Exploratory analysis revealed that network topology also mediated detrimental effects of the APOE ε4 allele but improved neurobehavioral outcomes for the APOE ε2 allele. Our results suggest that disruption of organization of large-scale networks may contribute to neurobehavioral dysfunction in adolescents with CHD and that this effect may interact with APOE genotype.

Basal ganglia dysfunction

MedlinePlus

... disease Metabolic problems Multiple sclerosis (MS) Poisoning with copper, manganese, or other heavy metals Stroke Tumors A ... the brain) Wilson disease (disorder causing too much copper in the body's tissues)

Communication disorders and executive function impairment after severe traumatic brain injury: an exploratory study using the GALI (a grid for linguistic analysis of free conversational interchange).

PubMed

Sainson, C; Barat, M; Aguert, M

2014-12-01

Following severe traumatic brain injury (TBI), failure to adjust language to communication abilities has been described and attributed by many authors to executive function impairment. Interactional dysfunctions may damage family-based, social and vocational equilibrium, and they are of key importance in prognosis of rehabilitation outcome. In conversation, frequently occurring inappropriate formulations connote difficulties in discursive organization and are likely to include numerous digressions, if not confabulations. The main objective of this study was to improve assessment of the non-verbal as well as the verbal aspects of the communication disorders observed in TBI subjects. We have developed and are proposing the grid for linguistic analysis (GALI) of free conversational interchange that constitutes an original French-language tool. We wish to demonstrate its validity as a means of measuring interactive skills in a given population. We assessed 17 severely brain injured patients presenting executive dysfunction, who were compared with 34 matched and healthy individuals. Fifty-one 10-minute sequences of free conversation between study participants and therapists were filmed and analyzed by applying the GALI. Three independent raters coded the conversations. Inter-rater reproducibility was considered statistically satisfactory. The results successfully distinguished TBI patients from healthy subjects and thereby underscored the discriminatory value of the tool. A significant correlation was found between the patients' performances in executive tests and in the GALI. In severe TBI a social handicap results from several associated cognitive disorders. Interactive discourse analysis combining non-verbal with verbal aspects confirms the existence of difficulties in communication that are usually underestimated in classic formal language testing methods. The GALI is likely to meet speech therapists' need for reliable assessment of their patients' interactional difficulties and their consequences in social life. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

"Brain-muscle loop" in the fragility of older persons: from pathophysiology to new organizing models.

PubMed

Lauretani, Fulvio; Meschi, Tiziana; Ticinesi, Andrea; Maggio, Marcello

2017-12-01

The imperative action of the geriatric medicine is to prevent disability in older persons. Many epidemiological studies have been conducted in the last decades for improving knowledge of the aging process and their interactions with age-related diseases, especially for the identification of the relationship between sarcopenia and loss of mobility. Factors influencing muscle integrity can be classified into six main physiologic subsystems, but the central nervous system certainly plays a crucial role for maintaining muscle integrity in older persons. Recent data show that the reduced muscle strength and not muscle mass could be considered the core of the fragility in predicting changes of gait velocity and mobility and conferring a higher risk of mortality in older persons. Sarcopenia and cognitive decline could, therefore, produce slow gait velocity in older persons, with devastating effect and consequences. Perhaps the most notorious corollary is falling, which is often caused by an underlying gait problem. Injuries caused by accidental falls range from relatively innocent bruises to major fractures or head trauma. Another important consequence is reduced mobility, which leads to loss of independence. This immobility is often compounded by a fear of falling, which further immobilises patients and affects their quality of life and physical performance. When we search the association between brain pathology and muscle function in older persons, we amazingly find that established composite measure of physical frailty is associated with brain pathology. Sarcopenia, which produces muscle dysfunction, slow gait velocity and cognitive decline, could share a strong bidirectional relationship, and this suggests the coexistence of both cognitive and motor dysfunctions in older persons to characterize a new syndrome characterized by slow gait and cognitive complaints, the motoric-cognitive risk syndrome (MRC). In this review, we want to emphasize the relationship between memory complaints with muscle function integrating cognitive and physical evaluation, even with amyloid PET study, to identify older patients at high risk of cognitive and physical decline.

[Clinical Characteristics of Metronidazole-induced Encephalopathy: A Report of Two Cases and a Review of 32 Japanese Cases in the Literature].

PubMed

Kato, Hideaki; Sosa, Hiroko; Mori, Masaaki; Kaneko, Takeshi

2015-09-01

Metronidazole is an antibiotic classically used against most anaerobic bacteria and protozoa. Because an intravenous form of metronidazole has recently entered the market, the use of this antibiotic is attracting renewed interest in many clinical settings in Japan. However, neurotoxicity is a major adverse event: in the central nervous system metronidazole-induced encephalopathy is a rare but serious condition. We performed a literature review of 34 cases including 2 of our cases, 25 from domestic conference abstracts, and 7 cases presented in full research papers. The mean patient age was 64.7 years. The conditions most commonly treated with metronidazole were brain abscess (35.3%), liver abscess (17.6%), and Clostridium difficile infection (14.7%). The most common predisposing conditions were liver dysfunction (26.5%), diabetes and other metabolic disorders (20.6%), and hematologic or solid organ malignancy (14.7%). The mean period of administration before the onset of encephalopathy symptoms was 61.3 days, and the mean total dose was 95.9g. The initial chief complaints were dysarthria (in 70.6% of the cases) and ataxia (61.8%); 82.4% of the cases were diagnosed on the basis of MRI (T2-weighted or FLAIR imaging). The key imaging finding was high intensity in the dentate nucleus bilaterally (82.4%). Stopping the metronidazole led to symptom remission within 8.5 days, but the MRI changes remained longer than the clinical symptoms. Two patients (6.0%) developed irreversible disturbance of consciousness. Although the mechanisms of this type of encephalopathy have not yet been elucidated, localized nerve-cell edema is likely caused by decreased metronidazole metabolism associated with liver and metabolic dysfunction. Careful observation for neurologic signs should be conducted during the treatment of brain abscesses associated with metronidazole administration, because patients with brain abscesses are naturally at high risk of metronidazole-induced encephalopathy.

Short-term fructose ingestion affects the brain independently from establishment of metabolic syndrome.

PubMed

Jiménez-Maldonado, Alberto; Ying, Zhe; Byun, Hyae Ran; Gomez-Pinilla, Fernando

2018-01-01

Chronic fructose ingestion is linked to the global epidemic of metabolic syndrome (MetS), and poses a serious threat to brain function. We asked whether a short period (one week) of fructose ingestion potentially insufficient to establish peripheral metabolic disorder could impact brain function. We report that the fructose treatment had no effect on liver/body weight ratio, weight gain, glucose tolerance and insulin sensitivity, was sufficient to reduce several aspects of hippocampal plasticity. Fructose consumption reduced the levels of the neuronal nuclear protein NeuN, Myelin Basic Protein, and the axonal growth-associated protein 43, concomitant with a decline in hippocampal weight. A reduction in peroxisome proliferator-activated receptor gamma coactivator-1 alpha and Cytochrome c oxidase subunit II by fructose treatment is indicative of mitochondrial dysfunction. Furthermore, the GLUT5 fructose transporter was increased in the hippocampus after fructose ingestion suggesting that fructose may facilitate its own transport to brain. Fructose elevated levels of ketohexokinase in the liver but did not affect SIRT1 levels, suggesting that fructose is metabolized in the liver, without severely affecting liver function commensurable to an absence of metabolic syndrome condition. These results advocate that a short period of fructose can influence brain plasticity without a major peripheral metabolic dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

Clematichinenoside protects blood brain barrier against ischemic stroke superimposed on systemic inflammatory challenges through up-regulating A20.

PubMed

Han, Dan; Fang, Weirong; Zhang, Rui; Wei, Jie; Kodithuwakku, Nandani Darshika; Sha, Lan; Ma, Wenhuan; Liu, Lifang; Li, Fengwen; Li, Yunman

2016-01-01

Suppression of excessive inflammation can ameliorate blood brain barrier (BBB) injury, which shows therapeutic potential for clinical treatment of brain injury induced by stroke superimposed on systemic inflammatory diseases. In this study, we investigated whether and how clematichinenoside (AR), an anti-inflammatory triterpene saponin, protects brain injury from stroke superimposed on systemic inflammation. Lipopolysaccharide (LPS) was intraperitoneally injected immediately after middle cerebral artery occlusion (MCAO) in rats. Rat microvessel endothelial cells (rBMECs) were exposed to hypoxia/reoxygenation (H/R) coexisting with LPS. The results revealed that AR suppressed the excessive inflammation, restored BBB dysfunction, alleviated brain edema, decreased neutrophil infiltration, lessened neurological dysfunction, and decreased infarct rate. Further study demonstrated that the expression of nucleus nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) were suppressed by AR via zinc finger protein A20. Besides, AR increased in vitro BBB integrity through A20. In conclusion, AR alleviated cerebral inflammatory injury through A20-NF-κB signal pathway, offering an alternative medication for stroke associated with systemic inflammatory diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients

PubMed Central

Rothman, Douglas L; Nordström, Carl-Henrik

2016-01-01

Cerebral microdialysis is a widely used clinical tool for monitoring extracellular concentrations of selected metabolites after brain injury and to guide neurocritical care. Extracellular glucose levels and lactate/pyruvate ratios have high diagnostic value because they can detect hypoglycemia and deficits in oxidative metabolism, respectively. In addition, patterns of metabolite concentrations can distinguish between ischemia and mitochondrial dysfunction, and are helpful to choose and evaluate therapy. Increased intracranial pressure can be life-threatening after brain injury, and hypertonic solutions are commonly used for pressure reduction. Recent reports have advocated use of hypertonic sodium lactate, based on claims that it is glucose sparing and provides an oxidative fuel for injured brain. However, changes in extracellular concentrations in microdialysate are not evidence that a rise in extracellular glucose level is beneficial or that lactate is metabolized and improves neuroenergetics. The increase in glucose concentration may reflect inhibition of glycolysis, glycogenolysis, and pentose phosphate shunt pathway fluxes by lactate flooding in patients with mitochondrial dysfunction. In such cases, lactate will not be metabolizable and lactate flooding may be harmful. More rigorous approaches are required to evaluate metabolic and physiological effects of administration of hypertonic sodium lactate to brain-injured patients. PMID:27604313

Impaired social brain network for processing dynamic facial expressions in autism spectrum disorders.

PubMed

Sato, Wataru; Toichi, Motomi; Uono, Shota; Kochiyama, Takanori

2012-08-13

Impairment of social interaction via facial expressions represents a core clinical feature of autism spectrum disorders (ASD). However, the neural correlates of this dysfunction remain unidentified. Because this dysfunction is manifested in real-life situations, we hypothesized that the observation of dynamic, compared with static, facial expressions would reveal abnormal brain functioning in individuals with ASD.We presented dynamic and static facial expressions of fear and happiness to individuals with high-functioning ASD and to age- and sex-matched typically developing controls and recorded their brain activities using functional magnetic resonance imaging (fMRI). Regional analysis revealed reduced activation of several brain regions in the ASD group compared with controls in response to dynamic versus static facial expressions, including the middle temporal gyrus (MTG), fusiform gyrus, amygdala, medial prefrontal cortex, and inferior frontal gyrus (IFG). Dynamic causal modeling analyses revealed that bi-directional effective connectivity involving the primary visual cortex-MTG-IFG circuit was enhanced in response to dynamic as compared with static facial expressions in the control group. Group comparisons revealed that all these modulatory effects were weaker in the ASD group than in the control group. These results suggest that weak activity and connectivity of the social brain network underlie the impairment in social interaction involving dynamic facial expressions in individuals with ASD.

Rehabilitation of Visual and Perceptual Dysfunction after Severe Traumatic Brain Injury

DTIC Science & Technology

2013-03-01

be virtual ma eality mode n which the cles (life-siz om the simu ived safe pa rtual reality ixate a cross ppears, move ure and the ntricity offset...AD_________________ Award Number: W81XWH-11-2-0082 TITLE: Rehabilitation of Visual and Perceptual...March 2012 – 28 February 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Rehabilitation of Visual and Perceptual Dysfunction after Severe Traumatic

Pathophysiological and Therapeutic Considerations for Non-Neurogenic Lower Urinary Tract Dysfunction in Children.

PubMed

Kakizaki, Hidehiro; Kita, Masafumi; Watanabe, Masaki; Wada, Naoki

2016-05-01

Non-neurogenic lower urinary tract dysfunction (LUTD) in children is very common in clinical practice and is important as an underlying cause of lower urinary tract symptoms, urinary tract infection and vesicoureteral reflux in affected children. LUTD in children is caused by multiple factors and might be related with a delay in functional maturation of the lower urinary tract. Behavioral and psychological problems often co-exist in children with LUTD and bowel dysfunction. Recent findings in functional brain imaging suggest that bladder bowel dysfunction and behavioral and psychiatric disorders in children might share common pathophysiological factors in the brain. Children with suspected LUTD should be evaluated properly by detailed history taking, validated questionnaire on voiding and defecation, voiding and bowel diary, urinalysis, screening ultrasound, uroflowmetry and post-void residual measurement. Invasive urodynamic study such as videourodynamics should be reserved for children in whom standard treatment fails. Initial treatment of non-neurogenic LUTD is standard urotherapy comprising education of the child and family, regular optimal voiding regimens and bowel programs. Pelvic floor muscle awareness, biofeedback and neuromodulation can be used as a supplementary purpose. Antimuscarinics and α-blockers are safely used for overactive bladder and dysfunctional voiding, respectively. For refractory cases, botulinum toxin A injection is a viable treatment option. Prudent use of urotherapy and pharmacotherapy for non-neurogenic LUTD should have a better chance to cure various problems and improve self-esteem and quality of life in affected children. © 2015 Wiley Publishing Asia Pty Ltd.

Trial-unique, delayed nonmatching-to-location (TUNL) touchscreen testing for mice: sensitivity to dorsal hippocampal dysfunction.

PubMed

Kim, Chi Hun; Romberg, Carola; Hvoslef-Eide, Martha; Oomen, Charlotte A; Mar, Adam C; Heath, Christopher J; Berthiaume, Andrée-Anne; Bussey, Timothy J; Saksida, Lisa M

2015-11-01

The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.

Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging

PubMed Central

Toth, Peter; Tarantini, Stefano; Csiszar, Anna

2017-01-01

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer’s disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) are expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function, and neurovascular coupling responses responsible for functional hyperemia. The pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction, and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID has captured in recent years, the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined. PMID:27793855

Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase.

PubMed

Villalba, Nuria; Sackheim, Adrian M; Nunez, Ivette A; Hill-Eubanks, David C; Nelson, Mark T; Wellman, George C; Freeman, Kalev

2017-01-01

Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial-dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production. The activity of arginase, which competes with endothelial NO synthase (eNOS) for the common substrate l-arginine, were also significantly increased in arteries, suggesting that arginase-mediated depletion of l-arginine underlies diminished NO production. Consistent with this, substrate restoration by exogenous application of l-arginine or inhibition of arginase recovered endothelial function. Moreover, evidence for increased reactive oxygen species production, a consequence of l-arginine starvation-dependent eNOS uncoupling, was detected in endothelium and plasma. Collectively, our findings demonstrate endothelial dysfunction in a remote vascular bed after TBI, manifesting as impaired endothelial-dependent vasodilation, with increased arginase activity, decreased generation of NO, and increased O 2 - production. We conclude that blood vessels have a "molecular memory" of neurotrauma, 24 h after injury, because of functional changes in vascular endothelial cells; these effects are pertinent to understanding the systemic inflammatory response that occurs after TBI even in the absence of polytrauma.

Brain endothelial dysfunction in cerebral adrenoleukodystrophy.

PubMed

Musolino, Patricia L; Gong, Yi; Snyder, Juliet M T; Jimenez, Sandra; Lok, Josephine; Lo, Eng H; Moser, Ann B; Grabowski, Eric F; Frosch, Matthew P; Eichler, Florian S

2015-11-01

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Estimation of sensitivity and specificity of brain magnetic resonance imaging and single photon emission computed tomography in the diagnosis of olfactory dysfunction after head traumas.

PubMed

Atighechi, Saeid; Zolfaghari, Aliasghar; Baradaranfar, Mohammadhossein; Dadgarnia, Mohammadhossein

2013-01-01

Olfactory dysfunction has an incidence of 5-10% after head injury. Several objective and subjective tests had been proposed. Recent studies showed that brain single photon emission computed tomography (SPECT) and brain magnetic resonance imaging (MRI) have good diagnostic value in this era in which the most common sites of involvement were olfactory bulb and olfactory nerve in MRI and frontal lobe in SPECT. This study aimed to estimate the sensitivity and specificity of brain MRI and brain SPECT in the diagnosis of traumatic hyposmia and anosmia. From February 2009 to March 2011, 63 patients with head injury and smell complaint were selected for this study. Using an identification test and a threshold smell test, 28 were anosmic and 27 had hyposmia and the remaining 8 were normosmic. All of them underwent brain MRI and SPECT. The sensitivity of SPECT was 81.5 and 85.7% in hyposmia and anosmia, respectively. Its specificity was 87.5% in anosmia and 87.7% in anosmia. MRI sensitivity was 66.7% in hyposmia but 82.1% in anosmia. Its specificity was 85.7% in anosmia and 87.7% in anosmia. If MRI and SPECT were considered together, the sensitivity was 92.3% in hyposmia and 92% in anosmia, but the specificity was 87% in both cases. According to our study, both brain MRI and SPECT have high sensitivity and specificity in the diagnosis of traumatic anosmia, although brain SPECT is slightly superior to MRI. If the two techniques are applied together, the accuracy will be increased.

[Bruxism--a function of the masticatory organ to cope with stress].

PubMed

Slavicek, Rudolf; Sato, Sadao

2004-12-01

Bruxism is generally defined as a parafunctional clenching and grinding action between the upper and lower teeth. During this activity, extremely strong forces can be applied for time periods exceeding those of functional mastication. These biomechanical loads create many dental problems, such as abfractions, hypersensitivity, periodontal distraction, and temporo-mandibular dysfunction. Researchers studying Bruxism have long discussed psychic stress and emotional tension. It has also been indicated that an aggressive biting is associated with a significant attenuation of the stress-induced increase of nor-adrenalin turnover in the brain, of the striatal DOPAC contents and with the prevention of stomach ulcer formation in experimental animals. The concept of stress management based on the psychological background of Bruxism and the benefits attributable to masticatory muscle activity in attenuating stress-related symptoms such as stomach ulcer. The clenching and bruxing function of the masticatory organ is an emergency exit during periods of psychic overloading. Therefore, occlusion of the masticatory organ contributes significantly to an individual's ability to manage stress. Bruxism in proper dentition can be recognized as a valid system prophylaxis for all stress related diseases.

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.

PubMed

Maestraggi, Quentin; Lebas, Benjamin; Clere-Jehl, Raphaël; Ludes, Pierre-Olivier; Chamaraux-Tran, Thiên-Nga; Schneider, Francis; Diemunsch, Pierre; Geny, Bernard; Pottecher, Julien

2017-01-01

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Pseudotumor Cerebri and Glymphatic Dysfunction.

PubMed

Bezerra, Marcio Luciano de Souza; Ferreira, Ana Carolina Andorinho de Freitas; de Oliveira-Souza, Ricardo

2017-01-01

In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of β-amyloid in Alzheimer's disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses.