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Sample records for active brain targeting

  1. Brain Activation Underlying Threat Detection to Targets of Different Races

    PubMed Central

    Senholzi, Keith B.; Depue, Brendan E.; Correll, Joshua; Banich, Marie T.; Ito, Tiffany A.

    2016-01-01

    The current study examined blood oxygen level dependent (BOLD) signal underlying racial differences in threat detection. During fMRI, participants determined whether pictures of Black or White individuals held weapons. They were instructed to make shoot responses when the picture showed armed individuals but don’t shoot responses to unarmed individuals, with the cost of not shooting armed individuals being greater than that of shooting unarmed individuals. Participants were faster to shoot armed Blacks than Whites, but faster in making don’t shoot responses to unarmed Whites than Blacks. Brain activity differed to armed versus unarmed targets depending on target race, suggesting different mechanisms underlying threat versus safety decisions. Anterior cingulate cortex was preferentially engaged for unarmed Whites than Blacks. Parietal and visual cortical regions exhibited greater activity for armed Blacks than Whites. Seed-based functional connectivity of the amygdala revealed greater coherence with parietal and visual cortices for armed Blacks than Whites. Furthermore, greater implicit Black-danger associations were associated with increased amygdala activation to armed Blacks, compared to armed Whites. Our results suggest that different neural mechanisms may underlie racial differences in responses to armed versus unarmed targets. PMID:26357911

  2. Active brain targeting of a fluorescent P-gp substrate using polymeric magnetic nanocarrier system.

    PubMed

    Kirthivasan, B; Singh, D; Bommana, M M; Raut, S L; Squillante, E; Sadoqi, M

    2012-06-29

    Magnetic nanoparticles (NP) were developed for the active brain targeting of water-soluble P-glycoprotein (P-gp) substrate rhodamine 123 (Rh123). The NP matrix of poly(lactide-co-glycolide) (PLGA) and methoxy poly(ethyleneglycol)-poly(lactic acid) (M-PEG-PLA) was prepared by single emulsion solvent evaporation of polymers with oleic acid-coated magnetic nanoparticles (OAMNP) and Rh123. All formulations were characterized in terms of morphology, particle size, magnetic content and Rh123 encapsulation efficiency. The maximum encapsulation efficiency of Rh123 was 45 ± 3% and of OAMNP was 42 ± 4%. The brain targeting and biodistribution study was performed on Sprague Dawley rats (3 groups, n = 6). Rh123 (0.4 mg kg(-1)) was administered in saline form, NP containing Rh123, and NP containing Rh123 in the presence of a magnetic field (0.8 T). The fluorimetric analysis of brain homogenates revealed a significant uptake (p < 0.05) of Rh123 in the magnetically targeted group relative to controls. These results were supported by fluorescence microscopy. This study reveals the ability of magnetically targeted nanoparticles to deliver substances to the brain, the permeation of which would otherwise be inhibited by the P-gp system.

  3. Active brain targeting of a fluorescent P-gp substrate using polymeric magnetic nanocarrier system

    NASA Astrophysics Data System (ADS)

    Kirthivasan, B.; Singh, D.; Bommana, M. M.; Raut, S. L.; Squillante, E.; Sadoqi, M.

    2012-06-01

    Magnetic nanoparticles (NP) were developed for the active brain targeting of water-soluble P-glycoprotein (P-gp) substrate rhodamine 123 (Rh123). The NP matrix of poly(lactide-co-glycolide) (PLGA) and methoxy poly(ethyleneglycol)-poly(lactic acid) (M-PEG-PLA) was prepared by single emulsion solvent evaporation of polymers with oleic acid-coated magnetic nanoparticles (OAMNP) and Rh123. All formulations were characterized in terms of morphology, particle size, magnetic content and Rh123 encapsulation efficiency. The maximum encapsulation efficiency of Rh123 was 45 ± 3% and of OAMNP was 42 ± 4%. The brain targeting and biodistribution study was performed on Sprague Dawley rats (3 groups, n = 6). Rh123 (0.4 mg kg-1) was administered in saline form, NP containing Rh123, and NP containing Rh123 in the presence of a magnetic field (0.8 T). The fluorimetric analysis of brain homogenates revealed a significant uptake (p < 0.05) of Rh123 in the magnetically targeted group relative to controls. These results were supported by fluorescence microscopy. This study reveals the ability of magnetically targeted nanoparticles to deliver substances to the brain, the permeation of which would otherwise be inhibited by the P-gp system.

  4. Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

    PubMed Central

    Seekaew, Pich

    2016-01-01

    Abstract Neural stem cells in the adult brain possess the ability to remain quiescent until needed in tissue homeostasis or repair. It was previously shown that traumatic brain injury (TBI) stimulated neural stem cell (NSC) proliferation in the adult hippocampus, indicating an innate repair mechanism, but it is unknown how TBI promotes NSC proliferation. In the present study, we observed dramatic activation of mammalian target of rapamycin complex 1 (mTORC1) in the hippocampus of mice with TBI from controlled cortical impact (CCI). The peak of mTORC1 activation in the hippocampal subgranular zone, where NSCs reside, is 24–48 h after trauma, correlating with the peak of TBI-enhanced NSC proliferation. By use of a Nestin-GFP transgenic mouse, in which GFP is ectopically expressed in the NSCs, we found that TBI activated mTORC1 in NSCs. With 5-bromo-2′-deoxyuridine labeling, we observed that TBI increased mTORC1 activation in proliferating NSCs. Furthermore, administration of rapamycin abolished TBI-promoted NSC proliferation. Taken together, these data indicate that mTORC1 activation is required for NSC proliferation postinjury, and thus might serve as a therapeutic target for interventions to augment neurogenesis for brain repair after TBI. PMID:27822507

  5. Targeting complement activation in brain-dead donors improves renal function after transplantation.

    PubMed

    Damman, Jeffrey; Hoeger, Simone; Boneschansker, Leo; Theruvath, Ashok; Waldherr, Ruediger; Leuvenink, Henri G; Ploeg, Rutger J; Yard, Benito A; Seelen, Marc A

    2011-05-01

    Kidneys recovered from brain-dead donors have inferior outcomes after transplantation compared to kidneys from living donors. Since complement activation plays an important role in renal transplant related injury, targeting complement activation in brain-dead donors might improve renal function after transplantation. Brain death (BD) was induced in Fisher rats by inflation of an epidurally placed balloon catheter and ventilated for 6h. BD animals were treated with soluble complement receptor 1 (sCR1) 1h before or 1h after BD. Kidney transplantation was performed and 7 days after transplantation animals were sacrificed. Plasma creatinine and urea were measured at days 0, 1, 3, 5 and 7 after transplantation. Renal function was significantly better at day 1 after transplantation in recipients receiving a sCR1 pre-treated donor kidney compared to recipients of a non-treated donor graft. Also treatment with sCR1, 1h after the diagnosis of BD, resulted in a better renal function after transplantation. Gene expression of IL-6, IL-1beta and TGF-beta were significantly lower in renal allografts recovered from treated donors. This study shows that targeting complement activation, during BD in the donor, leads to an improved renal function after transplantation in the recipient.

  6. Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation

    PubMed Central

    Panyakaew, Pattamon; Cho, Hyun Joo; Srivanitchapoom, Prachaya; Popa, Traian; Wu, Tianxia; Hallett, Mark

    2016-01-01

    Motor surround inhibition is the neural mechanism that selectively favors the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) as the target muscle, and the abductor digiti minimi (ADM), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) as surround muscles during rest and tonic activation of FDI in fourteen subjects. Cerebellar stimulation was performed under MRI-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90% to 120% of adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI was selected for use during tonic activation. During selective tonic activation of FDI, CBI was significantly reduced only for FDI but not for the surround muscles. Unconditioned MEP sizes were increased in all muscles during FDI tonic activation compared to rest, despite background EMG activity increasing only for the FDI. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle. PMID:26900871

  7. Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation.

    PubMed

    Panyakaew, Pattamon; Cho, Hyun Joo; Srivanitchapoom, Prachaya; Popa, Traian; Wu, Tianxia; Hallett, Mark

    2016-04-01

    Motor surround inhibition is the neural mechanism that selectively favours the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) muscle as the target muscle, and the abductor digiti minimi, flexor carpi radialis and extensor carpi radialis muscles as surround muscles, during rest and tonic activation of the FDI muscle in 21 subjects. Cerebellar stimulation was performed under magnetic resonance imaging-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90-120% of the adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI muscle was selected for use during tonic activation. During selective tonic activation of the FDI muscle, CBI was significantly reduced only for the FDI muscle, and not for the surround muscles. Unconditioned motor evoked potential sizes were increased in all muscles during FDI muscle tonic activation as compared with rest, despite background electromyography activity increasing only for the FDI muscle. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle.

  8. Current steering to activate targeted neural pathways during deep brain stimulation of the subthalamic region

    PubMed Central

    Chaturvedi, Ashutosh; Foutz, Thomas J.; McIntyre, Cameron C.

    2012-01-01

    Deep brain stimulation (DBS) has steadily evolved into an established surgical therapy for numerous neurological disorders, most notably Parkinson’s disease (PD). Traditional DBS technology relies on voltage-controlled stimulation with a single source; however, recent engineering advances are providing current-controlled devices with multiple independent sources. These new stimulators deliver constant current to the brain tissue, irrespective of impedance changes that occur around the electrode, and enable more specific steering of current towards targeted regions of interest. In this study, we examined the impact of current steering between multiple electrode contacts to directly activate three distinct neural populations in the subthalamic region commonly stimulated for the treatment of PD: projection neurons of the subthalamic nucleus (STN), globus pallidus internus (GPi) fibers of the lenticular fasiculus, and internal capsule (IC) fibers of passage. We used three-dimensional finite element electric field models, along with detailed multi-compartment cable models of the three neural populations to determine their activations using a wide range of stimulation parameter settings. Our results indicate that selective activation of neural populations largely depends on the location of the active electrode(s). Greater activation of the GPi and STN populations (without activating any side-effect related IC fibers) was achieved by current steering with multiple independent sources, compared to a single current source. Despite this potential advantage, it remains to be seen if these theoretical predictions result in a measurable clinical effect that outweighs the added complexity of the expanded stimulation parameter search space generated by the more flexible technology. PMID:22277548

  9. Plausible antioxidant biomechanics and anticonvulsant pharmacological activity of brain-targeted β-carotene nanoparticles

    PubMed Central

    Yusuf, Mohammad; Khan, Riaz A; Khan, Maria; Ahmed, Bahar

    2012-01-01

    β-Carotene has been established as a known free radical scavenger with chain-breaking antioxidant properties. It has been documented for the treatment of epileptic convulsions at a 200 mg/kg body weight dose. The reported pathogenesis for epileptic convulsions is oxidative stress. Hence, experimental epileptic convulsions via oxidative stress was induced in albino mice epileptic models (maximal electroshock seizure and pentylenetetrazole [PTZ]). A dose concentration equivalent to 2 mg/kg was efficaciously administered in the form of brain-targeted polysorbate-80-coated poly(d,l-lactide-co-glycolide) nanoparticles. The nanoparticles were prepared by solvent evaporation technique and further characterized for their physical parameters, in-vitro release kinetics, and in-vivo brain release via various standard methods. Normal β-carotene nanoparticles (BCNP) and polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP) of 169.8 ± 4.8 nm and 176.3 ± 3.2 nm in size, respectively, were formulated and characterized. Their zeta potential and polydispersity index were subsequently evaluated after 5 months of storage to confirm stability. In vivo activity results showed that a 2 mg unformulated β-carotene dose was ineffective as an anticonvulsant. However, salutary response was reported from BCNP at the same dose, as the hind limb duration decreased significantly in maximal electroshock seizure to 9.30 ± 0.86 seconds, which further decreased with polysorbate-80 coating to 2.10 ± 1.16 seconds as compared to normal control (15.8 ± 1.49 seconds) and placebo control (16.50 ± 1.43 seconds). In the PTZ model, the duration of general tonic–clonic seizures reduced significantly to 2.90 ± 0.98 seconds by the use of BCNP and was further reduced on P-80-BCNP to 1.20 ± 0.20 seconds as compared to PTZ control and PTZ-placebo control (8.09 ± 0.26 seconds). General tonic–clonic seizures latency was increased significantly to 191.0 ± 9.80 seconds in BCNP and was further

  10. Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors

    PubMed Central

    Warren, G; Makarov, E; Lu, Y; Senanayake, T; Rivera, K; Gorantla, S; Poluektova, LY; Vinogradov, SV

    2015-01-01

    Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-ε-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity. PMID:25559020

  11. Perspectives on Dual Targeting Delivery Systems for Brain Tumors.

    PubMed

    Gao, Huile

    2017-03-01

    Brain tumor remains one of the most serious threats to human beings. Different from peripheral tumors, drug delivery to brain tumor is largely restricted by the blood brain barrier (BBB). To fully conquer this barrier and specifically deliver drugs to brain tumor, dual targeting delivery systems were explored, which are functionalized with two active targeting ligands: one to the BBB and the other to the brain tumor. The development of dual targeting delivery system is still in its early stage, and attentions need to be paid to issues and concerns that remain unresolved in future studies.

  12. Deep brain stimulation for obesity: past, present, and future targets.

    PubMed

    Dupré, Derrick A; Tomycz, Nestor; Oh, Michael Y; Whiting, Donald

    2015-06-01

    The authors review the history of deep brain stimulation (DBS) in patients for treating obesity, describe current DBS targets in the brain, and discuss potential DBS targets and nontraditional stimulation parameters that may improve the effectiveness of DBS for ameliorating obesity. Deep brain stimulation for treating obesity has been performed both in animals and in humans with intriguing preliminary results. The brain is an attractive target for addressing obesity because modulating brain activity may permit influencing both sides of the energy equation--caloric intake and energy expenditure.

  13. Lipid metabolism as a target for brain cancer therapy: synergistic activity of lovastatin and sodium phenylacetate against human glioma cells.

    PubMed

    Prasanna, P; Thibault, A; Liu, L; Samid, D

    1996-02-01

    Malignant gliomas, the most common form of primary brain tumors, are highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical to cell replication. Human glioblastoma cells were found to be uniquely vulnerable to growth arrest by lovastatin, a competitive inhibitor of the enzyme regulating MVA synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. The sodium salt of phenylacetic acid (NaPA), an inhibitor of MVA-pyrophosphate decarboxylase, the enzyme that controls MVA use, acted synergistically with lovastatin to suppress malignant growth. When used at pharmacologically attainable concentrations, the two compounds induced profound cytostasis and loss of malignant properties such as invasiveness and expression of the transforming growth factor-beta 2 gene, coding for a potent immunosuppressive cytokine. Supplementation with exogenous ubiquinone, an end product of the MVA pathway, failed to rescue the cells, suggesting that decreased synthesis of intermediary products are responsible for the antitumor effects observed. In addition to blocking the MVA pathway, lovastatin alone and in combination with NaPA increased the expression of the peroxisome proliferator-activated receptor, a transcription factor implicated in the control of lipid metabolism, cell growth, and differentiation. Our results indicate that targeting lipid metabolism with lovastatin, used alone or in combination with the aromatic fatty acid NaPA, may offer a novel approach to the treatment of malignant gliomas.

  14. Cytomegalovirus Infection of the Rat Developing Brain In Utero Prominently Targets Immune Cells and Promotes Early Microglial Activation

    PubMed Central

    Cloarec, Robin; Bauer, Sylvian; Luche, Hervé; Buhler, Emmanuelle; Pallesi-Pocachard, Emilie; Salmi, Manal; Courtens, Sandra; Massacrier, Annick; Grenot, Pierre; Teissier, Natacha; Watrin, Françoise; Schaller, Fabienne; Adle-Biassette, Homa; Gressens, Pierre; Malissen, Marie; Stamminger, Thomas; Streblow, Daniel N.; Bruneau, Nadine; Szepetowski, Pierre

    2016-01-01

    Background Congenital cytomegalovirus infections are a leading cause of neurodevelopmental disorders in human and represent a major health care and socio-economical burden. In contrast with this medical importance, the pathophysiological events remain poorly known. Murine models of brain cytomegalovirus infection, mostly neonatal, have brought recent insights into the possible pathogenesis, with convergent evidence for the alteration and possible involvement of brain immune cells. Objectives and Methods In order to confirm and expand those findings, particularly concerning the early developmental stages following infection of the fetal brain, we have created a model of in utero cytomegalovirus infection in the developing rat brain. Rat cytomegalovirus was injected intraventricularly at embryonic day 15 (E15) and the brains analyzed at various stages until the first postnatal day, using a combination of gene expression analysis, immunohistochemistry and multicolor flow cytometry experiments. Results Rat cytomegalovirus infection was increasingly seen in various brain areas including the choroid plexi and the ventricular and subventricular areas and was prominently detected in CD45low/int, CD11b+ microglial cells, in CD45high, CD11b+ cells of the myeloid lineage including macrophages, and in CD45+, CD11b– lymphocytes and non-B non-T cells. In parallel, rat cytomegalovirus infection of the developing rat brain rapidly triggered a cascade of pathophysiological events comprising: chemokines upregulation, including CCL2-4, 7 and 12; infiltration by peripheral cells including B-cells and monocytes at E17 and P1, and T-cells at P1; and microglia activation at E17 and P1. Conclusion In line with previous findings in neonatal murine models and in human specimen, our study further suggests that neuroimmune alterations might play critical roles in the early stages following cytomegalovirus infection of the brain in utero. Further studies are now needed to determine which

  15. Pharmaceutical Targeting of the Brain.

    PubMed

    Krizbai, István A; Nyúl-Tóth, Ádám; Bauer, Hans-Christian; Farkas, Attila E; Traweger, Andreas; Haskó, János; Bauer, Hannelore; Wilhelm, Imola

    2016-01-01

    Besides being indispensable for the protection and nutrition of the central nervous system (CNS), blood-brain barrier (BBB)-forming cerebral endothelial cells (CECs) have a major role in hampering drugs to reach therapeutically relevant concentrations in the brain. In this respect, the most important defense systems of CECs are tight junctions (TJs) sealing the paracellular way of transport, efflux pumps (ABC transporters) and metabolic enzymes. Here we review current strategies aiming at overcoming the BBB with the purpose of effectively delivering drugs to the CNS. Besides chemical modification of drug candidates to improve CNS availability, the main strategies include: bypassing the BBB (intracranial or nasal routes), reversible opening of TJs (using hyperosmotic mannitol, ultrasounds, peptides and other physical methods or chemical agents), vector-mediated drug delivery systems (nanocarriers, exploitation of receptor- and carrier-mediated transport) and inhibition of efflux transporters. We discuss the main advantages, disadvantages and clinical relevance of each strategy. Special emphasis will be given to the description of the chemical characteristics of nanoparticles (lipidic, polymeric, inorganic, etc.) and the main strategies of targeting them to the CNS.

  16. Targeted polymeric magnetic nanoparticles for brain imaging

    NASA Astrophysics Data System (ADS)

    Kirthivasan, Bharat; Singh, Dhirender; Raut, Sangram; Bommana, Murali Mohan; Squillante, Emilio, III; Sadoqi, Mostafa

    2012-03-01

    the potential use of polymeric magnetically-targeted nanoparticles in active brain targeting and imaging.

  17. Targeting Brain-Eating Amoebae Infections.

    PubMed

    Khan, Naveed Ahmed; Ong, Timothy Yu Yee; Siddiqui, Ruqaiyyah

    2017-02-22

    Brain infections due to Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri often lead to death. Despite differences in the preferential sites of infection in the brain, the mode of delivery of drugs is often intravenous. Here, we discuss targeted therapeutic approach to affect parasite viability without affecting the host cells, with an eye to improve formulation of drugs and/or administration of drugs against brain-eating amoebae.

  18. Brain Correlates of Cognitive Remediation in Schizophrenia: Activation Likelihood Analysis Shows Preliminary Evidence of Neural Target Engagement

    PubMed Central

    Ramsay, Ian S.; MacDonald, Angus W.

    2015-01-01

    Cognitive remediation training (CRT) for schizophrenia has been found to improve cognitive functioning and influence neural plasticity. However, with various training approaches and mixed findings, the mechanisms driving generalization of cognitive skills from CRT are unclear. In this meta-analysis of extant imaging studies examining CRT’s effects, we sought to clarify whether varying approaches to CRT suggest common neural changes and whether such mechanisms are restorative or compensatory. We conducted a literature search to identify studies appropriate for inclusion in an activation likelihood estimation (ALE) meta-analysis. Our criteria required studies to consist of training-based interventions designed to improve patients’ cognitive or social functioning, including generalization to untrained circumstances. Studies were also required to examine changes in pre- vs posttraining functional activation using functional magnetic resonance imaging or positron emission tomography. The literature search identified 162 articles, 9 of which were appropriate for inclusion. ALE analyses comparing pre- and posttraining brain activation showed increased activity in the lateral and medial prefrontal cortex (PFC), parietal cortex, insula, and the caudate and thalamus. Notably, activation associated with CRT in the left PFC and thalamus partially overlapped with previous meta-analytically identified areas associated with deficits in working memory, executive control, and facial emotion processing in schizophrenia. We conclude that CRT interventions from varying theoretic modalities elicit plasticity in areas that support cognitive and socioemotional processes in this early set of studies. While preliminary, these changes appear to be both restorative and compensatory, though thalamocortical areas previously associated with dysfunction may be common sources of plasticity for cognitive remediation in schizophrenia. PMID:25800249

  19. Zika Virus Targeting in the Developing Brain.

    PubMed

    van den Pol, Anthony N; Mao, Guochao; Yang, Yang; Ornaghi, Sara; Davis, John N

    2017-02-22

    Zika virus (ZIKV), a positive-sense RNA flavivirus, has attracted considerable attention recently for its potential to cause serious neurological problems, including microcephaly, cortical thinning, and blindness during early development. Recent findings suggest that ZIKV infection of the brain can occur not only during very early stages of development, but also in later fetal/early neonatal stages of maturation. Surprisingly, after peripheral inoculation of immunocompetent mice on the day of birth, the first cells targeted throughout the brain were isolated astrocytes. At later stages, more neurons showed ZIKV immunoreactivity, in part potentially due to ZIKV release from infected astrocytes. In all developing mice studied, we detected infection of retinal neurons; in many mice, this was also associated with infection of the lateral geniculate, suprachiasmatic nuclei, and superior colliculus, suggesting a commonality for the virus to infect cells of the visual system. Interestingly, in mature mice lacking a Type 1 interferon response (IFNR(-/-)), after inoculation of the eye, the initial majority of infected cells in the visual system were glial cells along the optic tract. ZIKV microinjection into the somatosensory cortex on one side of the normal mouse brain resulted in mirror infection restricted to the contralateral somatosensory cortex without any infection of midline brain regions, indicating the virus can move by axonal transport to synaptically coupled brain loci. These data support the view that ZIKV shows considerable complexity in targeting the CNS and may target different cells at different stages of brain development.SIGNIFICANCE STATEMENT Zika virus (ZIKV) can cause substantial damage to the developing human brain. Here we examine a developmental mouse model of ZIKV infection in the newborn mouse in which the brain is developmentally similar to a second-trimester human fetus. After peripheral inoculation, the virus entered the CNS in all mice tested

  20. Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

    PubMed

    Rabiner, E A; Beaver, J; Makwana, A; Searle, G; Long, C; Nathan, P J; Newbould, R D; Howard, J; Miller, S R; Bush, M A; Hill, S; Reiley, R; Passchier, J; Gunn, R N; Matthews, P M; Bullmore, E T

    2011-08-01

    Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

  1. Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier

    PubMed Central

    Wang, Xiangru; Maruvada, Ravi; Morris, Andrew J.; Liu, Jun O.; Baek, Dong Jae; Kim, Kwang Sik

    2016-01-01

    Central nervous system (CNS) infection continues to be an important cause of mortality and morbidity, necessitating new approaches for investigating its pathogenesis, prevention and therapy. Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, which develops following penetration of the blood–brain barrier (BBB). By chemical library screening, we identified epidermal growth factor receptor (EGFR) as a contributor to E. coli invasion of the BBB in vitro. Here, we obtained the direct evidence that CNS-infecting E. coli exploited sphingosine 1-phosphate (S1P) for EGFR activation in penetration of the BBB in vitro and in vivo. We found that S1P was upstream of EGFR and participated in EGFR activation through S1P receptor as well as through S1P-mediated up-regulation of EGFR-related ligand HB-EGF, and blockade of S1P function through targeting sphingosine kinase and S1P receptor inhibited EGFR activation, and also E. coli invasion of the BBB. We further found that both S1P and EGFR activations occurred in response to the same E. coli proteins (OmpA, FimH, NlpI), and that S1P and EGFR promoted E. coli invasion of the BBB by activating the downstream c-Src. These findings indicate that S1P and EGFR represent the novel host targets for meningitic E. coli penetration of the BBB, and counteracting such targets provide a novel approach for controlling E. coli meningitis in the era of increasing resistance to conventional antibiotics. PMID:27711202

  2. Understanding the brain by controlling neural activity

    PubMed Central

    Krug, Kristine; Salzman, C. Daniel; Waddell, Scott

    2015-01-01

    Causal methods to interrogate brain function have been employed since the advent of modern neuroscience in the nineteenth century. Initially, randomly placed electrodes and stimulation of parts of the living brain were used to localize specific functions to these areas. Recent technical developments have rejuvenated this approach by providing more precise tools to dissect the neural circuits underlying behaviour, perception and cognition. Carefully controlled behavioural experiments have been combined with electrical devices, targeted genetically encoded tools and neurochemical approaches to manipulate information processing in the brain. The ability to control brain activity in these ways not only deepens our understanding of brain function but also provides new avenues for clinical intervention, particularly in conditions where brain processing has gone awry. PMID:26240417

  3. Developing brain as a target of toxicity.

    PubMed Central

    Rodier, P M

    1995-01-01

    The human brain forms over an unusually long period compared to other organs. While most of the basic structure is laid down before birth, neuron proliferation and migration continue in the postnatal period. The blood-brain barrier is not fully developed until the middle of the first year of life. The number of synaptic connections between neurons reaches a peak around age two and is then trimmed back by about half. Similarly, there is great postnatal activity in the development of receptors and transmitter systems as well as in the production of myelin. Many of the toxic agents known to damage the developing brain interfere with one or more of these developmental processes. Those with antimitotic action, such as X-ray and methyl mercury, have distinctly different effects on structure depending on which neurons are forming at the time of exposure. Vulnerability to agents that interfere with cell production decreases rapidly over the early postnatal period. Other toxic substances, such as psychoactive drugs and agents that alter hormone levels, are especially hazardous during synaptogenesis and the development of transmitter systems, and thus continue to be damaging for years after birth. Still other toxic substances such as lead, seem to have their greatest effects during even later stages of brain development, perhaps by interfering with the trimming back of connections. Guidelines designed to protect human populations from developmental neurotoxicity need to take into account the changing sensitivity of the brain as it passes through different developmental stages, as well as the fundamental differences in the effects of toxicants on the mature and the developing brain. PMID:8549496

  4. Phenylalanine-coupled solid lipid nanoparticles for brain tumor targeting

    NASA Astrophysics Data System (ADS)

    Kharya, Parul; Jain, Ashish; Gulbake, Arvind; Shilpi, Satish; Jain, Ankit; Hurkat, Pooja; Majumdar, Subrata; Jain, Sanjay K.

    2013-11-01

    The purpose of this study is to investigate the targeting potential of amino acid (phenylalanine)-coupled solid lipid nanoparticles (SLN) loaded with ionically complexed doxorubicin HCl (Dox). Ionic complexation was used to enhance the loading efficiency and release characteristics of water soluble form of Dox. l-Type amino acid transporters (LAT1) are highly expressed on blood brain barrier as well as on many brain cancer cells, thus targeting LAT1 using phenylalanine improved anticancer activity of prepared nanocarrier. The phenylalanine-coupled SLN were characterized by fourier transform infrared spectroscopy, scanning electron microscope, transmission electron microscopy, particle size, zeta potential, entrapment efficiency and in vitro release. The particle size of the resulting SLN was found to be in the range of 163.3 ± 5.2 to 113.0 ± 2.6 nm, with a slightly negative surface charge. In ex vivo study on C6 glioma cell lines, the cellular cytotoxicity of the SLN was highly increased when coupled with phenylalanine. In addition, stealthing sheath of PEG present on the surface of the SLN enhanced the cellular uptake of the SLN on C6 glioma cell line. Results of biodistribution and fluorescence studies clearly revealed that phenylalanine-coupled SLN could deliver high amount of drug into the brain tumor cells and showed the brain-targeting potential.

  5. Brain Activities and Educational Technology

    ERIC Educational Resources Information Center

    Riza, Emel

    2002-01-01

    There are close relationships between brain activities and educational technology. Brain is very important and so complicated part in our bodies. From long time scientists pay attention to that part and did many experiments, but they just reached little information like a drop in the sea. However from time to time they gave us some light to…

  6. [Physical activity and brain function].

    PubMed

    Kempermann, G

    2012-06-01

    Physical activity has direct and indirect effects on brain function in health and disease. Findings demonstrating that physical activity improves cognitive and non-cognitive functions and is preventive for several neuropsychiatric disorders have attracted particular interest. This short review focuses on sports and physical exercise in normal brain function and summarizes which mechanisms might underlie the observed effects, which methodological problems exist, which relationships exist to concepts of plasticity and neural reserves and what evolutionary relevance the initially surprising finding that physical exercise is good for the brain has.

  7. Brain Gym. Simple Activities for Whole Brain Learning.

    ERIC Educational Resources Information Center

    Dennison, Paul E.; Dennison, Gail E.

    This booklet contains simple movements and activities that are used with students in Educational Kinesiology to enhance their experience of whole brain learning. Whole brain learning through movement repatterning and Brain Gym activities enable students to access those parts of the brain previously unavailable to them. These movements of body and…

  8. The blood-brain barrier as a target in traumatic brain injury treatment.

    PubMed

    Thal, Serge C; Neuhaus, Winfried

    2014-11-01

    Traumatic brain injury (TBI) is one of the most frequent causes of death in the young population. Several clinical trials have unsuccessfully focused on direct neuroprotective therapies. Recently immunotherapeutic strategies shifted into focus of translational research in acute CNS diseases. Cross-talk between activated microglia and blood-brain barrier (BBB) could initiate opening of the BBB and subsequent recruitment of systemic immune cells and mediators into the brain. Stabilization of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage and acute neurodegeneration. This review provides an overview on the pathophysiology of TBI and brain edema formation including definitions and classification of TBI, current clinical treatment strategies, as well as current understanding on the underlying cellular processes. A summary of in vivo and in vitro models to study different aspects of TBI is presented. Three mechanisms proposed for stabilization of the BBB, myosin light chain kinases, glucocorticoid receptors and peroxisome proliferator-activated receptors are reviewed for their influence on barrier-integrity and outcome after TBI. In conclusion, the BBB is recommended as a promising target for the treatment of traumatic brain injury, and it is suggested that a combination of BBB stabilization and neuroprotectants may improve therapeutic success.

  9. Leptin targets in the mouse brain.

    PubMed

    Scott, Michael M; Lachey, Jennifer L; Sternson, Scott M; Lee, Charlotte E; Elias, Carol F; Friedman, Jeffrey M; Elmquist, Joel K

    2009-06-10

    The central actions of leptin are essential for homeostatic control of adipose tissue mass, glucose metabolism, and many autonomic and neuroendocrine systems. In the brain, leptin acts on numerous different cell types via the long-form leptin receptor (LepRb) to elicit its effects. The precise identification of leptin's cellular targets is fundamental to understanding the mechanism of its pleiotropic central actions. We have systematically characterized LepRb distribution in the mouse brain using in situ hybridization in wildtype mice as well as by EYFP immunoreactivity in a novel LepRb-IRES-Cre EYFP reporter mouse line showing high levels of LepRb mRNA/EYFP coexpression. We found substantial LepRb mRNA and EYFP expression in hypothalamic and extrahypothalamic sites described before, including the dorsomedial nucleus of the hypothalamus, ventral premammillary nucleus, ventral tegmental area, parabrachial nucleus, and the dorsal vagal complex. Expression in insular cortex, lateral septal nucleus, medial preoptic area, rostral linear nucleus, and in the Edinger-Westphal nucleus was also observed and had been previously unreported. The LepRb-IRES-Cre reporter line was used to chemically characterize a population of leptin receptor-expressing neurons in the midbrain. Tyrosine hydroxylase and Cre reporter were found to be coexpressed in the ventral tegmental area and in other midbrain dopaminergic neurons. Lastly, the LepRb-IRES-Cre reporter line was used to map the extent of peripheral leptin sensing by central nervous system (CNS) LepRb neurons. Thus, we provide data supporting the use of the LepRb-IRES-Cre line for the assessment of the anatomic and functional characteristics of neurons expressing leptin receptor.

  10. Fueling and imaging brain activation

    PubMed Central

    Dienel, Gerald A

    2012-01-01

    Metabolic signals are used for imaging and spectroscopic studies of brain function and disease and to elucidate the cellular basis of neuroenergetics. The major fuel for activated neurons and the models for neuron–astrocyte interactions have been controversial because discordant results are obtained in different experimental systems, some of which do not correspond to adult brain. In rats, the infrastructure to support the high energetic demands of adult brain is acquired during postnatal development and matures after weaning. The brain's capacity to supply and metabolize glucose and oxygen exceeds demand over a wide range of rates, and the hyperaemic response to functional activation is rapid. Oxidative metabolism provides most ATP, but glycolysis is frequently preferentially up-regulated during activation. Underestimation of glucose utilization rates with labelled glucose arises from increased lactate production, lactate diffusion via transporters and astrocytic gap junctions, and lactate release to blood and perivascular drainage. Increased pentose shunt pathway flux also causes label loss from C1 of glucose. Glucose analogues are used to assay cellular activities, but interpretation of results is uncertain due to insufficient characterization of transport and phosphorylation kinetics. Brain activation in subjects with low blood-lactate levels causes a brain-to-blood lactate gradient, with rapid lactate release. In contrast, lactate flooding of brain during physical activity or infusion provides an opportunistic, supplemental fuel. Available evidence indicates that lactate shuttling coupled to its local oxidation during activation is a small fraction of glucose oxidation. Developmental, experimental, and physiological context is critical for interpretation of metabolic studies in terms of theoretical models. PMID:22612861

  11. Anatomical brain atlas for NIRS measurements of brain activation

    NASA Astrophysics Data System (ADS)

    Caffini, Matteo; Zucchelli, Lucia; Contini, Davide; Cubeddu, Rinaldo; Spinelli, Lorenzo; Boas, David; Torricelli, Alessandro

    2011-07-01

    Anatomical brain atlases have been introduced in the analysis NIRS data of brain activation and good spatial activation localization has been proved. We applied this method to visualize NIRS data from different protocols.

  12. Target coverage and selectivity in field steering brain stimulation.

    PubMed

    Cubo, Ruben; Åstrom, Mattias; Medvedev, Alexander

    2014-01-01

    Deep Brain Stimulation (DBS) is an established treatment in Parkinson's Disease. The target area is defined based on the state and brain anatomy of the patient. The stimulation delivered via state-of-the-art DBS leads that are currently in clinical use is difficult to individualize to the patient particularities. Furthermore, the electric field generated by such a lead has a limited selectivity, resulting in stimulation of areas adjacent to the target and thus causing undesirable side effects. The goal of this study is, using actual clinical data, to compare in silico the stimulation performance of a symmetrical generic lead to a more versatile and adaptable one allowing, in particular, for asymmetric stimulation. The fraction of the volume of activated tissue in the target area and the fraction of the stimulation field that spreads beyond it are computed for a clinical data set of patients in order to quantify the lead performance. The obtained results suggest that using more versatile DBS leads might reduce the stimulation area beyond the target and thus lessen side effects for the same achieved therapeutical effect.

  13. Magnetic Resonance Imaging-Based Target Volume Delineation in Radiation Therapy Treatment Planning for Brain Tumors Using Localized Region-Based Active Contour

    SciTech Connect

    Aslian, Hossein; Sadeghi, Mahdi; Mahdavi, Seied Rabie; Babapour Mofrad, Farshid; Astarakee, Mahdi; Khaledi, Navid; Fadavi, Pedram

    2013-09-01

    Purpose: To evaluate the clinical application of a robust semiautomatic image segmentation method to determine the brain target volumes in radiation therapy treatment planning. Methods and Materials: A local robust region-based algorithm was used on MRI brain images to study the clinical target volume (CTV) of several patients. First, 3 oncologists delineated CTVs of 10 patients manually, and the process time for each patient was calculated. The averages of the oncologists’ contours were evaluated and considered as reference contours. Then, to determine the CTV through the semiautomatic method, a fourth oncologist who was blind to all manual contours selected 4-8 points around the edema and defined the initial contour. The time to obtain the final contour was calculated again for each patient. Manual and semiautomatic segmentation were compared using 3 different metric criteria: Dice coefficient, Hausdorff distance, and mean absolute distance. A comparison also was performed between volumes obtained from semiautomatic and manual methods. Results: Manual delineation processing time of tumors for each patient was dependent on its size and complexity and had a mean (±SD) of 12.33 ± 2.47 minutes, whereas it was 3.254 ± 1.7507 minutes for the semiautomatic method. Means of Dice coefficient, Hausdorff distance, and mean absolute distance between manual contours were 0.84 ± 0.02, 2.05 ± 0.66 cm, and 0.78 ± 0.15 cm, and they were 0.82 ± 0.03, 1.91 ± 0.65 cm, and 0.7 ± 0.22 cm between manual and semiautomatic contours, respectively. Moreover, the mean volume ratio (=semiautomatic/manual) calculated for all samples was 0.87. Conclusions: Given the deformability of this method, the results showed reasonable accuracy and similarity to the results of manual contouring by the oncologists. This study shows that the localized region-based algorithms can have great ability in determining the CTV and can be appropriate alternatives for manual approaches in brain cancer.

  14. SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.

    PubMed

    Zhang, Siyuan; Huang, Wen-Chien; Zhang, Lin; Zhang, Chenyu; Lowery, Frank J; Ding, Zhaoxi; Guo, Hua; Wang, Hai; Huang, Suyun; Sahin, Aysegul A; Aldape, Kenneth D; Steeg, Patricia S; Yu, Dihua

    2013-09-15

    Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis.

  15. Antagonist Targeting microRNA-155 Protects against Lithium-Pilocarpine-Induced Status Epilepticus in C57BL/6 Mice by Activating Brain-Derived Neurotrophic Factor

    PubMed Central

    Cai, Zhengxu; Li, Song; Li, Sheng; Song, Fan; Zhang, Zhen; Qi, Guanhua; Li, Tianbai; Qiu, Juanjuan; Wan, Jiajia; Sui, Hua; Guo, Huishu

    2016-01-01

    Epilepsy is a severe brain disorder affecting numerous patients. Recently, it is inferred that modulation of microRNA-155 (miR-155) could serve as a promising treatment of mesial temporal lobe epilepsy. In the current study, the therapeutic potential of miR-155 antagonist against temporal lobe epilepsy (TLE) was evaluated and the underlying mechanism involved in this regulation was explored. TLE model was induced by lithium-pilocarpine method. The effect of miR-155 antagonist on epilepticus symptoms of TLE mice was assessed using Racine classification and electroencephalogram (EEG) recordings. The expression of brain-derived neurotrophic factor (BDNF) and its association with miR-155 were also assessed with a series of experiments. Our results showed that level of miR-155 was significantly up-regulated after induction of TLE model. Based on the results of EEG and behavior analyses, seizures in mice were alleviated by miR-155 antagonist. Moreover, administration of miR-155 antagonist also significantly increased the level of BDNF. The results of dual luciferase assay and Western blotting showed that miR-155 antagonist exerted its action on status epilepticus by directly regulating the activity of BDNF. Taken all the information together, our results demonstrated that miR-155 antagonist might firstly induce the expression of BDNF, which then contributed to the alleviation of epilepsy in the current study. PMID:27303295

  16. Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-12-1-0316 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES 14. ABSTRACT Brain metastasis occurs in ~30% of metastatic breast cancer patients. The prognosis is extremely poor, with a...Introduction Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, with a median survival of 4-6 months even

  17. Transferrin liposomes of docetaxel for brain-targeted cancer applications: formulation and brain theranostics.

    PubMed

    Sonali; Singh, Rahul Pratap; Singh, Nitesh; Sharma, Gunjan; Vijayakumar, Mahalingam R; Koch, Biplob; Singh, Sanjay; Singh, Usha; Dash, Debabrata; Pandey, Bajarangprasad L; Muthu, Madaswamy S

    2016-05-01

    Diagnosis and therapy of brain cancer was often limited due to low permeability of delivery materials across the blood-brain barrier (BBB) and their poor penetration into the brain tissue. This study explored the possibility of utilizing theranostic d-alpha-tocopheryl polyethylene glycol 1000 succinate mono-ester (TPGS) liposomes as nanocarriers for minimally invasive brain-targeted imaging and therapy (brain theranostics). The aim of this work was to formulate transferrin conjugated TPGS coated theranostic liposomes, which contain both docetaxel and quantum dots (QDs) for imaging and therapy of brain cancer. The theranostic liposomes with and without transferrin decoration were prepared and characterized for their particle size, polydispersity, morphology, drug encapsulation efficiency, in-vitro release study and brain theranostics. The particle sizes of the non-targeted and targeted theranostic liposomes were found below 200 nm. Nearly, 71% of drug encapsulation efficiency was achieved with liposomes. The drug release from transferrin conjugated theranostic liposomes was sustained for more than 72 h with 70% of drug release. The in-vivo results indicated that transferrin receptor-targeted theranostic liposomes could be a promising carrier for brain theranostics due to nano-sized delivery and its permeability which provided an improved and prolonged brain targeting of docetaxel and QDs in comparison to the non-targeted preparations.

  18. Development of risperidone liposomes for brain targeting through intranasal route.

    PubMed

    Narayan, Reema; Singh, Mohan; Ranjan, OmPrakash; Nayak, Yogendra; Garg, Sanjay; Shavi, Gopal V; Nayak, Usha Y

    2016-10-15

    The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential.

  19. Targeted Therapies for Brain Metastases from Breast Cancer

    PubMed Central

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways. PMID:27649142

  20. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2013-10-01

    3                          4                  Stack    Autoradiograph a b c I‐ 124 ‐PGN635 PET/CT 231BR normal d d. Detection and...in mice bearing brain metastases. PGN635F(ab’)2 were successfully labeled with I- 124 or I-125 to study its specific targeting of brain metastases...brain metastases in mice. 9 Fig. 4 Autoradiography and PET imaging of I- 124 /125 labeled PGN635 in targeting brain metastases. a

  1. Targeted blood-to-brain drug delivery --10 key development criteria.

    PubMed

    Gaillard, Pieter J; Visser, Corine C; Appeldoorn, Chantal C M; Rip, Jaap

    2012-09-01

    Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood-brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development.

  2. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Dawen Zhao, M.D., Ph.D. CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center at Dallas Dallas, TX 75390 REPORT DATE...a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically to tumor...Furthermore, pretreatment with 10Gy of whole brain radiation significantly increased PGN635 binding to tumor vascular endothelial cells and tumor

  3. Clinical science workshop: targeting the gut-liver-brain axis.

    PubMed

    Patel, Vishal C; White, Helen; Støy, Sidsel; Bajaj, Jasmohan S; Shawcross, Debbie L

    2016-12-01

    A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that inter-organ ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of

  4. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

    PubMed

    Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

    2015-10-01

    The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

  5. Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells

    PubMed Central

    Li, Xue-tao; Tang, Wei; Jiang, Ying; Wang, Xiao-min; Wang, Yan-hong; Cheng, Lan; Meng, Xian-sheng

    2016-01-01

    Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

  6. Blood-brain barrier transport machineries and targeted therapy of brain diseases

    PubMed Central

    Barar, Jaleh; Rafi, Mohammad A.; Pourseif, Mohammad M.; Omidi, Yadollah

    2016-01-01

    Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB), drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS). However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs). Conclusions: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs) can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain. PMID:28265539

  7. Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson's disease.

    PubMed

    Liu, Yang; Guo, Yubo; An, Sai; Kuang, Yuyang; He, Xi; Ma, Haojun; Li, Jianfeng; Lu, Jing; Lv, Jing; Zhang, Ning; Jiang, Chen

    2013-01-01

    The activation of caspase-3 is an important hallmark in Parkinson's disease. It could induce neuron death by apoptosis and microglia activation by inflammation. As a result, inhibition the activation of caspase-3 would exert synergistic dual effect in brain in order to prevent the progress of Parkinson's disease. Silencing caspase-3 genes by RNA interference could inhibit the activation of caspase-3. We developed a brain-targeted gene delivery system based on non-viral gene vector, dendrigraft poly-L-lysines. A rabies virus glycoprotein peptide with 29 amino-acid linked to dendrigraft poly-L-lysines could render gene vectors the ability to get across the blood brain barrier by specific receptor mediated transcytosis. The resultant brain-targeted vector was complexed with caspase-3 short hairpin RNA coding plasmid DNA, yielding nanoparticles. In vivo imaging analysis indicated the targeted nanoparticles could accumulate in brain more efficiently than non-targeted ones. A multiple dosing regimen by weekly intravenous administration of the nanoparticles could reduce activated casapse-3 levels, significantly improve locomotor activity and rescue dopaminergic neuronal loss and in Parkinson's disease rats' brain. These results indicated the rabies virus glycoprotein peptide modified brain-targeted nanoparticles were promising gene delivery system for RNA interference to achieve anti-apoptotic and anti-inflammation synergistic therapeutic effects by down-regulation the expression and activation of caspase-3.

  8. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Rolf A. Brekken CONTRACTING ORGANIZATION: U niveristy of Texas Southwestern Medical Center Dallas, TX 75390-9105 REPORT DATE: December...COVERED (From - To) 30 Sep 2012 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Phosphatidylserine for Radioimmunotherapy of Breast...antibody, PGN635, a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically

  9. Mood-Stabilizers Target the Brain Arachidonic Acid Cascade

    PubMed Central

    Rao, Jagadeesh S.; Rapoport, Stanley I.

    2009-01-01

    Bipolar disorder (BD) is a severe psychiatric illness characterized by recurrent manic and depressive episodes, without a characteristic neuropathology or clear etiology. Drugs effective in BD target many key signaling pathways in animal and cell studies. However, their mode of action in the BD brain remains elusive. In the rat brain, some of the mood stabilizers effective in treating mania (lithium, carbamazepine, valproate) or depression (lamotrigine) in BD are reported to decrease transcription of cytosolic phospholipase A2 and cyclooxygenase-2 and to reduce levels of AP-2 and NF-κB, transcription factors of the two enzymes. The anti-manic drugs also decrease arachidonic acid (AA) turnover in brain phospholipids when given chronically to rats. Thus, drugs effective in BD commonly target AA cascade kinetics as well as AA cascade enzymes and their transcription factors in the rat brain. These studies suggest that BD is associated with increased AA signaling in the brain. Developing therapeutic agents that suppress brain AA signaling could lead to additional treatments for BD. In this review, we discuss the mechanisms of action of mood stabilizers and the effects of docosahexaenoic acid on AA cascade enzymes in relation to BD. PMID:20021459

  10. Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment.

    PubMed

    Wang, Jun; Ferruzzi, Mario G; Ho, Lap; Blount, Jack; Janle, Elsa M; Gong, Bing; Pan, Yong; Gowda, G A Nagana; Raftery, Daniel; Arrieta-Cruz, Isabel; Sharma, Vaishali; Cooper, Bruce; Lobo, Jessica; Simon, James E; Zhang, Chungfen; Cheng, Alice; Qian, Xianjuan; Ono, Kenjiro; Teplow, David B; Pavlides, Constantine; Dixon, Richard A; Pasinetti, Giulio M

    2012-04-11

    While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

  11. Brain: The Potential Diagnostic and Therapeutic Target for Glaucoma.

    PubMed

    Faiq, Muneeb A; Dada, Rima; Kumar, Ashutosh; Saluja, Daman; Dada, Tanuj

    2016-01-01

    Glaucoma is a form of multifactorial ocular neurodegeneration with immensely complex etiology, pathogenesis and pathology. Though the mainstream therapeutic management of glaucoma is lowering of intraocular pressure, there is, as of now, no cure for the disease. New evidences ardently suggest brain involvement in all aspects of this malady. This consequently advocates the opinion that brain should be the spotlight of glaucoma research and may form the impending and promising target for glaucoma diagnosis and treatment. The present analysis endeavors at understanding glaucoma vis-à-vis brain structural and/or functional derangement and central nervous system (CNS) degeneration. Commencing with the premise of developing some understanding about the brain-nature of ocular structures; we discuss the nature of the cellular and molecular moieties involved in glaucoma and Alzheimer's disease. Substantial deal of literature implies that glaucoma may well be a disease of the brain, nevertheless, manifesting as progressive loss of vision. If that is the case, then targeting brain will be far more imperative in glaucoma therapeutics than any other remedial regimen currently being endorsed.

  12. Metabolic connectomics targeting brain pathology in dementia with Lewy bodies.

    PubMed

    Caminiti, Silvia P; Tettamanti, Marco; Sala, Arianna; Presotto, Luca; Iannaccone, Sandro; Cappa, Stefano F; Magnani, Giuseppe; Perani, Daniela

    2017-04-01

    Dementia with Lewy bodies is characterized by α-synuclein accumulation and degeneration of dopaminergic and cholinergic pathways. To gain an overview of brain systems affected by neurodegeneration, we characterized the [18F]FDG-PET metabolic connectivity in 42 dementia with Lewy bodies patients, as compared to 42 healthy controls, using sparse inverse covariance estimation method and graph theory. We performed whole-brain and anatomically driven analyses, targeting cholinergic and dopaminergic pathways, and the α-synuclein spreading. The first revealed substantial alterations in connectivity indexes, brain modularity, and hubs configuration. Namely, decreases in local metabolic connectivity within occipital cortex, thalamus, and cerebellum, and increases within frontal, temporal, parietal, and basal ganglia regions. There were also long-range disconnections among these brain regions, all supporting a disruption of the functional hierarchy characterizing the normal brain. The anatomically driven analysis revealed alterations within brain structures early affected by α-synuclein pathology, supporting Braak's early pathological staging in dementia with Lewy bodies. The dopaminergic striato-cortical pathway was severely affected, as well as the cholinergic networks, with an extensive decrease in connectivity in Ch1-Ch2, Ch5-Ch6 networks, and the lateral Ch4 capsular network significantly towards the occipital cortex. These altered patterns of metabolic connectivity unveil a new in vivo scenario for dementia with Lewy bodies underlying pathology in terms of changes in whole-brain metabolic connectivity, spreading of α-synuclein, and neurotransmission impairment.

  13. Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

    PubMed

    Gao, Jian-Qing; Lv, Qing; Li, Li-Ming; Tang, Xin-Jiang; Li, Fan-Zhu; Hu, Yu-Lan; Han, Min

    2013-07-01

    Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.

  14. Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies.

    PubMed

    Zuchero, Y Joy Yu; Chen, Xiaocheng; Bien-Ly, Nga; Bumbaca, Daniela; Tong, Raymond K; Gao, Xiaoying; Zhang, Shuo; Hoyte, Kwame; Luk, Wilman; Huntley, Melanie A; Phu, Lilian; Tan, Christine; Kallop, Dara; Weimer, Robby M; Lu, Yanmei; Kirkpatrick, Donald S; Ernst, James A; Chih, Ben; Dennis, Mark S; Watts, Ryan J

    2016-01-06

    The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies for neurological diseases. Using transcriptomic and proteomic profiling, we searched for proteins in mouse brain endothelial cells (BECs) that could potentially be exploited to transport antibodies across the BBB. Due to their limited protein abundance, neither antibodies against literature-identified targets nor BBB-enriched proteins identified by microarray facilitated significant antibody brain uptake. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. Antibodies to each of these targets were significantly enriched in the brain after administration in vivo. In particular, antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain Aβ reduction. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies.

  15. Neural dynamics underlying target detection in the human brain.

    PubMed

    Bansal, Arjun K; Madhavan, Radhika; Agam, Yigal; Golby, Alexandra; Madsen, Joseph R; Kreiman, Gabriel

    2014-02-19

    Sensory signals must be interpreted in the context of goals and tasks. To detect a target in an image, the brain compares input signals and goals to elicit the correct behavior. We examined how target detection modulates visual recognition signals by recording intracranial field potential responses from 776 electrodes in 10 epileptic human subjects. We observed reliable differences in the physiological responses to stimuli when a cued target was present versus absent. Goal-related modulation was particularly strong in the inferior temporal and fusiform gyri, two areas important for object recognition. Target modulation started after 250 ms post stimulus, considerably after the onset of visual recognition signals. While broadband signals exhibited increased or decreased power, gamma frequency power showed predominantly increases during target presence. These observations support models where task goals interact with sensory inputs via top-down signals that influence the highest echelons of visual processing after the onset of selective responses.

  16. Neural Dynamics Underlying Target Detection in the Human Brain

    PubMed Central

    Bansal, Arjun K.; Madhavan, Radhika; Agam, Yigal; Golby, Alexandra; Madsen, Joseph R.

    2014-01-01

    Sensory signals must be interpreted in the context of goals and tasks. To detect a target in an image, the brain compares input signals and goals to elicit the correct behavior. We examined how target detection modulates visual recognition signals by recording intracranial field potential responses from 776 electrodes in 10 epileptic human subjects. We observed reliable differences in the physiological responses to stimuli when a cued target was present versus absent. Goal-related modulation was particularly strong in the inferior temporal and fusiform gyri, two areas important for object recognition. Target modulation started after 250 ms post stimulus, considerably after the onset of visual recognition signals. While broadband signals exhibited increased or decreased power, gamma frequency power showed predominantly increases during target presence. These observations support models where task goals interact with sensory inputs via top-down signals that influence the highest echelons of visual processing after the onset of selective responses. PMID:24553944

  17. Identification of multi-targeted anti-migraine potential of nystatin and development of its brain targeted chitosan nanoformulation.

    PubMed

    Girotra, Priti; Thakur, Aman; Kumar, Ajay; Singh, Shailendra Kumar

    2017-03-01

    The complex pathophysiology involved in migraine necessitates the drug treatment to act on several receptors simultaneously. The present investigation was an attempt to discover the unidentified anti-migraine activity of the already marketed drugs. Shared featured pharmacophore modeling was employed for this purpose on six target receptors (β2 adrenoceptor, Dopamine D3, 5HT1B, TRPV1, iGluR5 kainate and CGRP), resulting in the generation of five shared featured pharmacophores, which were further subjected to virtual screening of the ligands obtained from Drugbank database. Molecular docking, performed on the obtained hit compounds from virtual screening, indicated nystatin to be the only active lead against the receptors iGluR5 kainate receptor (1VSO), CGRP (3N7R), β2 adrenoceptor (3NYA) and Dopamine D3 (3PBL) with a high binding energy of -11.1, -10.9, -10.2 and -12kcal/mole respectively. The anti-migraine activity of nystatin was then adjudged by fabricating its brain targeted chitosan nanoparticles. Its brain targeting efficacy, analyzed qualitatively by confocal laser scanning microscopy, demonstrated a significant amount of drug reaching the brain. The pharmacodynamic models on Swiss male albino mice revealed significant anti-migraine activity of the nanoformulation. The present study reports for the first time the therapeutic potential of nystatin in migraine management, hence opening avenues for its future exploration.

  18. Blood-brain barrier drug targeting: the future of brain drug development.

    PubMed

    Pardridge, William M

    2003-03-01

    As human longevity increases, the likelihood of the onset of diseases of the brain (and other organs) also increases. Clinical therapeutics offer useful long-term treatments, if not cures, if drugs can be delivered appropriately and effectively. Unfortunately, research in drug transport to the brain has not advanced very far. Through better characterization of the transport systems utilized within the blood-brain barrier, a greater understanding of how to exploit these systems will lead to effective treatments for brain disorders. Pardridge reviews the functions of the various known transport systems in the brain and discusses how the development of BBB drug-targeting programs in pharmaceutical and academic settings may lead to more efficacious treatments.

  19. Alterations of brain activity in fibromyalgia patients.

    PubMed

    Sawaddiruk, Passakorn; Paiboonworachat, Sahattaya; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2017-04-01

    Fibromyalgia is a chronic pain syndrome, characterized by widespread musculoskeletal pain with diffuse tenderness at multiple tender points. Despite intense investigations, the pathophysiology of fibromyalgia remains elusive. Evidence shows that it could be due to changes in either the peripheral or central nervous system (CNS). For the CNS changes, alterations in the high brain area of fibromyalgia patients have been investigated but the definite mechanisms are still unclear. Magnetic Resonance Imaging (MRI) and Functional Magnetic Resonance (fMRI) have been used to gather evidence regarding the changes of brain morphologies and activities in fibromyalgia patients. Nevertheless, due to few studies, limited knowledge for alterations in brain activities in fibromyalgia is currently available. In this review, the changes in brain activity in various brain areas obtained from reports in fibromyalgia patients are comprehensively summarized. Changes of the grey matter in multiple regions such as the superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, SII, caudate and putamen from the MRI as well as the increase of brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, insula in fMRI studies are presented and discussed. Moreover, evidence from pharmacological interventions offering benefits for fibromyalgia patients by reducing brain activity is presented. Because of limited knowledge regarding the roles of brain activity alterations in fibromyalgia, this summarized review will encourage more future studies to elucidate the underlying mechanisms involved in the brains of these patients.

  20. Focused ultrasound modulates region-specific brain activity

    PubMed Central

    Yoo, Seung-Schik; Bystritsky, Alexander; Lee, Jong-Hwan; Zhang, Yongzhi; Fischer, Krisztina; Min, Byoung-Kyong; McDannold, Nathan J.; Pascual-Leone, Alvaro; Jolesz, Ferenc A.

    2012-01-01

    We demonstrated the in vivo feasibility of using focused ultrasound (FUS) to transiently modulate (through either stimulation or suppression) the function of regional brain tissue in rabbits. FUS was delivered in a train of pulses at low acoustic energy, far below the cavitation threshold, to the animal's somatomotor and visual areas, as guided by anatomical and functional information from magnetic resonance imaging (MRI). The temporary alterations in the brain function affected by the sonication were characterized by both electrophysiological recordings and functional brain mapping achieved through the use of functional MRI (fMRI). The modulatory effects were bimodal, whereby the brain activity could either be stimulated or selectively suppressed. Histological analysis of the excised brain tissue after the sonication demonstrated that the FUS did not elicit any tissue damages. Unlike transcranial magnetic stimulation, FUS can be applied to deep structures in the brain with greater spatial precision. Transient modulation of brain function using image-guided and anatomically-targeted FUS would enable the investigation of functional connectivity between brain regions and will eventually lead to a better understanding of localized brain functions. It is anticipated that the use of this technology will have an impact on brain research and may offer novel therapeutic interventions in various neurological conditions and psychiatric disorders. PMID:21354315

  1. The restless brain: how intrinsic activity organizes brain function.

    PubMed

    Raichle, Marcus E

    2015-05-19

    Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease.

  2. The restless brain: how intrinsic activity organizes brain function

    PubMed Central

    Raichle, Marcus E.

    2015-01-01

    Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease. PMID:25823869

  3. Circulating biomarker panels for targeted therapy in brain tumors.

    PubMed

    Tanase, Cristiana; Albulescu, Radu; Codrici, Elena; Popescu, Ionela Daniela; Mihai, Simona; Enciu, Ana Maria; Cruceru, Maria Linda; Popa, Adrian Claudiu; Neagu, Ana Iulia; Necula, Laura Georgiana; Mambet, Cristina; Neagu, Monica

    2015-01-01

    An important goal of oncology is the development of cancer risk-identifier biomarkers that aid early detection and target therapy. High-throughput profiling represents a major concern for cancer research, including brain tumors. A promising approach for efficacious monitoring of disease progression and therapy could be circulating biomarker panels using molecular proteomic patterns. Tailoring treatment by targeting specific protein-protein interactions and signaling networks, microRNA and cancer stem cell signaling in accordance with tumor phenotype or patient clustering based on biomarker panels represents the future of personalized medicine for brain tumors. Gathering current data regarding biomarker candidates, we address the major challenges surrounding the biomarker field of this devastating tumor type, exploring potential perspectives for the development of more effective predictive biomarker panels.

  4. MRI virtual biopsy and treatment of brain metastatic tumors with targeted nanobioconjugates: nanoclinic in the brain.

    PubMed

    Patil, Rameshwar; Ljubimov, Alexander V; Gangalum, Pallavi R; Ding, Hui; Portilla-Arias, Jose; Wagner, Shawn; Inoue, Satoshi; Konda, Bindu; Rekechenetskiy, Arthur; Chesnokova, Alexandra; Markman, Janet L; Ljubimov, Vladimir A; Li, Debiao; Prasad, Ravi S; Black, Keith L; Holler, Eggehard; Ljubimova, Julia Y

    2015-05-26

    Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections, or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise noninvasive MRI diagnostic method, we have engineered a new class of poly(β-l-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood-brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in a significant increase in animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.

  5. PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain.

    PubMed

    Henriksson, Richard; Bäckman, Cristina M; Harvey, Brandon K; Kadyrova, Helena; Bazov, Igor; Shippenberg, Toni S; Bakalkin, Georgy

    2014-11-01

    The dynorphin κ-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.

  6. Targeting Neuronal Networks with Combined Drug and Stimulation Paradigms Guided by Neuroimaging to Treat Brain Disorders.

    PubMed

    Faingold, Carl L; Blumenfeld, Hal

    2015-10-01

    Improved therapy of brain disorders can be achieved by focusing on neuronal networks, utilizing combined pharmacological and stimulation paradigms guided by neuroimaging. Neuronal networks that mediate normal brain functions, such as hearing, interact with other networks, which is important but commonly neglected. Network interaction changes often underlie brain disorders, including epilepsy. "Conditional multireceptive" (CMR) brain areas (e.g., brainstem reticular formation and amygdala) are critical in mediating neuroplastic changes that facilitate network interactions. CMR neurons receive multiple inputs but exhibit extensive response variability due to milieu and behavioral state changes and are exquisitely sensitive to agents that increase or inhibit GABA-mediated inhibition. Enhanced CMR neuronal responsiveness leads to expression of emergent properties--nonlinear events--resulting from network self-organization. Determining brain disorder mechanisms requires animals that model behaviors and neuroanatomical substrates of human disorders identified by neuroimaging. However, not all sites activated during network operation are requisite for that operation. Other active sites are ancillary, because their blockade does not alter network function. Requisite network sites exhibit emergent properties that are critical targets for pharmacological and stimulation therapies. Improved treatment of brain disorders should involve combined pharmacological and stimulation therapies, guided by neuroimaging, to correct network malfunctions by targeting specific network neurons.

  7. The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders.

    PubMed

    Nithianantharajah, Jess; Hannan, Anthony J

    2009-12-01

    The concept of 'cognitive reserve', and a broader theory of 'brain reserve', were originally proposed to help explain epidemiological data indicating that individuals who engaged in higher levels of mental and physical activity via education, occupation and recreation, were at lower risk of developing Alzheimer's disease and other forms of dementia. Subsequently, behavioral, cellular and molecular studies in animals (predominantly mice and rats) have revealed dramatic effects of environmental enrichment, which involves enhanced levels of sensory, cognitive and motor stimulation via housing in novel, complex environments. Furthermore, increasing levels of voluntary physical exercise, via ad libitum access to running wheels, can have significant effects on brain and behavior, thus informing the relative effects of mental and physical activity. More recently, animal models of brain disorders have been compared under environmentally stimulating and standard housing conditions, and this has provided new insights into environmental modulators and gene-environment interactions involved in pathogenesis. Here, we review animal studies that have investigated the effects of modifying mental and physical activity via experimental manipulations, and discuss their relevance to brain and cognitive reserve (BCR). Recent evidence suggests that the concept of BCR is not only relevant to brain aging, neurodegenerative diseases and dementia, but also to other neurological and psychiatric disorders. Understanding the cellular and molecular mechanisms mediating BCR may not only facilitate future strategies aimed at optimising healthy brain aging, but could also identify molecular targets for novel pharmacological approaches aimed at boosting BCR in 'at risk' and symptomatic individuals with various brain disorders.

  8. Response to Deep Brain Stimulation in Three Brain Targets with Implications in Mental Disorders: A PET Study in Rats

    PubMed Central

    Casquero-Veiga, Marta; Hadar, Ravit; Pascau, Javier; Winter, Christine; Desco, Manuel; Soto-Montenegro, María Luisa

    2016-01-01

    Objective To investigate metabolic changes in brain networks by deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) and dorsomedial thalamus (DM) using positron emission tomography (PET) in naïve rats. Methods 43 male Wistar rats underwent stereotactic surgery and concentric bipolar platinum-iridium electrodes were bilaterally implanted into one of the three brain sites. [18F]-fluoro-2-deoxy-glucose-PET (18FDG-PET) and computed tomography (CT) scans were performed at the 7th (without DBS) and 9th day (with DBS) after surgery. Stimulation period matched tracer uptake period. Images were acquired with a small-animal PET-CT scanner. Differences in glucose uptake between groups were assessed with Statistical Parametric Mapping. Results DBS induced site-specific metabolic changes, although a common increased metabolic activity in the piriform cortex was found for the three brain targets. mPFC-DBS increased metabolic activity in the striatum, temporal and amygdala, and reduced it in the cerebellum, brainstem (BS) and periaqueductal gray matter (PAG). NAcc-DBS increased metabolic activity in the subiculum and olfactory bulb, and decreased it in the BS, PAG, septum and hypothalamus. DM-DBS increased metabolic activity in the striatum, NAcc and thalamus and decreased it in the temporal and cingulate cortex. Conclusions DBS induced significant changes in 18FDG uptake in brain regions associated with the basal ganglia-thalamo-cortical circuitry. Stimulation of mPFC, NAcc and DM induced different patterns of 18FDG uptake despite interacting with the same circuitries. This may have important implications to DBS research suggesting individualized target selection according to specific neural modulatory requirements. PMID:28033356

  9. Computational Modeling and Neuroimaging Techniques for Targeting during Deep Brain Stimulation

    PubMed Central

    Sweet, Jennifer A.; Pace, Jonathan; Girgis, Fady; Miller, Jonathan P.

    2016-01-01

    Accurate surgical localization of the varied targets for deep brain stimulation (DBS) is a process undergoing constant evolution, with increasingly sophisticated techniques to allow for highly precise targeting. However, despite the fastidious placement of electrodes into specific structures within the brain, there is increasing evidence to suggest that the clinical effects of DBS are likely due to the activation of widespread neuronal networks directly and indirectly influenced by the stimulation of a given target. Selective activation of these complex and inter-connected pathways may further improve the outcomes of currently treated diseases by targeting specific fiber tracts responsible for a particular symptom in a patient-specific manner. Moreover, the delivery of such focused stimulation may aid in the discovery of new targets for electrical stimulation to treat additional neurological, psychiatric, and even cognitive disorders. As such, advancements in surgical targeting, computational modeling, engineering designs, and neuroimaging techniques play a critical role in this process. This article reviews the progress of these applications, discussing the importance of target localization for DBS, and the role of computational modeling and novel neuroimaging in improving our understanding of the pathophysiology of diseases, and thus paving the way for improved selective target localization using DBS. PMID:27445709

  10. Activities That Build the Young Child's Brain.

    ERIC Educational Resources Information Center

    Gellens, Suzanne R.

    This book presents 350 classroom-tested activities for use with children to create an environment that will stimulate young children's brains. Designed to be used by families, classroom teachers, family childcare providers, or others caring for young children, the book includes information on current brain research and describes interest areas in…

  11. Evaluation of brain targeting efficiency of intranasal microemulsion containing olanzapine: pharmacodynamic and pharmacokinetic consideration.

    PubMed

    Patel, Rashmin B; Patel, Mrunali R; Bhatt, Kashyap K; Patel, Bharat G; Gaikwad, Rajiv V

    2016-01-01

    The objective of this study was to develop and evaluate olanzapine (OZP) -loaded microemulsions (OZPME) for intranasal delivery in the treatment of schizophrenia. The OZPME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine - induced compulsive behavior and spontaneous locomotor activity) were performed using mice. All formulations were radiolabeled with technetium-99 ((99m)Tc), and biodistribution of drug in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rabbits was performed to determine the uptake of the OZP into the brain. OZPME were found clear and stable with average globule size of 23.87 ± 1.07 nm. In pharmacodynamic assessments, significant (p < 0.05) difference in parameters estimated were found between the treated and control groups. (99m)Tc-labeled OZP solution (OZPS)/OZPME/OZP mucoadhesive microemulsion (OZPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of OZPMME compared to intravenous OZPME was found to be five to six times higher signifying larger extent of distribution of the OZP in brain. Drug targeting efficiency and direct drug transport were found to be highest for intranasal OZPMME, compared to intravenous OZPME. Furthermore, rabbit brain scintigraphy also demonstrated higher intranasal uptake of the OZP into the brain. This investigation demonstrates a prompt and larger extent of transport of OZP into the brain through intranasal OZPMME, which may prove beneficial for treatment of schizophrenia.

  12. The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release

    PubMed Central

    Neasta, Jérémie; Valmalle, Charlène; Coyne, Anne‐Claire; Carnazzi, Eric; Subra, Gilles; Galleyrand, Jean‐Claude; Gagne, Didier; M'Kadmi, Céline; Bernad, Nicole; Bergé, Gilbert; Cantel, Sonia; Marin, Philippe; Marie, Jacky; Banères, Jean‐Louis; Kemel, Marie‐Lou; Daugé, Valérie; Puget, Karine

    2016-01-01

    Background and Purpose Using an in‐house bioinformatics programme, we identified and synthesized a novel nonapeptide, H‐Pro‐Pro‐Thr‐Thr‐Thr‐Lys‐Phe‐Ala‐Ala‐OH. Here, we have studied its biological activity, in vitro and in vivo, and have identified its target in the brain. Experimental Approach The affinity of the peptide was characterized using purified whole brain and striatal membranes from guinea pigs and rats . Its effect on behaviour in rats following intra‐striatal injection of the peptide was investigated. A photoaffinity UV cross‐linking approach combined with subsequent affinity purification of the ligand covalently bound to its receptor allowed identification of its target. Key Results The peptide bound with high affinity to a single class of binding sites, specifically localized in the striatum and substantia nigra of brains from guinea pigs and rats. When injected within the striatum of rats, the peptide stimulated in vitro and in vivo dopamine release and induced dopamine‐like motor effects. We purified the target of the peptide, a ~151 kDa protein that was identified by MS/MS as angiotensin converting enzyme (ACE I). Therefore, we decided to name the peptide acein. Conclusion and Implications The synthetic nonapeptide acein interacted with high affinity with brain membrane‐bound ACE. This interaction occurs at a different site from the active site involved in the well‐known peptidase activity, without modifying the peptidase activity. Acein, in vitro and in vivo, significantly increased stimulated release of dopamine from the brain. These results suggest a more important role for brain ACE than initially suspected. PMID:27027724

  13. Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices

    NASA Astrophysics Data System (ADS)

    Varela, Juan A.; Dupuis, Julien P.; Etchepare, Laetitia; Espana, Agnès; Cognet, Laurent; Groc, Laurent

    2016-03-01

    Single-molecule imaging has changed the way we understand many biological mechanisms, particularly in neurobiology, by shedding light on intricate molecular events down to the nanoscale. However, current single-molecule studies in neuroscience have been limited to cultured neurons or organotypic slices, leaving as an open question the existence of fast receptor diffusion in intact brain tissue. Here, for the first time, we targeted dopamine receptors in vivo with functionalized quantum dots and were able to perform single-molecule tracking in acute rat brain slices. We propose a novel delocalized and non-inflammatory way of delivering nanoparticles (NPs) in vivo to the brain, which allowed us to label and track genetically engineered surface dopamine receptors in neocortical neurons, revealing inherent behaviour and receptor activity regulations. We thus propose a NP-based platform for single-molecule studies in the living brain, opening new avenues of research in physiological and pathological animal models.

  14. Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors.

    PubMed

    Blanco, Víctor M; Chu, Zhengtao; Vallabhapurapu, Subrahmanya D; Sulaiman, Mahaboob K; Kendler, Ady; Rixe, Olivier; Warnick, Ronald E; Franco, Robert S; Qi, Xiaoyang

    2014-08-30

    Brain tumors, either primary (e.g., glioblastoma multiforme) or secondary (metastatic), remain among the most intractable and fatal of all cancers. We have shown that nanovesicles consisting of Saposin C (SapC) and dioleylphosphatidylserine (DOPS) are able to effectively target and kill cancer cells both in vitro and in vivo. These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature. In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity. Second, we demonstrate that SapC-DOPS selectively targets brain metastases-forming cancer cells both in vitro, in co-cultures with human astrocytes, and in vivo, in mouse models of brain metastases derived from human breast or lung cancer cells. Third, we demonstrate that SapC-DOPS have cytotoxic activity against metastatic breast cancer cells in vitro, and prolong the survival of mice harboring brain metastases. Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

  15. Staying Socially Active Nourishes the Aging Brain

    MedlinePlus

    ... fullstory_163679.html Staying Socially Active Nourishes the Aging Brain Researchers suggest making friends of all ages ... and Human Services. More Health News on: Healthy Aging Recent Health News Related MedlinePlus Health Topics Healthy ...

  16. Targeted, noninvasive blockade of cortical neuronal activity

    NASA Astrophysics Data System (ADS)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-11-01

    Here we describe a novel method to noninvasively modulate targeted brain areas through the temporary disruption of the blood-brain barrier (BBB) via focused ultrasound, enabling focal delivery of a neuroactive substance. Ultrasound was used to locally disrupt the BBB in rat somatosensory cortex, and intravenous administration of GABA then produced a dose-dependent suppression of somatosensory-evoked potentials in response to electrical stimulation of the sciatic nerve. No suppression was observed 1-5 days afterwards or in control animals where the BBB was not disrupted. This method has several advantages over existing techniques: it is noninvasive; it is repeatable via additional GABA injections; multiple brain regions can be affected simultaneously; suppression magnitude can be titrated by GABA dose; and the method can be used with freely behaving subjects. We anticipate that the application of neuroactive substances in this way will be a useful tool for noninvasively mapping brain function, and potentially for surgical planning or novel therapies.

  17. Brain extraction using geodesic active contours

    NASA Astrophysics Data System (ADS)

    Huang, Albert; Abugharbieh, Rafeef; Tam, Roger; Traboulsee, Anthony

    2006-03-01

    Extracting the brain cortex from magnetic resonance imaging (MRI) head scans is an essential preprocessing step of which the accuracy greatly affects subsequent image analysis. The currently popular Brain Extraction Tool (BET) produces a brain mask which may be too smooth for practical use. This paper presents a novel brain extraction tool based on three-dimensional geodesic active contours, connected component analysis and mathematical morphology. Based on user-specified intensity and contrast levels, the proposed algorithm allows an active contour to evolve naturally and extract the brain cortex. Experiments on synthetic MRI data and scanned coronal and axial MRI image volumes indicate successful extraction of tight perimeters surrounding the brain cortex. Quantitative evaluations on both synthetic phantoms and manually labeled data resulted in better accuracy than BET in terms of true and false voxel assignment. Based on these results, we illustrate that our brain extraction tool is a robust and accurate approach for the challenging task of automatically extracting the brain cortex in MRI data.

  18. Mechanism of brain targeting by dexibuprofen prodrugs modified with ethanolamine-related structures

    PubMed Central

    Li, Yanping; Zhou, Yangyang; Jiang, Jiayu; Wang, Xinyi; Fu, Yao; Gong, Tao; Sun, Xun; Zhang, Zhirong

    2015-01-01

    The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energy-independent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H+/OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs. PMID:26154870

  19. Vocal Tremor: Novel Therapeutic Target for Deep Brain Stimulation

    PubMed Central

    Ravikumar, Vinod K.; Ho, Allen L.; Parker, Jonathon J.; Erickson-DiRenzo, Elizabeth; Halpern, Casey H.

    2016-01-01

    Tremulous voice is characteristically associated with essential tremor, and is referred to as essential vocal tremor (EVT). Current estimates suggest that up to 40% of individuals diagnosed with essential tremor also present with EVT, which is associated with an impaired quality of life. Traditional EVT treatments have demonstrated limited success in long-term management of symptoms. However, voice tremor has been noted to decrease in patients receiving deep brain stimulation (DBS) with the targeting of thalamic nuclei. In this study, we describe our multidisciplinary procedure for awake, frameless DBS with optimal stimulation targets as well as acoustic analysis and laryngoscopic assessment to quantify tremor reduction. Finally, we investigate the most recent clinical evidence regarding the procedure. PMID:27735866

  20. Whole-brain activity mapping onto a zebrafish brain atlas.

    PubMed

    Randlett, Owen; Wee, Caroline L; Naumann, Eva A; Nnaemeka, Onyeka; Schoppik, David; Fitzgerald, James E; Portugues, Ruben; Lacoste, Alix M B; Riegler, Clemens; Engert, Florian; Schier, Alexander F

    2015-11-01

    In order to localize the neural circuits involved in generating behaviors, it is necessary to assign activity onto anatomical maps of the nervous system. Using brain registration across hundreds of larval zebrafish, we have built an expandable open-source atlas containing molecular labels and definitions of anatomical regions, the Z-Brain. Using this platform and immunohistochemical detection of phosphorylated extracellular signal–regulated kinase (ERK) as a readout of neural activity, we have developed a system to create and contextualize whole-brain maps of stimulus- and behavior-dependent neural activity. This mitogen-activated protein kinase (MAP)-mapping assay is technically simple, and data analysis is completely automated. Because MAP-mapping is performed on freely swimming fish, it is applicable to studies of nearly any stimulus or behavior. Here we demonstrate our high-throughput approach using pharmacological, visual and noxious stimuli, as well as hunting and feeding. The resultant maps outline hundreds of areas associated with behaviors.

  1. Using perturbations to identify the brain circuits underlying active vision.

    PubMed

    Wurtz, Robert H

    2015-09-19

    The visual and oculomotor systems in the brain have been studied extensively in the primate. Together, they can be regarded as a single brain system that underlies active vision--the normal vision that begins with visual processing in the retina and extends through the brain to the generation of eye movement by the brainstem. The system is probably one of the most thoroughly studied brain systems in the primate, and it offers an ideal opportunity to evaluate the advantages and disadvantages of the series of perturbation techniques that have been used to study it. The perturbations have been critical in moving from correlations between neuronal activity and behaviour closer to a causal relation between neuronal activity and behaviour. The same perturbation techniques have also been used to tease out neuronal circuits that are related to active vision that in turn are driving behaviour. The evolution of perturbation techniques includes ablation of both cortical and subcortical targets, punctate chemical lesions, reversible inactivations, electrical stimulation, and finally the expanding optogenetic techniques. The evolution of perturbation techniques has supported progressively stronger conclusions about what neuronal circuits in the brain underlie active vision and how the circuits themselves might be organized.

  2. Identifying radiotherapy target volumes in brain cancer by image analysis.

    PubMed

    Cheng, Kun; Montgomery, Dean; Feng, Yang; Steel, Robin; Liao, Hanqing; McLaren, Duncan B; Erridge, Sara C; McLaughlin, Stephen; Nailon, William H

    2015-10-01

    To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required.

  3. Identifying radiotherapy target volumes in brain cancer by image analysis

    PubMed Central

    Cheng, Kun; Montgomery, Dean; Feng, Yang; Steel, Robin; Liao, Hanqing; McLaren, Duncan B.; Erridge, Sara C.; McLaughlin, Stephen

    2015-01-01

    To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required. PMID:26609418

  4. Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

    PubMed Central

    Jangra, Ashok; Sriram, Chandra Shaker; Pandey, Suryanarayan; Choubey, Priyansha; Rajput, Prabha; Saroha, Babita; Bezbaruah, Babul Kumar; Lahkar, Mangala

    2016-01-01

    Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development. PMID:27780992

  5. Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma.

    PubMed

    Delač, Mateja; Motaln, Helena; Ulrich, Henning; Lah, Tamara T

    2015-09-01

    Aptamers are short single-stranded nucleic acids (RNA or ssDNA), identified by an in vitro selection process, denominated SELEX, from a partially random oligonucleotide library. They bind to a molecular target, a protein or other complex macromolecular structures of interest with high affinity and specificity, comparable to those of antibodies. Recently, aptamer selection protocols were developed for targeting living cells, including tumors. Chemical modifications of the aptamers and modalities of their detection and delivery systems are already available with high selectivity and targeting ability for the desired cancer cell type, making them promising for diagnosis and therapy. Glioblastoma multiformae represents the most malignant and fatal stage of glioma, and is also the most frequent brain tumor. Glioblastoma-specific aptamers were developed by either targeting the whole cell surface or known glioma biomarkers. These aptamers may gain importance for imaging, tumor cell isolation from biopsies and drug delivery. In biomedical imaging techniques, aptamers coupled with radionuclide or fluorescent labels, bioconjugates and nanoparticles offer an advanced, noninvasive manner for defining the glioblastoma tissue border. Though single modality aptamer imaging probes have some limitations, these are overcome by the use of multimodal probes. Due to selectivity and chemical characteristics, aptamers can be coupled to functionalized nanoparticles and loaded with a drug, appeared promising for in vivo targeting of glioblastoma. Finally, aptamers are effective mediators for gene silencing when coupled to small interfering RNA and a viral vector, thus providing a novel tool with enhanced targeting capability in drug delivery, designed for tailored treatment of glioblastoma patients.

  6. Purification of neuropathy target esterase from avian brain after prelabelling with [3H]diisopropyl phosphorofluoridate.

    PubMed

    Rüffer-Turner, M E; Read, D J; Johnson, M K

    1992-01-01

    Neuropathy target esterase from hen brains was radiolabelled at the active site with [3H]diisopropyl phosphorofluoridate. The labelled protein was purified by differential centrifugation and Nonidet P40 solubilization, detergent phase partitioning, anion exchange, and preparative sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The volatilizable counts assay and analytical SDS-PAGE were used to monitor the protein. The 150-kDa subunit polypeptide appears as a single band on analytical SDS-PAGE.

  7. Nanotools for Neuroscience and Brain Activity Mapping

    PubMed Central

    Alivisatos, A. Paul; Andrews, Anne M.; Boyden, Edward S.; Chun, Miyoung; Church, George M.; Deisseroth, Karl; Donoghue, John P.; Fraser, Scott E.; Lippincott-Schwartz, Jennifer; Looger, Loren L.; Masmanidis, Sotiris; McEuen, Paul L.; Nurmikko, Arto V.; Park, Hongkun; Peterka, Darcy S.; Reid, Clay; Roukes, Michael L.; Scherer, Axel; Schnitzer, Mark; Sejnowski, Terrence J.; Shepard, Kenneth L.; Tsao, Doris; Turrigiano, Gina; Weiss, Paul S.; Xu, Chris; Yuste, Rafael; Zhuang, Xiaowei

    2013-01-01

    Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function. PMID:23514423

  8. GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease

    PubMed Central

    Pierson, Emily R.; Goverman, Joan M.

    2017-01-01

    Experimental autoimmune encephalomyelitis (EAE) has been used as an animal model of multiple sclerosis to identify pathogenic cytokines that could be therapeutic targets. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is the only cytokine reported to be essential for EAE. We investigated the role of GM-CSF in EAE in C3HeB/FeJ mice that uniquely exhibit extensive brain and spinal cord inflammation. Unexpectedly, GM-CSF–deficient C3HeB/FeJ mice were fully susceptible to EAE because IL-17 activity compensated for the loss of GM-CSF during induction of spinal cord–targeted disease. In contrast, both GM-CSF and IL-17 were needed to fully overcome the inhibitory influence of IFN-γ on the induction of inflammation in the brain. Both GM-CSF and IL-17 independently promoted neutrophil accumulation in the brain, which was essential for brain-targeted disease. These results identify a GM-CSF/IL-17/IFN-γ axis that regulates inflammation in the central nervous system and suggest that a combination of cytokine-neutralizing therapies may be needed to dampen central nervous system autoimmunity.

  9. Active Targets For Capacitive Proximity Sensors

    NASA Technical Reports Server (NTRS)

    Jenstrom, Del T.; Mcconnell, Robert L.

    1994-01-01

    Lightweight, low-power active targets devised for use with improved capacitive proximity sensors described in "Capacitive Proximity Sensor Has Longer Range" (GSC-13377), and "Capacitive Proximity Sensors With Additional Driven Shields" (GSC-13475). Active targets are short-distance electrostatic beacons; they generate known alternating electro-static fields used for alignment and/or to measure distances.

  10. The primate thalamus is a key target for brain dopamine.

    PubMed

    Sánchez-González, Miguel Angel; García-Cabezas, Miguel Angel; Rico, Beatriz; Cavada, Carmen

    2005-06-29

    The thalamus relays information to the cerebral cortex from subcortical centers or other cortices; in addition, it projects to the striatum and amygdala. The thalamic relay function is subject to modulation, so the flow of information to the target regions may change depending on behavioral demands. Modulation of thalamic relay by dopamine is not currently acknowledged, perhaps because dopamine innervation is reportedly scant in the rodent thalamus. We show that dopaminergic axons profusely target the human and macaque monkey thalamus using immunolabeling with three markers of the dopaminergic phenotype (tyrosine hydroxylase, dopamine, and the dopamine transporter). The dopamine innervation is especially prominent in specific association, limbic, and motor thalamic nuclei, where the densities of dopaminergic axons are as high as or higher than in the cortical area with the densest dopamine innervation. We also identified the dopaminergic neurons projecting to the macaque thalamus using retrograde tract-tracing combined with immunohistochemistry. The origin of thalamic dopamine is multiple, and thus more complex, than in any other dopaminergic system defined to date: dopaminergic neurons of the hypothalamus, periaqueductal gray matter, ventral mesencephalon, and the lateral parabrachial nucleus project bilaterally to the monkey thalamus. We propose a novel dopaminergic system that targets the primate thalamus and is independent from the previously defined nigrostriatal, mesocortical, and mesolimbic dopaminergic systems. Investigating this "thalamic dopaminergic system" should further our understanding of higher brain functions and conditions such as Parkinson's disease, schizophrenia, and drug addiction.

  11. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase.

    PubMed

    Zhang, Lixin; Sullivan, Peggy S; Goodman, Jerry C; Gunaratne, Preethi H; Marchetti, Dario

    2011-02-01

    Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular.

  12. Thinking Patterns, Brain Activity and Strategy Choice

    NASA Astrophysics Data System (ADS)

    Nishimura, Kazuo; Okada, Akira; Inagawa, Michiyo; Tobinaga, Yoshikazu

    2012-03-01

    In this study we analyzed the relationship between thinking patterns, behavior and associated brain activity. Subjects completed a self-report assessing whether they could voluntarily stop thinking or not, and were then divided into two groups: those with the ability to stop thinking and those without. We measured subjects' brain activity using magnetoencephalography while giving them a series of tasks intended to encourage or discourage spontaneous thinking. Our findings revealed differences between the two groups in terms of which portions of the brain were active during the two types of task. A second questionnaire confirmed a relationship between the ability to stop thinking and strategy choices in a dilemma game. We found that subjects without the ability to stop thinking had a tendency to choose cooperative behavior.

  13. Dissection of the Process of Brain Metastasis Reveals Targets and Mechanisms for Molecular-based Intervention.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Brain metastases outnumber the incidence of brain tumors by a factor of ten. Patients with brain metastases have a dismal prognosis and current treatment modalities achieve only a modest clinical benefit. We discuss the process of brain metastasis with respect to mechanisms and involved targets to outline options for therapeutic intervention and focus on breast and lung cancer, as well as melanoma. We describe the process of penetration of the blood-brain-barrier (BBB) by disseminated tumor cells, establishment of a metastatic niche, colonization and outgrowth in the brain parenchyma. Furthermore, the role of angiogenesis in colonization of the brain parenchyma, interactions of extravasated tumor cells with microglia and astrocytes, as well as their propensity for neuromimicry, is discussed. We outline targets suitable for prevention of metastasis and summarize targets suitable for treatment of established brain metastases. Finally, we highlight the implications of findings revealing druggable mutations in brain metastases that cannot be identified in matching primary tumors.

  14. Molecular contributions to neurovascular unit dysfunctions after brain injuries: lessons for target-specific drug development

    PubMed Central

    Jullienne, Amandine; Badaut, Jérôme

    2014-01-01

    The revised ‘expanded’ neurovascular unit (eNVU) is a physiological and functional unit encompassing endothelial cells, pericytes, smooth muscle cells, astrocytes and neurons. Ischemic stroke and traumatic brain injury are acute brain injuries directly affecting the eNVU with secondary damage, such as blood–brain barrier (BBB) disruption, edema formation and hypoperfusion. BBB dysfunctions are observed at an early postinjury time point, and are associated with eNVU activation of proteases, such as tissue plasminogen activator and matrix metalloproteinases. BBB opening is accompanied by edema formation using astrocytic AQP4 as a key protein regulating water movement. Finally, nitric oxide dysfunction plays a dual role in association with BBB injury and dysregulation of cerebral blood flow. These mechanisms are discussed including all targets of eNVU encompassing endothelium, glial cells and neurons, as well as larger blood vessels with smooth muscle. In fact, the feeding blood vessels should also be considered to treat stroke and traumatic brain injury. This review underlines the importance of the eNVU in drug development aimed at improving clinical outcome after stroke and traumatic brain injury. PMID:24489483

  15. Informing pedagogy through the brain-targeted teaching model.

    PubMed

    Hardiman, Mariale

    2012-01-01

    Improving teaching to foster creative thinking and problem-solving for students of all ages will require two essential changes in current educational practice. First, to allow more time for deeper engagement with material, it is critical to reduce the vast number of topics often required in many courses. Second, and perhaps more challenging, is the alignment of pedagogy with recent research on cognition and learning. With a growing focus on the use of research to inform teaching practices, educators need a pedagogical framework that helps them interpret and apply research findings. This article describes the Brain-Targeted Teaching Model, a scheme that relates six distinct aspects of instruction to research from the neuro- and cognitive sciences.

  16. Informing Pedagogy Through the Brain-Targeted Teaching Model

    PubMed Central

    Hardiman, Mariale

    2012-01-01

    Improving teaching to foster creative thinking and problem-solving for students of all ages will require two essential changes in current educational practice. First, to allow more time for deeper engagement with material, it is critical to reduce the vast number of topics often required in many courses. Second, and perhaps more challenging, is the alignment of pedagogy with recent research on cognition and learning. With a growing focus on the use of research to inform teaching practices, educators need a pedagogical framework that helps them interpret and apply research findings. This article describes the Brain-Targeted Teaching Model, a scheme that relates six distinct aspects of instruction to research from the neuro- and cognitive sciences. PMID:23653775

  17. Ion channels in postnatal neurogenesis: potential targets for brain repair.

    PubMed

    Swayne, Leigh Anne; Wicki-Stordeur, Leigh

    2012-01-01

    Neural stem and progenitor cells (NSC/NPCs) are unspecialized cells found in the adult peri-ventricular and sub-granular zones that are capable of self-renewal, migration, and differentiation into new neurons through the remarkable process of postnatal neurogenesis. We are now beginning to understand that the concerted action of ion channels, multi-pass transmembrane proteins that allow passage of ions across otherwise impermeable cellular membranes tightly regulate this process. Specific ion channels control proliferation, differentiation and survival. Furthermore, they have the potential to be highly selective drug targets due to their complex structures. As such, these proteins represent intriguing prospects for control and optimization of postnatal neurogenesis for neural regeneration following brain injury or disease. Here, we concentrate on ion channels identified in adult ventricular zone NSC/NPCs that have been found to influence the stages of neurogenesis. Finally, we outline the potential of these channels to elicit repair, and highlight the outstanding challenges.

  18. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain.

    PubMed

    Spiteri, Elizabeth; Konopka, Genevieve; Coppola, Giovanni; Bomar, Jamee; Oldham, Michael; Ou, Jing; Vernes, Sonja C; Fisher, Simon E; Ren, Bing; Geschwind, Daniel H

    2007-12-01

    Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.

  19. Targeting the Brain Reservoirs: Toward an HIV Cure

    PubMed Central

    Marban, Céline; Forouzanfar, Faezeh; Ait-Ammar, Amina; Fahmi, Faiza; El Mekdad, Hala; Daouad, Fadoua; Rohr, Olivier; Schwartz, Christian

    2016-01-01

    One of the top research priorities of the international AIDS society by the action “Towards an HIV Cure” is the purge or the decrease of the pool of all latently infected cells. This strategy is based on reactivation of latently reservoirs (the shock) followed by an intensifying combination antiretroviral therapy (cART) to kill them (the kill). The central nervous system (CNS) has potential latently infected cells, i.e., perivascular macrophages, microglial cells, and astrocytes that will need to be eliminated. However, the CNS has several characteristics that may preclude the achievement of a cure. In this review, we discuss several limitations to the eradication of brain reservoirs and how we could circumvent these limitations by making it efforts in four directions: (i) designing efficient latency-reversal agents for CNS-cell types, (ii) improving cART by targeting HIV transcription, (iii) improving delivery of HIV drugs in the CNS and in the CNS-cell types, and (iv) developing therapeutic immunization. As a prerequisite to these efforts, we also believe that a better comprehension of molecular mechanisms involved in establishment and persistence of HIV latency in brain reservoirs are essential to design new molecules for strategies aiming to achieve a cure for instance the “shock and kill” strategy. PMID:27746784

  20. Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine.

    PubMed

    Kelestemur, Taha; Yulug, Burak; Caglayan, Ahmet Burak; Beker, Mustafa Caglar; Kilic, Ulkan; Caglayan, Berrak; Yalcin, Esra; Gundogdu, Reyhan Zeynep; Kilic, Ertugrul

    2016-01-26

    The tissue damage that emerges during traumatic brain injury (TBI) is a consequence of a variety of pathophysiological events, including free radical generation and over-activation of N-methyl-d-aspartate-type glutamate receptors (NMDAR). Considering the complex pathophysiology of TBI, we hypothesized that combination of neuroprotective compounds, targeting different events which appear during injury, may be a more promising approach for patients. In this context, both NMDAR antagonist memantine and free radical scavenger melatonin are safe in humans and promising agents for the treatment of TBI. Herein, we examined the effects of melatonin administered alone or in combination with memantine on the activation of signaling pathways, injury development and DNA fragmentation. Both compounds reduced brain injury moderately and the density of DNA fragmentation significantly. Notably, melatonin/memantine combination decreased brain injury and DNA fragmentation significantly, which was associated with reduced p38 and ERK-1/2 phosphorylation. As compared with melatonin and memantine groups, SAPK/JNK-1/2 phosphorylation was also reduced in melatonin/memantine combined animals. In addition, melatonin, memantine and their combination decreased iNOS activity significantly. Here, we provide evidence that melatonin/memantine combination protects brain from traumatic injury, which was associated with decreased DNA fragmentation, p38 phosphorylation and iNOS activity.

  1. Defining functional changes in the brain caused by targeted stereotaxic radiosurgery.

    PubMed

    Parihar, Vipan K; Acharya, Munjal M; Roa, Dante E; Bosch, Omar; Christie, Lori-Ann; Limoli, Charles L

    2014-04-01

    Brain tumor patients routinely undergo cranial radiotherapy, and while beneficial, this treatment often results in debilitating cognitive dysfunction. This serious and unresolved problem has at present, no clinical recourse, and has driven our efforts to more clearly define the consequences of different brain irradiation paradigms on specific indices of cognitive performance and on the underlying cellular mechanisms believed to affect these processes. To accomplish this we have developed the capability to deliver highly focused X-ray beams to small and precisely defined volumes of the athymic rat brain, thereby providing more realistic simulations of clinical irradiation scenarios. Using this technique, termed stereotaxic radiosurgery, we evaluated the cognitive consequences of irradiation targeted to the hippocampus in one or both hemispheres of the brain, and compared that to whole brain irradiation. While whole brain irradiation was found to elicit significant deficits in novel place recognition and fear conditioning, standard platforms for quantifying hippocampal and non-hippocampal decrements, irradiation targeted to both hippocampi was only found to elicit deficits in fear conditioning. Cognitive decrements were more difficult to demonstrate in animals subjected to unilateral hippocampal ablation. Immunohistochemical staining for newly born immature (doublecortin positive) and mature (NeuN positive) neurons confirmed our capability to target irradiation to the neurogenic regions of the hippocampus. Stereotaxic radiosurgery (SRS) of the ipsilateral hemisphere reduced significantly the number of doublecortin and NeuN positive neurons by 80% and 27% respectively. Interestingly, neurogenesis on the contralateral side was upregulated in response to stereotaxic radiosurgery, where the number of doublecortin and NeuN positive neurons increased by 22% and 36% respectively. Neuroinflammation measured by immunostaining for activated microglia (ED1 positive cells) was

  2. "Heart-cut" bidimensional achiral-chiral liquid chromatography applied to the evaluation of stereoselective metabolism, in vivo biological activity and brain response to chiral drug candidates targeting the central nervous system.

    PubMed

    Battisti, Umberto M; Citti, Cinzia; Larini, Martina; Ciccarella, Giuseppe; Stasiak, Natalia; Troisi, Luigino; Braghiroli, Daniela; Parenti, Carlo; Zoli, Michele; Cannazza, Giuseppe

    2016-04-22

    A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug

  3. [Glial activation and brain aging].

    PubMed

    Sugaya, K

    2001-10-01

    While basal forebrain cholinergic neurons degenerate in aging and Alzheimer's disease, the cholinergic groups of the upper brainstem are preserved. Since the brainstem reticular-like cholinergic neurons differ from the rostral cholinergic phenotype by their high expression of nitric oxide synthase (NOS) mRNA, we hypothesized that they contain biochemical mechanisms to protect themselves against self-induced damage by nitric oxide (NO). Our initial question was a source of the NO during the aging process. We found a significant correlation between cognitive function and markers for glial activation and oxidative stress using aged rats. This result indicates that oxidative stress accompanied by glial activation may be occurred in the cognitively impaired animals. We also found mitochondrial DNA (mDNA) was significantly damaged in these animals, while accumulation of oxidative damage was not evident in other molecules. Therefore, oxidative damage to the mDNA by glial activation may occur in the cells having poor protection against oxidative stress during aging. Then the dysfunction of mitochondria, induced by the mDNA damage, may induce cell death as well as produce another oxidative stress to cause neuronal damage. The damaged neurons induce further glial activation and such self-accelerated immune-like response results in progressive neurodegeneration.

  4. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination

    PubMed Central

    Fancy, Stephen P.J.; Harrington, Emily P.; Yuen, Tracy J.; Silbereis, John C.; Zhao, Chao; Baranzini, Sergio E.; Bruce, Charlotte C.; Otero, Jose J.; Huang, Eric J.; Nusse, Roel; Franklin, Robin J.M.; Rowitch, David H.

    2011-01-01

    Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of newborn brain injuries that cause cerebral palsy and cognitive disabilities as well as multiple sclerosis (MS) in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. Here, we report expression of AXIN2 in immature oligodendrocyte progenitor cells (OLP) within white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as active MS lesions in adults. Axin2 is a target of Wnt transcriptional activation that feeds back negatively on the pathway, promoting β-catenin degradation. We show Axin2 function is essential for normal kinetics of remyelination. Small molecule inhibitor XAV939, which targets enzymatic activity of Tankyrase, acts to stabilize Axin2 levels in OLP from brain and spinal cord and accelerates their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process. PMID:21706018

  5. Brain Activity on Navigation in Virtual Environments.

    ERIC Educational Resources Information Center

    Mikropoulos, Tassos A.

    2001-01-01

    Assessed the cognitive processing that takes place in virtual environments by measuring electrical brain activity using Fast Fourier Transform analysis. University students performed the same task in a real and a virtual environment, and eye movement measurements showed that all subjects were more attentive when navigating in the virtual world.…

  6. Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?

    PubMed

    Bazinet, Richard P

    2009-10-01

    Although lithium has been used therapeutically to treat patients with bipolar disorder for over 50 years, its mechanism of action, as well as that of other drugs used to treat bipolar disorder, is not agreed upon. In the present paper, I review studies in unanaesthetized rats using a neuropharmacological approach, combined with kinetic, biochemical and molecular biology techniques, demonstrating that chronic administration of three commonly used mood stabilizers (lithium, valproic acid and carbamazepine), at therapeutically relevant doses, selectively target the brain arachidonic acid cascade. Upon chronic administration, lithium and carbamazepine decrease the binding activity of activator protein-2 and, in turn, the transcription, translation and activity of its arachidonic acid-selective calcium-dependent phospholipase A(2) gene product, whereas chronic valproic acid non-competitively inhibits long-chain acyl-CoA synthetase. The net overlapping effects of the three mood stabilizers are decreased turnover of arachidonic acid, but not of docosahexaenoic acid, in rat brain phospholipids, as well as decreased brain cyclo-oxygenase-2 and prostaglandin E(2). As an extension of this theory, drugs that are thought to induce switching to mania, especially when administered during bipolar depression (fluoxetine and imipramine), up-regulate enzymes of the arachidonic acid cascade and turnover of arachidonic acid in rat brain phospholipids. Future basic and clinical studies on the arachidonic acid hypothesis of bipolar disorder are warranted.

  7. ATP as a multi-target danger signal in the brain

    PubMed Central

    Rodrigues, Ricardo J.; Tomé, Angelo R.; Cunha, Rodrigo A.

    2015-01-01

    ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, in astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection. PMID:25972780

  8. Targeted Multifunctional Nanoparticles cure and image Brain Tumors: Selective MRI Contrast Enhancement and Photodynamic Therapy

    NASA Astrophysics Data System (ADS)

    Kopelman, Raoul

    2008-03-01

    Aimed at targeted therapy and imaging of brain tumors, our approach uses targeted, multi-functional nano-particles (NP). A typical nano-particle contains a biologically inert, non-toxic matrix, biodegradable and bio-eliminable over a long time period. It also contains active components, such as fluorescent chemical indicators, photo-sensitizers, MRI contrast enhancement agents and optical imaging dyes. In addition, its surface contains molecular targeting units, e.g. peptides or antibodies, as well as a cloaking agent, to prevent uptake by the immune system, i.e. enabling control of the plasma residence time. These dynamic nano-platforms (DNP) contain contrast enhancement agents for the imaging (MRI, optical, photo-acoustic) of targeted locations, i.e. tumors. Added to this are targeted therapy agents, such as photosensitizers for photodynamic therapy (PDT). A simple protocol, for rats implanted with human brain cancer, consists of tail injection with DNPs, followed by 5 min red light illumination of the tumor region. It resulted in excellent cure statistics for 9L glioblastoma.

  9. Targeted delivery of nano-PTX to the brain tumor-associated macrophages

    PubMed Central

    Zou, Lei; Tao, Youhua; Payne, Gregory; Do, Linh; Thomas, Tima; Rodriguez, Juan; Dou, Huanyu

    2017-01-01

    Nanoparticles containing mixed lipid monolayer shell, biodegradable polymer core and rabies virus glycoprotein (RVG) peptide as brain targeting ligand, were developed for brain targeted delivery of paclitaxel (PTX) to treat malignant glioma. RVG conjugated PTX loaded NPs (RVG-PTX-NPs) had the desirable size (~140 nm), narrow size distribution and spherical shape. RVG-PTX-NPs showed poor uptake by neurons and selective targeting to the brain tumor associated macrophages (TAMs) with controlled release and tumor specific toxicity. In vivo studies revealed that RVG-PTX-NPs were significant to cross the blood-brain barrier (BBB) and had specific targeting to the brain. Most importantly, RVG-PTX-NPs showed effectiveness for anti-glioma therapy on human glioma of mice model. We concluded that RVG-PTX-NPs provided an effective approach for brain-TAMs targeted delivery for the treatment of glioma. PMID:28036254

  10. Transferrin receptor-targeted vitamin E TPGS micelles for brain cancer therapy: preparation, characterization and brain distribution in rats.

    PubMed

    Sonali; Agrawal, Poornima; Singh, Rahul Pratap; Rajesh, Chellappa V; Singh, Sanjay; Vijayakumar, Mahalingam R; Pandey, Bajrangprasad L; Muthu, Madaswamy Sona

    2016-06-01

    The effective treatment of brain cancer is hindered by the poor transport across the blood-brain barrier (BBB) and the low penetration across the blood-tumor barrier (BTB). The objective of this work was to formulate transferrin-conjugated docetaxel (DTX)-loaded d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) micelles for targeted brain cancer therapy. The micelles with and without transferrin conjugation were prepared by the solvent casting method and characterized for their particle size, polydispersity, drug encapsulation efficiency, drug loading, in vitro release study and brain distribution study. Particle sizes of prepared micelles were determined at 25 °C by dynamic light scattering technique. The external surface morphology was determined by transmission electron microscopy analysis and atomic force microscopy. The encapsulation efficiency was determined by spectrophotometery. In vitro release studies of micelles and control formulations were carried out by dialysis bag diffusion method. The particle sizes of the non-targeted and targeted micelles were <20 nm. About 85% of drug encapsulation efficiency was achieved with micelles. The drug release from transferrin-conjugated micelles was sustained for >24 h with 50% of drug release. The in vivo results indicated that transferrin-targeted TPGS micelles could be a promising carrier for brain targeting due to nano-sized drug delivery, solubility enhancement and permeability which provided an improved and prolonged brain targeting of DTX in comparison to the non-targeted micelles and marketed formulation.

  11. Polymersomes conjugated to 83-14 monoclonal antibodies: in vitro targeting of brain capillary endothelial cells.

    PubMed

    Dieu, Le-Ha; Wu, Dalin; Palivan, Cornelia G; Balasubramanian, Vimalkumar; Huwyler, Jörg

    2014-10-01

    The blood-brain barrier (BBB) remains an obstacle for many drugs to reach the brain. A strategy to cross the BBB is to modify nanocarrier systems with ligands that bind to endogenous receptors expressed at the BBB to induce receptor-mediated transport. The aim of the present study was to investigate the potential of polymersomes composed of the amphiphilic diblock copolymer poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline), PDMS-b-PMOXA, for active targeting of brain capillary endothelial cells. We conjugated PDMS-b-PMOXA polymersomes to the anti-human insulin receptor antibody 83-14 and studied their uptake by brain capillary endothelial cells. Transmission electron micrography and light scattering measurements revealed the self-assembly of the block copolymers into 200 nm vesicles after extrusion. Fluorescence correlation spectroscopy was employed to calculate the number of antibodies coupled to one polymersome. Binding and uptake of the polymersomes conjugated to 83-14 mAb were studied in the human BBB in vitro model hCMEC/D3 expressing the human insulin receptor. Competitive inhibition with an excess of free 83-14 mAb demonstrated the specificity of cellular binding and uptake. Our results suggest that PDMS-b-PMOXA polymersomes conjugated to 83-14 mAb may be suitable nanocarriers for drug delivery to the brain.

  12. Brain targeting effect of camptothecin-loaded solid lipid nanoparticles in rat after intravenous administration.

    PubMed

    Martins, Susana M; Sarmento, Bruno; Nunes, Cláudia; Lúcio, Marlene; Reis, Salette; Ferreira, Domingos C

    2013-11-01

    This study intended to investigate the ability of solid lipid nanoparticles (SLN) to deliver camptothecin into the brain parenchyma after crossing the blood-brain barrier. For that purpose, camptothecin-loaded SLN with mean size below 200 nm, low polydispersity index (<0.25), negative surface charge (-20 mV), and high camptothecin association efficiency (>94%) were produced. Synchrotron small and wide angle X-ray scattering (SAXS/WAXS) analysis indicates that SLN maintain their physical stability in contact with DMPC membrane, whereas SLN change the lamellar structure of DMPC into a cubic phase, which is associated with efficient release of the incorporated drugs. Cytotoxicity studies against glioma and macrophage human cell lines revealed that camptothecin-loaded SLN induced cell death with the lowest maximal inhibitory concentration (IC50) values, revealing higher antitumour activity of camptothecin-loaded SLN against gliomas. Furthermore, in vivo biodistribution studies of intravenous camptothecin-loaded SLN performed in rats proved the positive role of SLN on the brain targeting since significant higher brain accumulation of camptothecin was observed, compared to non-encapsulated drug. Pharmacokinetic studies further demonstrated lower deposition of camptothecin in peripheral organs, when encapsulated into SLN, with consequent decrease in potential side toxicological effects. These results confirmed the potential of camptothecin-loaded SLN for antitumour brain treatments.

  13. Electromagnetic imaging of dynamic brain activity

    SciTech Connect

    Mosher, J.; Leahy, R. . Dept. of Electrical Engineering); Lewis, P.; Lewine, J.; George, J. ); Singh, M. . Dept. of Radiology)

    1991-01-01

    Neural activity in the brain produces weak dynamic electromagnetic fields that can be measured by an array of sensors. Using a spatio-temporal modeling framework, we have developed a new approach to localization of multiple neural sources. This approach is based on the MUSIC algorithm originally developed for estimating the direction of arrival of signals impinging on a sensor array. We present applications of this technique to magnetic field measurements of a phantom and of a human evoked somatosensory response. The results of the somatosensory localization are mapped onto the brain anatomy obtained from magnetic resonance images.

  14. Electromagnetic imaging of dynamic brain activity

    SciTech Connect

    Mosher, J.; Leahy, R.; Lewis, P.; Lewine, J.; George, J.; Singh, M.

    1991-12-31

    Neural activity in the brain produces weak dynamic electromagnetic fields that can be measured by an array of sensors. Using a spatio-temporal modeling framework, we have developed a new approach to localization of multiple neural sources. This approach is based on the MUSIC algorithm originally developed for estimating the direction of arrival of signals impinging on a sensor array. We present applications of this technique to magnetic field measurements of a phantom and of a human evoked somatosensory response. The results of the somatosensory localization are mapped onto the brain anatomy obtained from magnetic resonance images.

  15. Target activation by regulatory RNAs in bacteria

    PubMed Central

    Papenfort, Kai; Vanderpool, Carin K.

    2015-01-01

    Bacterial small regulatory RNAs (sRNAs) are commonly known to repress gene expression by base pairing to target mRNAs. In many cases, sRNAs base pair with and sequester mRNA ribosome-binding sites, resulting in translational repression and accelerated transcript decay. In contrast, a growing number of examples of translational activation and mRNA stabilization by sRNAs have now been documented. A given sRNA often employs a conserved region to interact with and regulate both repressed and activated targets. However, the mechanisms underlying activation differ substantially from repression. Base pairing resulting in target activation can involve sRNA interactions with the 5′ untranslated region (UTR), the coding sequence or the 3′ UTR of the target mRNAs. Frequently, the activities of protein factors such as cellular ribonucleases and the RNA chaperone Hfq are required for activation. Bacterial sRNAs, including those that function as activators, frequently control stress response pathways or virulence-associated functions required for immediate responses to changing environments. This review aims to summarize recent advances in knowledge regarding target mRNA activation by bacterial sRNAs, highlighting the molecular mechanisms and biological relevance of regulation. PMID:25934124

  16. Antidepressant effect of electroacupuncture regulates signal targeting in the brain and increases brain-derived neurotrophic factor levels

    PubMed Central

    Duan, Dong-mei; Tu, Ya; Liu, Ping; Jiao, Shuang

    2016-01-01

    Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we established a rat model of chronic unpredicted mild stress, and then treated these rats with electroacupuncture at Yintang (EX-HN3) and Baihui (DU20) with sparse waves at 2 Hz and 0.6 mA for 30 minutes, once a day. We found increased horizontal and vertical activity, and decreased immobility time, at 2 and 4 weeks after treatment. Moreover, levels of neurotransmitters (5-hydroxytryptamine, glutamate, and γ-aminobutyric acid) and protein levels of brain-derived neurotrophic factor and brain-derived neurotrophic factor-related proteins (TrkB, protein kinase A, and phosphorylation of cyclic adenosine monophosphate response element binding protein) were increased in the hippocampus. Similarly, protein kinase A and TrkB mRNA levels were increased, and calcium-calmodulin-dependent protein kinase II levels decreased. These findings suggest that electroacupuncture increases phosphorylation of cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor levels by regulating multiple targets in the cyclic adenosine monophosphate response element binding protein signaling pathway, thereby promoting nerve regeneration, and exerting an antidepressive effect. PMID:27904490

  17. Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators.

    PubMed

    Weinreb, Orly; Mandel, Silvia; Youdim, Moussa B H; Amit, Tamar

    2013-09-01

    Brain iron accumulation has been implicated in a host of chronic neurological diseases, including Parkinson's disease (PD). The elevated iron levels observed in the substantia nigra of PD subjects have been suggested to incite the generation of reactive oxygen species and intracellular α-synuclein aggregation, terminating in the oxidative neuronal destruction of this brain area. Thus, elucidation of the molecular mechanisms involved in iron dysregulation and oxidative stress-induced neurodegeneration is a crucial step in deciphering PD pathology and in developing novel iron-complexing compounds aimed at restoring brain iron homeostasis and attenuating neurodegeneration. This review discusses the involvement of dysregulation of brain iron homeostasis in PD pathology, with an emphasis on the potential effectiveness of naturally occurring compounds and novel iron-chelating/antioxidant therapeutic hybrid molecules, exerting a spectrum of neuroprotective interrelated activities: antioxidant/monoamine oxidase inhibition, activation of the hypoxia-inducible factor (HIF)-1 signaling pathway, induction of HIF-1 target iron-regulatory and antioxidative genes, and inhibition of α-synuclein accumulation and aggregation.

  18. Automatic target and trajectory identification for deep brain stimulation (DBS) procedures.

    PubMed

    Guo, Ting; Parrent, Andrew G; Peters, Terry M

    2007-01-01

    This paper presents an automatic surgical target and trajectory identification technique for planning deep brain stimulation (DBS) procedures. The probabilistic functional maps, constructed from population-based actual stimulating field information and intra-operative electrophysiological activities, were integrated into a neurosurgical visualization and navigation system to facilitate the surgical planning and guidance. In our preliminary studies, we compared the actual surgical target locations and trajectories established by an experienced stereotactic neurosurgeon with those automatically planned using our probabilistic functional maps on 10 subthalamic nucleus (STN) DBS procedures. The average displacement between the surgical target locations in both groups was 1.82mm with a standard deviation of 0.77mm. The difference between the surgical trajectories was 3.1 degrees and 2.3 degrees in the lateral-to-medial and anterior-to-posterior orientations respectively.

  19. Scalable fluidic injector arrays for viral targeting of intact 3-D brain circuits.

    PubMed

    Chan, Stephanie; Bernstein, Jacob; Boyden, Edward

    2010-01-21

    Our understanding of neural circuits--how they mediate the computations that subserve sensation, thought, emotion, and action, and how they are corrupted in neurological and psychiatric disorders--would be greatly facilitated by a technology for rapidly targeting genes to complex 3-dimensional neural circuits, enabling fast creation of "circuit-level transgenics." We have recently developed methods in which viruses encoding for light-sensitive proteins can sensitize specific cell types to millisecond-timescale activation and silencing in the intact brain. We here present the design and implementation of an injector array capable of delivering viruses (or other fluids) to dozens of defined points within the 3-dimensional structure of the brain (Figure. 1A, 1B). The injector array comprises one or more displacement pumps that each drive a set of syringes, each of which feeds into a polyimide/fused-silica capillary via a high-pressure-tolerant connector. The capillaries are sized, and then inserted into, desired locations specified by custom-milling a stereotactic positioning board, thus allowing viruses or other reagents to be delivered to the desired set of brain regions. To use the device, the surgeon first fills the fluidic subsystem entirely with oil, backfills the capillaries with the virus, inserts the device into the brain, and infuses reagents slowly (<0.1 microliters/min). The parallel nature of the injector array facilitates rapid, accurate, and robust labeling of entire neural circuits with viral payloads such as optical sensitizers to enable light-activation and silencing of defined brain circuits. Along with other technologies, such as optical fiber arrays for light delivery to desired sets of brain regions, we hope to create a toolbox that enables the systematic probing of causal neural functions in the intact brain. This technology may not only open up such systematic approaches to circuit-focused neuroscience in mammals, and facilitate labeling of

  20. Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0414 TITLE: Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors PRINCIPAL INVESTIGATOR: Jean Mulcahy...29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-14-1-0414 Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors 5b. GRANT...ABSTRACT 200 words most significant findings 15. SUBJECT TERMS autophagy, BRAF, brain tumor. pediatric 16. SECURITY CLASSIFICATION OF: 17

  1. Phage display: development of nanocarriers for targeted drug delivery to the brain

    PubMed Central

    Bakhshinejad, Babak; Karimi, Marzieh; Khalaj-Kondori, Mohammad

    2015-01-01

    The blood brain barrier represents a formidable obstacle for the transport of most systematically administered neurodiagnostics and neurotherapeutics to the brain. Phage display is a high throughput screening strategy that can be used for the construction of nanomaterial peptide libraries. These libraries can be screened for finding brain targeting peptide ligands. Surface functionalization of a variety of nanocarriers with these brain homing peptides is a sophisticated way to develop nanobiotechnology-based drug delivery platforms that are able to cross the blood brain barrier. These efficient drug delivery systems raise our hopes for the diagnosis and treatment of various brain disorders in the future. PMID:26199590

  2. Brain Distribution of Cediranib Is Limited by Active Efflux at the Blood-Brain Barrier

    PubMed Central

    Wang, Tianli; Agarwal, Sagar

    2012-01-01

    Cediranib is an orally active tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor family. Because of its potent antiangiogenic and antitumor activities, cediranib has been evaluated for therapy in glioma, a primary brain tumor. This study investigated the influence of two important efflux transporters at the blood-brain barrier, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), on the delivery of cediranib to the central nervous system. In vitro studies indicated that cediranib is a dual substrate for both P-gp and Bcrp. It is noteworthy that in spite of the in vitro data the in vivo mouse disposition studies conclusively showed that P-gp was the dominant transporter restricting the brain distribution of cediranib. The brain-to-plasma partitioning (AUCbrain/AUCplasma, where AUC is area under the curve) and the steady-state brain-to-plasma concentration ratio of cediranib were approximately 20-fold higher in Mdr1a/b(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice compared with wild-type and Bcrp1(−/−) mice. Moreover, there was no significant difference in brain distribution of cediranib between wild-type and Bcrp1(−/−) mice and between Mdr1a/b(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice. These results show that, unlike other tyrosine kinase inhibitors that are dual substrates for P-gp and Bcrp, Bcrp does not restrict the distribution of cediranib across the blood-brain barrier. We also show that inhibition of P-gp using specific or nonspecific inhibitors resulted in significantly enhanced delivery of cediranib to the brain. Concurrent administration of cediranib with chemical modulators of efflux transporters can be used as a strategy to enhance delivery and thus efficacy of cediranib in the brain. These findings are clinically relevant to the efficacy of cediranib chemotherapy in glioma. PMID:22323823

  3. Chaperone proteins and brain tumors: Potential targets and possible therapeutics1

    PubMed Central

    Graner, Michael W.; Bigner, Darell D.

    2005-01-01

    Chaperone proteins are most notable for the proteo- and cyotoprotective capacities they afford during cellular stress. Under conditions of cellular normalcy, chaperones still play integral roles in the folding of nascent polypeptides into functional entities, in assisting in intracellular/intraorganellar transport, in assembly and maintenance of multi-subunit protein complexes, and in aiding and abetting the degradation of senescent proteins. Tumors frequently have relatively enhanced needs for chaperone number and activity because of the stresses of rapid proliferation, increased metabolism, and overall genetic instability. Thus, it may be possible to take advantage of this reliance that tumor cells have on chaperones by pharmacologic and biologic means. Certain chaperones are abundant in the brain, which implies important roles for them. While it is presumed that the requirements of brain tumors for chaperone proteins are similar to those of any other cell type, tumor or otherwise, very little inquiry has been directed at the possibility of using chaperone proteins as therapeutic targets or even as therapeutic agents against central nervous system malignancies. This review highlights some of the research on the functions of chaperone proteins, on what can be done to modify those functions, and on the physiological responses that tumors and organisms can have to chaperone-targeted or chaperone-based therapies. In particular, this review will also underscore areas of research where brain tumors have been part of the field, although in general those instances are few and far between. This relative dearth of research devoted to chaperone protein targets and therapeutics in brain tumors reveals much untrodden turf to explore for potential treatments of these dreadfully refractive diseases. PMID:16053701

  4. Identifying lipidic emulsomes for improved oxcarbazepine brain targeting: In vitro and rat in vivo studies.

    PubMed

    El-Zaafarany, Ghada M; Soliman, Mahmoud E; Mansour, Samar; Awad, Gehanne A S

    2016-04-30

    Lipid-based nanovectors offer effective carriers for brain delivery by improving drug potency and reducing off-target effects. Emulsomes are nano-triglyceride (TG) carriers formed of lipid cores supported by at least one phospholipid (PC) sheath. Due to their surface active properties, PC forms bilayers at the aqueous interface, thereby enabling encapsulated drug to benefit from better bioavailability and stability. Emulsomes of oxcarbazepine (OX) were prepared, aimed to offer nanocarriers for nasal delivery for brain targeting. Different TG cores (Compritol(®), tripalmitin, tristearin and triolein) and soya phosphatidylcholine in different amounts and ratios were used for emulsomal preparation. Particles were modulated to generate nanocarriers with suitable size, charge, encapsulation efficiency and prolonged release. Cytotoxicity and pharmacokinetic studies were also implemented. Nano-spherical OX-emulsomes with maximal encapsulation of 96.75% were generated. Stability studies showed changes within 30.6% and 11.2% in the size and EE% after 3 months. MTT assay proved a decrease in drug toxicity by its encapsulation in emulsomes. Incorporation of OX into emulsomes resulted in stable nanoformulations. Tailoring emulsomes properties by modulating the surface charge and particle size produced a stable system for the lipophilic drug with a prolonged release profile and mean residence time and proved direct nose-to-brain transport in rats.

  5. Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification

    NASA Astrophysics Data System (ADS)

    Yang, Jun; Fan, Lixue; Wang, Feijian; Luo, Yuan; Sui, Xin; Li, Wanhua; Zhang, Xiaohong; Wang, Yongan

    2016-05-01

    The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration.The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and

  6. Using Brain Electrical Activity Mapping to Diagnose Learning Disabilities.

    ERIC Educational Resources Information Center

    Torello, Michael, W.; Duffy, Frank H.

    1985-01-01

    Cognitive neuroscience assumes that measurement of brain electrical activity should relate to cognition. Brain Electrical Activity Mapping (BEAM), a non-invasive technique, is used to record changes in activity from one brain area to another and is 80 to 90 percent successful in classifying subjects as dyslexic or normal. (MT)

  7. Drugs, biogenic amine targets and the developing brain.

    PubMed

    Frederick, Aliya L; Stanwood, Gregg D

    2009-01-01

    Defects in the development of the brain have a profound impact on mature brain functions and underlying psychopathology. Classical neurotransmitters and neuromodulators, such as dopamine, serotonin, norepinephrine, acetylcholine, glutamate and GABA, have pleiotropic effects during brain development. In other words, these molecules produce multiple diverse effects to serve as regulators of distinct cellular functions at different times in neurodevelopment. These systems are impacted upon by abuse of a variety of illicit drugs, neurotherapeutics and environmental contaminants. In this review, we describe the impact of drugs and chemicals on brain formation and function in animal models and in human populations, highlighting sensitive periods and effects that may not emerge until later in life.

  8. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction.

    PubMed

    Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

    2015-10-01

    Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.

  9. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

    PubMed Central

    Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

    2016-01-01

    Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. PMID:26235983

  10. Brain Activation During Singing: "Clef de Sol Activation" Is the "Concert" of the Human Brain.

    PubMed

    Mavridis, Ioannis N; Pyrgelis, Efstratios-Stylianos

    2016-03-01

    Humans are the most complex singers in nature, and the human voice is thought by many to be the most beautiful musical instrument. Aside from spoken language, singing represents a second mode of acoustic communication in humans. The purpose of this review article is to explore the functional anatomy of the "singing" brain. Methodologically, the existing literature regarding activation of the human brain during singing was carefully reviewed, with emphasis on the anatomic localization of such activation. Relevant human studies are mainly neuroimaging studies, namely functional magnetic resonance imaging and positron emission tomography studies. Singing necessitates activation of several cortical, subcortical, cerebellar, and brainstem areas, served and coordinated by multiple neural networks. Functionally vital cortical areas of the frontal, parietal, and temporal lobes bilaterally participate in the brain's activation process during singing, confirming the latter's role in human communication. Perisylvian cortical activity of the right hemisphere seems to be the most crucial component of this activation. This also explains why aphasic patients due to left hemispheric lesions are able to sing but not speak the same words. The term clef de sol activation is proposed for this crucial perisylvian cortical activation due to the clef de sol shape of the topographical distribution of these cortical areas around the sylvian fissure. Further research is needed to explore the connectivity and sequence of how the human brain activates to sing.

  11. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

    PubMed Central

    Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

    2016-01-01

    Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries. PMID:27351915

  12. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

    NASA Astrophysics Data System (ADS)

    Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

    2016-06-01

    Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.

  13. Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors

    NASA Astrophysics Data System (ADS)

    Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.; Broome, Ann-Marie

    2015-01-01

    Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.

  14. Active Targets for Experiments with Rare Isotopes

    NASA Astrophysics Data System (ADS)

    Wiedenhoever, Ingo

    2014-09-01

    Experimental studies of un-bound nuclear states and nuclear reaction rates relevant for astrophysical processes are an important area of research with rare isotope beams. Both topics require the development of specialized experimental methods to study resonant reactions. The so-called active target approach, where the target material becomes part of the detection process, promises to combine high yields from thicker targets and low background with high resolution. This presentation will describe the implementation of the active-target technique in the ANASEN detector, which was developed by researchers from Louisiana State University and Florida State University. ANASEN was used in a number of stable and rare iosotope experiments in α- and proton scattering, as well as (α , p) and (d , p) reactions at FSU's in-flight radioactive beam facility RESOLUT. ANASEN also was used to perform the first experiment, proton scattering off a 37K beam at the ReA3 facility. Another active-target detector with a very different approach is found in the Active Target Time-Projection Chamber, which was developed by a collaboration between researchers from MSU, the University of Notre Dame, Western Michigan University, LLNL, LBNL, and St. Mary's University (Canada). First experiments with an AT-TPC prototype have been reported. The talk will summarize the results from the first experiments with these systems, describe further development and future research projects. Experimental studies of un-bound nuclear states and nuclear reaction rates relevant for astrophysical processes are an important area of research with rare isotope beams. Both topics require the development of specialized experimental methods to study resonant reactions. The so-called active target approach, where the target material becomes part of the detection process, promises to combine high yields from thicker targets and low background with high resolution. This presentation will describe the implementation of the

  15. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease.

    PubMed

    Ho, Lap; Ferruzzi, Mario G; Janle, Elsa M; Wang, Jun; Gong, Bing; Chen, Tzu-Ying; Lobo, Jessica; Cooper, Bruce; Wu, Qing Li; Talcott, Stephen T; Percival, Susan S; Simon, James E; Pasinetti, Giulio Maria

    2013-02-01

    Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ(1-40) and Aβ(1-42) that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.

  16. Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel.

    PubMed

    Li, Hua-Juan; Zhang, Yu-Jiao; Zhou, Li; Han, Feng; Wang, Ming-Yan; Xue, Mao-Qiang; Qi, Zhi

    2014-07-15

    Chlorpromazine (CPZ) is a well-known antipsychotic drug, still widely being used to treat symptoms of schizophrenia, psychotic depression and organic psychoses. We have previously reported that CPZ activates the BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BKCa channels without changing its single channel amplitude. As BKCa channel is one of the molecular targets of brain ischemia, we explored a possible new use of this old drug on ischemic brain injury. In middle cerebral artery occlusion (MCAO) focal cerebral ischemia, a single intraperitoneal injection of CPZ at several dosages (5mg/kg, 10mg/kg and 20mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BKCa channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BKCa channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BKCa channels and merits exploration as a potential therapeutic agent for treating ischemic stroke.

  17. Insight into role of microbiota-gut-brain peptides as a target for biotechnology innovations.

    PubMed

    Elisei, Carina; de Castro, Alinne Pereira

    2017-01-01

    It has long been understood that some microorganisms may modify their hosts behavior in various systems. Nevertheless, it has only been in recent years that gut microbiota have opened new perspectives to appreciate their potential for affect complex neurological function in mammals. Efforts have demonstrated the ability of these gut-microbiota to impact neurological outcomes, suggested a prominent role for the gut microbiota in the gut-brain interactions, indicating that alterations in bidirectional microbiota-brain-gut may be involved in a number of brain disorders. Further, the identification of bioactive microbial signals, including their immune mediators, gut hormones and/or peptides, during health and disease situations, can serve as a tool for discovering novel activities that influence behavior and neurological function in hosts. Current review aims to provide an overview and shed some light on fundamental characteristics of the gut microbiota in modulating neurological disorders and consequently to draw up alternative strategies for using the gut microbiota or their active molecules as a therapeutic target for future diagnoses.

  18. Scale-free brain activity: past, present and future

    PubMed Central

    He, Biyu J.

    2014-01-01

    Brain activity observed at many spatiotemporal scales exhibits a 1/f-like power spectrum, including neuronal membrane potentials, neural field potentials, noninvasive electroencephalography, magnetoencephalography and functional magnetic resonance imaging signals. A 1/f-like power spectrum is indicative of arrhythmic brain activity that does not contain a predominant temporal scale (hence, “scale-free”). This characteristic of scale-free brain activity distinguishes it from brain oscillations. While scale-free brain activity and brain oscillations coexist, our understanding of the former remains very limited. Recent research has shed light on the spatiotemporal organization, functional significance and potential generative mechanisms of scale-free brain activity, as well as its developmental and clinical relevance. A deeper understanding of this prevalent brain signal should provide new insights and analytical tools for cognitive neuroscience. PMID:24788139

  19. Targeting the brain--surmounting or bypassing the blood-brain barrier.

    PubMed

    Potschka, Heidrun

    2010-01-01

    The constituents of the blood-brain barrier, including its efflux transporter system, can efficiently limit brain penetration of potential CNS therapeutics. Effective extrusion from the brain by transporters is a frequent reason for the pharmaceutical industry to exclude novel compounds from further development for CNS therapeutics. Moreover, high transporter expression levels that are present in individual patients or may be generally associated with the pathophysiology seem to be a major cause of therapeutic failure in a variety of CNS diseases including brain tumors, epilepsy, brain HIV infection, and psychiatric disorders. Increasing knowledge of the structure and function of the blood-brain barrier creates a basis for the development of strategies which aim to enhance brain uptake of beneficial pharmaceutical compounds. The different strategies discussed in this review aim to modulate blood-brain barrier function or to bypass constituents of the blood-brain barrier.

  20. Probabilistic Analysis of Activation Volumes Generated During Deep Brain Stimulation

    PubMed Central

    Butson, Christopher R.; Cooper, Scott E.; Henderson, Jaimie M.; Wolgamuth, Barbara; McIntyre, Cameron C.

    2010-01-01

    Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson’s disease (PD) and shows great promise for the treatment of several other disorders. However, while the clinical analysis of DBS has received great attention, a relative paucity of quantitative techniques exists to define the optimal surgical target and most effective stimulation protocol for a given disorder. In this study we describe a methodology that represents an evolutionary addition to the concept of a probabilistic brain atlas, which we call a probabilistic stimulation atlas (PSA). We outline steps to combine quantitative clinical outcome measures with advanced computational models of DBS to identify regions where stimulation-induced activation could provide the best therapeutic improvement on a per-symptom basis. While this methodology is relevant to any form of DBS, we present example results from subthalamic nucleus (STN) DBS for PD. We constructed patient-specific computer models of the volume of tissue activated (VTA) for 163 different stimulation parameter settings which were tested in six patients. We then assigned clinical outcome scores to each VTA and compiled all of the VTAs into a PSA to identify stimulation-induced activation targets that maximized therapeutic response with minimal side effects. The results suggest that selection of both electrode placement and clinical stimulation parameter settings could be tailored to the patient’s primary symptoms using patient-specific models and PSAs. PMID:20974269

  1. Probabilistic analysis of activation volumes generated during deep brain stimulation.

    PubMed

    Butson, Christopher R; Cooper, Scott E; Henderson, Jaimie M; Wolgamuth, Barbara; McIntyre, Cameron C

    2011-02-01

    Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD) and shows great promise for the treatment of several other disorders. However, while the clinical analysis of DBS has received great attention, a relative paucity of quantitative techniques exists to define the optimal surgical target and most effective stimulation protocol for a given disorder. In this study we describe a methodology that represents an evolutionary addition to the concept of a probabilistic brain atlas, which we call a probabilistic stimulation atlas (PSA). We outline steps to combine quantitative clinical outcome measures with advanced computational models of DBS to identify regions where stimulation-induced activation could provide the best therapeutic improvement on a per-symptom basis. While this methodology is relevant to any form of DBS, we present example results from subthalamic nucleus (STN) DBS for PD. We constructed patient-specific computer models of the volume of tissue activated (VTA) for 163 different stimulation parameter settings which were tested in six patients. We then assigned clinical outcome scores to each VTA and compiled all of the VTAs into a PSA to identify stimulation-induced activation targets that maximized therapeutic response with minimal side effects. The results suggest that selection of both electrode placement and clinical stimulation parameter settings could be tailored to the patient's primary symptoms using patient-specific models and PSAs.

  2. Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling.

    PubMed

    Zou, Jian Y; Crews, Fulton T

    2014-01-01

    Neuroimmune gene induction is involved in many brain pathologies including addiction. Although increased expression of proinflammatory cytokines has been found in ethanol-treated mouse brain and rat brain slice cultures as well as in post-mortem human alcoholic brain, the mechanisms remain elusive. High-mobility group box 1 (HMGB1) protein is a nuclear protein that has endogenous cytokine-like activity. We previously found increased HMGB1 in post-mortem alcoholic human brain as well as in ethanol treated mice and rat brain slice cultures. The present study investigated the mechanisms for ethanol-induced release of HMGB1 and neuroimmune activation in a model of rat hippocampal-entorhinal cortex (HEC) brain slice cultures. Ethanol exposure triggered dose-dependent HMGB1 release, predominantly from neuronal cells. Inhibitors of histone deacetylases (HDACs) promoted nucleocytoplasmic mobilization of HDAC1/4 and HMGB1 resulting in increased total HMGB1 and acetylated HMGB1 release. Similarly, ethanol treatment was found to induce the translocation of HDAC1/4 and HMGB1 proteins from nuclear to cytosolic fractions. Furthermore, ethanol treatment reduced HDAC1/4 mRNA and increased acetylated HMGB1 release into the media. These results suggest decreased HDAC activity may be critical in regulating acetylated HMGB1 release from neurons in response to ethanol. Ethanol and HMGB1 treatment increased mRNA expression of proinflammatory cytokines TNFα and IL-1β as well as toll-like receptor 4 (TLR4). Targeting HMGB1 or microglial TLR4 by using siRNAs to HMGB1 and TLR4, HMGB1 neutralizing antibody, HMGB1 inhibitor glycyrrhizin and TLR4 antagonist as well as inhibitor of microglial activation all blocked ethanol-induced expression of proinflammatory cytokines TNFα and IL-1β. These results support the hypothesis that ethanol alters HDACs that regulate HMGB1 release and that danger signal HMGB1 as endogenous ligand for TLR4 mediates ethanol-induced brain neuroimmune signaling

  3. Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

    PubMed Central

    MacDiarmid, Jennifer A.; Langova, Veronika; Bailey, Dale; Pattison, Scott T.; Pattison, Stacey L.; Christensen, Neil; Armstrong, Luke R.; Brahmbhatt, Vatsala N.; Smolarczyk, Katarzyna; Harrison, Matthew T.; Costa, Marylia; Mugridge, Nancy B.; Sedliarou, Ilya; Grimes, Nicholas A.; Kiss, Debra L.; Stillman, Bruce; Hann, Christine L.; Gallia, Gary L.; Graham, Robert M.; Brahmbhatt, Himanshu

    2016-01-01

    Background Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On

  4. Noninvasive and targeted drug delivery to the brain using focused ultrasound.

    PubMed

    Burgess, Alison; Hynynen, Kullervo

    2013-04-17

    Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer's disease. The requirements for clinical translation of FUS will be discussed.

  5. Active interoceptive inference and the emotional brain

    PubMed Central

    Friston, Karl J.

    2016-01-01

    We review a recent shift in conceptions of interoception and its relationship to hierarchical inference in the brain. The notion of interoceptive inference means that bodily states are regulated by autonomic reflexes that are enslaved by descending predictions from deep generative models of our internal and external milieu. This re-conceptualization illuminates several issues in cognitive and clinical neuroscience with implications for experiences of selfhood and emotion. We first contextualize interoception in terms of active (Bayesian) inference in the brain, highlighting its enactivist (embodied) aspects. We then consider the key role of uncertainty or precision and how this might translate into neuromodulation. We next examine the implications for understanding the functional anatomy of the emotional brain, surveying recent observations on agranular cortex. Finally, we turn to theoretical issues, namely, the role of interoception in shaping a sense of embodied self and feelings. We will draw links between physiological homoeostasis and allostasis, early cybernetic ideas of predictive control and hierarchical generative models in predictive processing. The explanatory scope of interoceptive inference ranges from explanations for autism and depression, through to consciousness. We offer a brief survey of these exciting developments. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’. PMID:28080966

  6. Permanent Genetic Access to Transiently Active Neurons via TRAP: Targeted Recombination in Active Populations

    PubMed Central

    Guenthner, Casey J.; Miyamichi, Kazunari; Yang, Helen H.; Heller, H. Craig; Luo, Liqun

    2013-01-01

    SUMMARY Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed a new approach, Targeted Recombination in Active Populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreERT2 is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that express CreERT2 can undergo recombination only when tamoxifen is present, allowing genetic access to neurons that are active during a time window of less than 12 h. We show that TRAP can selectively provide access to neurons activated by specific somatosensory, visual, and auditory stimuli, and by experience in a novel environment. When combined with tools for labeling, tracing, recording, and manipulating neurons, TRAP offers a powerful new approach for understanding how the brain processes information and generates behavior. PMID:23764283

  7. CFTR targeting during activation of human neutrophils.

    PubMed

    Ng, Hang Pong; Valentine, Vincent G; Wang, Guoshun

    2016-12-01

    Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, plays critical roles in phagocytic host defense. However, how activated neutrophils regulate CFTR channel distribution subcellularly is not well defined. To investigate, we tested multiple Abs against different CFTR domains, to examine CFTR expression in human peripheral blood neutrophils by flow cytometry. The data confirmed that resting neutrophils had pronounced CFTR expression. Activation of neutrophils with soluble or particulate agonists did not significantly increase CFTR expression level, but induced CFTR redistribution to cell surface. Such CFTR mobilization correlated with cell-surface recruitment of formyl-peptide receptor during secretory vesicle exocytosis. Intriguingly, neutrophils from patients with ΔF508-CF, despite expression of the mutant CFTR, showed little cell-surface mobilization upon stimulation. Although normal neutrophils effectively targeted CFTR to their phagosomes, ΔF508-CF neutrophils had impairment in that process, resulting in deficient hypochlorous acid production. Taken together, activated neutrophils regulate CFTR distribution by targeting this chloride channel to the subcellular sites of activation, and ΔF508-CF neutrophils fail to achieve such targeting, thus undermining their host defense function.

  8. A vaccine for nicotine dependence: targeting the drug rather than the brain.

    PubMed

    Pentel, Paul; Malin, David

    2002-01-01

    Nicotine is the principal addictive component of tobacco. Vaccination of rats against nicotine elicits the production of nicotine-specific antibodies which can bind and sequester nicotine in serum and extracellular fluid, reduce nicotine distribution to brain, and reduce many of nicotine's physiologic and behavioral effects. Vaccination reduces the distribution to brain of both a single nicotine dose and chronic nicotine infusion at rates approximating cigarette smoking. The passive transfer of nicotine-specific antibodies (from vaccinated rabbits) into rats attenuates numerous actions of nicotine: increases in blood pressure and locomotor activity, the induction of nicotine dependence, the relief of nicotine withdrawal by subsequent nicotine and the stimulus properties that allow rats to discriminate a nicotine from a saline injection. Vaccination of rats against nicotine also reduces nicotine-induced dopamine release in the reward pathway of the brain and the reinstatement of nicotine responding, a model for relapse. Because nicotine vaccines target the drug rather than the brain, and the antibodies themselves do not cross the blood-brain barrier, immunization should circumvent the central nervous system side effects that limit the usable dosage of other medications for tobacco dependence. Nicotine vaccines have not yet been tested in humans. The effects of these vaccines in rats are highly dependent upon the concentration of antibody in serum, and are more often partial than complete. If effective for treating tobacco dependence in humans, vaccination will likely benefit from concurrent use of counseling (as is the case with other medications for smoking cessation) and perhaps from its combination with other medications that act via different mechanisms.

  9. Anxiety and error-related brain activity.

    PubMed

    Hajcak, Greg; McDonald, Nicole; Simons, Robert F

    2003-10-01

    Error-related negativity (ERN/Ne) is a component of the event-related brain potential (ERP) associated with monitoring action and detecting errors. It is a sharp negative deflection that generally occurs from 50 to 150 ms following response execution and has been associated with anterior cingulate cortex (ACC) activity. An enhanced ERN has been observed in patients with obsessive-compulsive disorder (OCD)--reflecting abnormal ACC activity hypothesized as part of the pathophysiology of OCD. We recently reported that the ERN is also enhanced in a group of college students with OC characteristics. The present study extended these findings by measuring the ERN in college undergraduates who scored high on either the Penn State Worry Questionnaire (PSWQ) or a combined version of the Snake (SNAQ) and Spider (SPQ) Questionnaires. Results indicate that, like OC subjects, subjects who score high on a measure of general anxiety and worry have enhanced error-related brain activity relative to both phobic and non-anxious control subjects. The enhanced ERN was found to generalize beyond OCD within the anxiety spectrum disorders but also shows some specificity within these disorders.

  10. Targeted Lipid Profiling Discovers Plasma Biomarkers of Acute Brain Injury

    PubMed Central

    Sheth, Sunil A.; Iavarone, Anthony T.; Liebeskind, David S.; Won, Seok Joon; Swanson, Raymond A.

    2015-01-01

    Prior efforts to identify a blood biomarker of brain injury have relied almost exclusively on proteins; however their low levels at early time points and poor correlation with injury severity have been limiting. Lipids, on the other hand, are the most abundant molecules in the brain and readily cross the blood-brain barrier. We previously showed that certain sphingolipid (SL) species are highly specific to the brain. Here we examined the feasibility of using SLs as biomarkers for acute brain injury. A rat model of traumatic brain injury (TBI) and a mouse model of stroke were used to identify candidate SL species though our mass-spectrometry based lipid profiling approach. Plasma samples collected after TBI in the rat showed large increases in many circulating SLs following injury, and larger lesions produced proportionately larger increases. Plasma samples collected 24 hours after stroke in mice similarly revealed a large increase in many SLs. We constructed an SL score (sum of the two SL species showing the largest relative increases in the mouse stroke model) and then evaluated the diagnostic value of this score on a small sample of patients (n = 14) who presented with acute stroke symptoms. Patients with true stroke had significantly higher SL scores than patients found to have non-stroke causes of their symptoms. The SL score correlated with the volume of ischemic brain tissue. These results demonstrate the feasibility of using lipid biomarkers to diagnose brain injury. Future studies will be needed to further characterize the diagnostic utility of this approach and to transition to an assay method applicable to clinical settings. PMID:26076478

  11. Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

    PubMed

    Van Goietsenoven, Gwendoline; Mathieu, Véronique; Lefranc, Florence; Kornienko, Alexander; Evidente, Antonio; Kiss, Robert

    2013-03-01

    The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.

  12. A Mathematical Model to Elucidate Brain Tumor Abrogation by Immunotherapy with T11 Target Structure

    PubMed Central

    Chaudhuri, Swapna

    2015-01-01

    T11 Target structure (T11TS), a membrane glycoprotein isolated from sheep erythrocytes, reverses the immune suppressed state of brain tumor induced animals by boosting the functional status of the immune cells. This study aims at aiding in the design of more efficacious brain tumor therapies with T11 target structure. We propose a mathematical model for brain tumor (glioma) and the immune system interactions, which aims in designing efficacious brain tumor therapy. The model encompasses considerations of the interactive dynamics of glioma cells, macrophages, cytotoxic T-lymphocytes (CD8+ T-cells), TGF-β, IFN-γ and the T11TS. The system undergoes sensitivity analysis, that determines which state variables are sensitive to the given parameters and the parameters are estimated from the published data. Computer simulations were used for model verification and validation, which highlight the importance of T11 target structure in brain tumor therapy. PMID:25955428

  13. Reaching a Moveable Visual Target: Dissociations in Brain Tumour Patients

    ERIC Educational Resources Information Center

    Buiatti, Tania; Skrap, Miran; Shallice, Tim

    2013-01-01

    Damage to the posterior parietal cortex (PPC) can lead to Optic Ataxia (OA), in which patients misreach to peripheral targets. Recent research suggested that the PPC might be involved not only in simple reaching tasks toward peripheral targets, but also in changing the hand movement trajectory in real time if the target moves. The present study…

  14. Order/disorder in brain electrical activity

    NASA Astrophysics Data System (ADS)

    Rosso, O. A.; Figliola, Y. A.

    2004-04-01

    The processing of information by the brain is reflected in dynamical changes of the electrical activity in time, frequency, and space. Therefore, the concomitant studies require methods capable of describing the quantitative variation of the signal in both time and frequency. Here we present a quantitative EEG (qEEG) analysis, based on the Orthogonal Discrete Wavelet Transform (ODWT), of generalized epileptic tonic-clonic EEG signals. Two quantifiers: the Relative Wavelet Energy (RWE) and the Normalized Total Wavelet Entropy (NTWS) have been used. The RWE gives information about the relative energy associated with the different frequency bands present in the EEG and their corresponding degree of importance. The NTWS is a measure of the order/disorder degree in the EEG signal. These two quantifiers were computing in EEG signals as provided by scalp electrodes of epileptic patients. We showed that the epileptic recruitment rhythm observed for generalized epileptic tonic-clonic seizures is accurately described by the RWE quantifier. In addition, a significant decrease in the NTWS was observed in the recruitment epoch, indicating a more rhythmic and ordered behavior in the brain electrical activity.

  15. The developing oligodendrocyte: key cellular target in brain injury in the premature infant.

    PubMed

    Volpe, Joseph J; Kinney, Hannah C; Jensen, Frances E; Rosenberg, Paul A

    2011-06-01

    Brain injury in the premature infant, a problem of enormous importance, is associated with a high risk of neurodevelopmental disability. The major type of injury involves cerebral white matter and the principal cellular target is the developing oligodendrocyte. The specific phase of the oligodendroglial lineage affected has been defined from study of both human brain and experimental models. This premyelinating cell (pre-OL) is vulnerable because of a series of maturation-dependent events. The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischemia and systemic infection/inflammation, both of which are common occurrences in premature infants. The focus of this review and of our research over the past 15-20 years has been the cellular and molecular bases for the maturation-dependent vulnerability of the pre-OL to the action of the two upstream mechanisms. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack. The work in both experimental models and human brain has identified a remarkable confluence of maturation-dependent factors that render the pre-OL so exquisitely vulnerable to these downstream mechanisms. Most importantly, elucidation of these factors has led to delineation of a series of potential therapeutic interventions, which in experimental models show marked protective properties. The critical next step, i.e., clinical trials in the living infant, is now on the horizon.

  16. Separating esterase targets of organophosphorus compounds in the brain by preparative chromatography.

    PubMed

    Mangas, I; Vilanova, E; Benabent, M; Estévez, J

    2014-02-10

    Low level exposure to organophosphorus esters (OPs) may cause long-term neurological effects and affect specific cognition domains in experimental animals and humans. Action on known targets cannot explain most of these effects by. Soluble carboxylesterases (EC 3.1.1.1) of chicken brain have been kinetically discriminated using paraoxon, mipafox and phenylmethyl sulfonylfluoride as inhibitors and phenyl valerate as a substrate. Three different enzymatic components were discriminated and called Eα, Eβ and Eγ. In this work, a fractionation procedure with various steps was developed using protein native separation methods by preparative HPLC. Gel permeation chromatography followed by ion exchange chromatography allowed enriched fractions with different kinetic behaviors. The soluble chicken brain fraction was fractionated, while total esterase activity, proteins and enzymatic components Eα, Eβ and Eγ were monitored in each subfraction. After the analysis, 13 fractions were pooled and conserved. Preincubation of the soluble chicken brain fraction of with the organophosphorus mipafox gave rise to a major change in the ion exchange chromatography profile, but not in the molecular exchanged chromatography profile, which suggest that mipafox permanently modifies the ionic properties of numerous proteins.

  17. Brain Activity with Reading Sentences and Emoticons

    NASA Astrophysics Data System (ADS)

    Yuasa, Masahide; Saito, Keiichi; Mukawa, Naoki

    In this paper, we describe a person's brain activity when he/she sees an emoticon at the end of a sentence. An emoticon consists of some characters that resemble the human face and expresses a sender's emotion. With the help of a computer network, we use e-mail, messenger, avatars and so on, in order to convey what we wish to, to a receiver. Moreover, we send an emotional expression by using an emoticon at the end of a sentence. In this research, we investigate the effect of an emoticon as nonverbal information, using an fMRI study. The experimental results show that the right and left inferior frontal gyrus were activated and we detect a sentence with an emoticon as the verbal and nonverval information.

  18. Delivery of a peptide-drug conjugate targeting the blood brain barrier improved the efficacy of paclitaxel against glioma

    PubMed Central

    Li, Ying; Zheng, Xuemin; Gong, Min; Zhang, Jianning

    2016-01-01

    The challenge of effectively delivering therapeutic agents to the brain has created an entire field of active research devoted to overcoming the blood brain barrier (BBB) and efficiently delivering drugs to the brain. Angiopep-2 can trigger transcytosis and traverse the BBB by recognizing low-density lipoprotein related protein-1 (LRP-1) expressed on the brain capillary endothelial cells. Here, we designed a novel strategy for the delivery of drugs to the brain. The novel drug delivery system was a combination of a receptor-targeting ligand, such as low-density lipoprotein related protein 1, and a cell-penetrating peptide (CPP). It was hypothesized that this conjugate will enhance the delivery of associated therapeutic cargo across the BBB and increase the permeability of a solid tumor. Our findings indicate that the combination of these two agents in a delivery vehicle significantly improved translocation of small molecules (paclitaxel) into the brain compared to the vehicle treatment, which contained only receptor-targeting ligand. The application of this strategy could potentially expand the horizons for the treatment of central nervous system disorders. PMID:27765902

  19. Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma

    PubMed Central

    Ponzoni, M.; Issa, S.; Batchelor, T. T.; Rubenstein, J. L.

    2014-01-01

    Background While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease. Patients and methods We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology. Results While PCNSL tumors usually express a BCL6+, MUM1+ ‘activated, germinal center’ immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses. Conclusions There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease. PMID:24265352

  20. Photo-acoustic imaging of blue nanoparticle targeted brain tumor for intra-operative glioma delineation

    NASA Astrophysics Data System (ADS)

    Ray, Aniruddha; Wang, Xueding; Koo Lee, Yong-Eun; Hah, HoeJin; Kim, Gwangseong; Chen, Thomas; Orrienger, Daniel; Sagher, Oren; Kopelman, Raoul

    2011-07-01

    Distinguishing the tumor from the background neo-plastic tissue is challenging for cancer surgery such as surgical resection of glioma. Attempts have been made to use visible or fluorescent markers to delineate the tumors during surgery. However, the systemic injection of the dyes requires high dose, resulting in negative side effects. A novel method to delineate rat brain tumors intra-operatively, as well as post-operatively, using a highly sensitive photoacoustic imaging technique enhanced by tumor targeting blue nanoparticle as contrast agent is demonstrated. The nanoparticles are made of polyacrylamide (PAA) matrix with covalently linked Coomassie-Blue dye. They contain 7.0% dye and the average size is 80nm. Their surface was conjugated with F3 peptide for active tumor targeting. These nanoparticles are nontoxic, chemically inert and have long plasma circulation lifetime, making them suitable as nanodevices for imaging using photoacoustics. Experiments on phantoms and rat brains tumors ex-vivo demonstrate the high sensitivity of photoacoustic imaging in delineating the tumor, containing contrast agent at concentrations too low to be visualized by eye. The control tumors without nanoparticles did not show any enhanced signal. This study shows that photoacoustic imaging facilitated with the nanoparticle contrast agent could contribute to future surgical procedures for glioma.

  1. Getting mixed messages: the impact of conflicting social signals on the brain's target emotional response.

    PubMed

    Amting, Jayna M; Miller, Jodi E; Chow, Melody; Mitchell, Derek G V

    2009-10-01

    Amidst a barrage of sensory information in the environment, the impact that individual stimuli have on our behaviour is thought to depend on the outcome of competition that occurs within and between multiple brain regions. Although biased competition models of attention have been tested in visual cortices and to a lesser extent in auditory cortex, little is known about the nature of stimulus competition outside of sensory areas. Given the hypothesized role of multiple pathways (cortical and subcortical) and specialized brain regions for processing valence information, studies involving conflicting basic emotional stimuli provide a unique opportunity to examine whether the principles of biased competition apply outside of sensory cortex. We used fMRI to examine the neural representation and resolution of emotional conflict in a sample of healthy individuals. Participants made explicit judgments about the valence of happy or fearful target facial expressions in the context of emotionally congruent, neutral, or incongruent distracters. The results suggest that emotional conflict is reflected in a dissociable manner across distinct neural regions. Posterior areas of visual cortex showed enhanced responding to congruent relative to neutral or incongruent stimuli. Orbitofrontal cortex remained sensitive to positive affect in the context of conflicting emotional stimuli. In contrast, within the amygdala, activity associated with identifying positive target expressions declined with the introduction of neutral and incongruent expressions; however, activity associated with fearful target expressions was less susceptible to the influence of emotional context. Enhanced functional connectivity was observed between medial prefrontal cortex and the amygdala during incongruent trials; the degree of connectivity was correlated with reaction time costs incurred during incongruent trials. The results are interpreted with reference to current models of emotional attention and

  2. Brain activation related to combinations of gaze position, visual input, and goal-directed hand movements.

    PubMed

    Bédard, Patrick; Wu, Min; Sanes, Jerome N

    2011-06-01

    Humans reach to and acquire objects by transforming visual targets into action commands. How the brain integrates goals specified in a visual framework to signals into a suitable framework for an action plan requires clarification whether visual input, per se, interacts with gaze position to formulate action plans. To further evaluate brain control of visual-motor integration, we assessed brain activation, using functional magnetic resonance imaging. Humans performed goal-directed movements toward visible or remembered targets while fixating gaze left or right from center. We dissociated movement planning from performance using a delayed-response task and manipulated target visibility by its availability throughout the delay or blanking it 500 ms after onset. We found strong effects of gaze orientation on brain activation during planning and interactive effects of target visibility and gaze orientation on movement-related activation during performance in parietal and premotor cortices (PM), cerebellum, and basal ganglia, with more activation for rightward gaze at a visible target and no gaze modulation for movements directed toward remembered targets. These results demonstrate effects of gaze position on PM and movement-related processes and provide new information how visual signals interact with gaze position in transforming visual inputs into motor goals.

  3. Targeting Epigenetic Mechanisms in Pain Due to Trauma and Traumatic Brain Injury (TBI)

    DTIC Science & Technology

    2015-10-01

    brain or peripheral trauma may support chronic pain. Our work to-date has established a rodent model of TBI in combination with injury to a limb as a...AWARD NUMBER: W81XWH-14-1-0579 TITLE: Targeting Epigenetic Mechanisms in Pain due to Trauma and Traumatic Brain Injury (TBI) PRINCIPAL...SUBTITLE Targeting Epigenetic Mechanisms in Pain due to Trauma and Traumatic Brain Injury (TBI) 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0579 5c

  4. Cerebral Edema in Traumatic Brain Injury: Pathophysiology and Prospective Therapeutic Targets.

    PubMed

    Winkler, Ethan A; Minter, Daniel; Yue, John K; Manley, Geoffrey T

    2016-10-01

    Traumatic brain injury is a heterogeneous disorder resulting from an external force applied to the head. The development of cerebral edema plays a central role in the evolution of injury following brain trauma and is closely associated with neurologic outcomes. Recent advances in the understanding of the molecular and cellular pathways contributing to the posttraumatic development of cerebral edema have led to the identification of multiple prospective therapeutic targets. The authors summarize the pathogenic mechanisms underlying cerebral edema and highlight the molecular pathways that may be therapeutically targeted to mitigate cerebral edema and associated sequelae following traumatic brain injury.

  5. Enhanced brain targeting efficacy of Olanzapine through solid lipid nanoparticles.

    PubMed

    Natarajan, Jawahar; Baskaran, Mahendran; Humtsoe, Lireni C; Vadivelan, R; Justin, A

    2017-03-01

    Olanzapine (OLZ) is a typical anti-psychotic drug, which is highly lipophilic in nature, belongs to Biopharmaceutical Classification System (BCS) class II category. Though OLZ is an effective agent in the treatment of Schizophrenia, but it exhibits poor bioavailability (57%) due to extensive first-pass metabolism resulted in high dose is required to achieve therapeutic concentration in brain. Emerging evidences are indicating that high dose administration of OLZ may cause Extrapyramidal symptoms (EPS) in the psychotic patients. Hence, the present study is designed to develop Olanzapine solid lipid (OLZ-SLNs) using minimal dose of OLZ thereby enhancing the brain efficacy as well as to reduce the side effects associated with OLZ. OLZ-SLNs have been prepared by "solvent diffusion method" using lipids, such as glyceryl monostearate (GMS), tripalmitin (TP), Tween 80, and Stearyl amine as positive charge inducer. The prepared OLZ-SLNs were subjected to particle size analysis, zeta potential, and poly dispersity index measurement by using Malvern Zetasizer. Pharmacokinetics assessments of OLZ-SLNs were carried in conscious male Wistar rats through intravenous administration. Results have shown that average particle size and zeta potential of SLNs of GMS and TP were ranged from 165.1 ± 2.2 to 110.5 ± 0.5 and 35.29 ± 1.2 and 66.50 ± 0.7 mV, respectively. Relative bioavailability of OLZ in the brain was increased up to 23-fold and clearance was decreased when OLZ-SLNs while administrated intravenously. The area under the curve (AUC) and mean residence time (MRT) of OLZ-SLNs in brain were higher than OLZ suspension. These results indicate that SLNs are a promising drug delivery for OLZ. It may be an effective tool to enhance the bioavailability of OLZ in the brain with less dose administration, which could reduce the EPS associated with OLZ.

  6. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier

    PubMed Central

    Georgieva, Julia V.; Hoekstra, Dick; Zuhorn, Inge S.

    2014-01-01

    The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood–brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier–drug system (“Trojan horse complex”) is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain. PMID:25407801

  7. On a Quantum Model of Brain Activities

    NASA Astrophysics Data System (ADS)

    Fichtner, K.-H.; Fichtner, L.; Freudenberg, W.; Ohya, M.

    2010-01-01

    One of the main activities of the brain is the recognition of signals. A first attempt to explain the process of recognition in terms of quantum statistics was given in [6]. Subsequently, details of the mathematical model were presented in a (still incomplete) series of papers (cf. [7, 2, 5, 10]). In the present note we want to give a general view of the principal ideas of this approach. We will introduce the basic spaces and justify the choice of spaces and operations. Further, we bring the model face to face with basic postulates any statistical model of the recognition process should fulfill. These postulates are in accordance with the opinion widely accepted in psychology and neurology.

  8. Ultrasound/Magnetic Targeting with SPIO-DOX-Microbubble Complex for Image-Guided Drug Delivery in Brain Tumors

    PubMed Central

    Fan, Ching-Hsiang; Cheng, Yu-Hang; Ting, Chien-Yu; Ho, Yi-Ju; Hsu, Po-Hung; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    One of the greatest challenges in the deployment of chemotherapeutic drugs against brain tumors is ensuring that sufficient drug concentrations reach the tumor, while minimizing drug accumulation at undesired sites. Recently, injection of therapeutic agents following blood-brain barrier (BBB) opening by focused ultrasound (FUS) with microbubbles (MBs) has been shown to enhance drug delivery in targeted brain regions. Nevertheless, the distribution and quantitative deposition of agents delivered to the brain are still hard to estimate. Based on our previous work on superparamagnetic iron oxide (SPIO)-loaded MBs, we present a novel theranostic complex of SPIO-Doxorubicin (DOX)-conjugated MB (SD-MB) for drug delivery to the brain. Magnetic labeling of the drug enables direct visualization via magnetic resonance imaging, and also facilitates magnetic targeting (MT) to actively enhance targeted deposition of the drug. In a rat glioma model, we demonstrated that FUS sonication can be used with SD-MBs to simultaneously facilitate BBB opening and allow dual ultrasound/magnetic targeting of chemotherapeutic agent (DOX) delivery. The accumulation of SD complex within brain tumors can be significantly enhanced by MT (25.7 fold of DOX, 7.6 fold of SPIO). The change in relaxation rate R2 (1/T2) within tumors was highly correlated with SD deposition as quantified by high performance liquid chromatography (R2 = 0.93) and inductively coupled plasma-atomic emission spectroscopy (R2 = 0.94), demonstrating real-time monitoring of DOX distribution. Our results suggest that SD-MBs can serve as multifunction agents to achieve advanced molecular theranostics. PMID:27446489

  9. Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication.

    PubMed

    Rummel, Christoph

    2016-05-01

    Immune-to-brain communication pathways involve humoral mediators, including cytokines, central modulation by neuronal afferents and immune cell trafficking to the brain. During systemic inflammation these pathways contribute to mediating brain-controlled sickness symptoms including fever. Experimentally, activation of these signaling pathways can be mimicked and studied when injecting animals with pathogen associated molecular patterns (PAMPS). One central component of the brain inflammatory response, which leads, for example, to fever induction, is transcriptional activation of brain cells via cytokines and PAMPS. We and others have studied the spatiotemporal activation and the physiological significance of transcription factors for the induction of inflammation within the brain and the manifestation of fever. Evidence has revealed a role of nuclear factor (NF)κB in the initiation, signal transducer and activator of transcription (STAT)3 in the maintenance and NF-interleukin (IL)6 in the maintenance or even termination of brain-inflammation and fever. Moreover, psychological stressors, such as exposure to a novel environment, leads to increased body core temperature and genomic NF-IL6-activation, suggesting a potential use of NF-IL6-immunohistochemistry as a multimodal brain cell activation marker and a role for NF-IL6 for differential brain activity. In addition, the nutritional status, as reflected by circulating levels of the cytokine-like hormone leptin, influence immune-to-brain communication and age-dependent changes in LPS-induced fever. Overall, transcription factors remain therapeutically important targets for the treatment of brain-inflammation and fever induction during infectious/non-infectious inflammatory and psychological stress. However, the exact physiological role and significance of these transcription factors requires to be further investigated.

  10. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

    PubMed

    Shinde, Rajshree L; Bharkad, Gopal P; Devarajan, Padma V

    2015-10-01

    Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery.

  11. Internalization of targeted quantum dots by brain capillary endothelial cells in vivo.

    PubMed

    Paris-Robidas, Sarah; Brouard, Danny; Emond, Vincent; Parent, Martin; Calon, Frédéric

    2016-04-01

    Receptors located on brain capillary endothelial cells forming the blood-brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery.

  12. The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    PubMed Central

    Agrahari, Vivek

    2017-01-01

    Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant advantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

  13. Nonpharmacological Interventions in Targeting Pain-Related Brain Plasticity

    PubMed Central

    Clark, J. David

    2017-01-01

    Chronic pain is a highly prevalent and debilitating condition that is frequently associated with multiple comorbid psychiatric conditions and functional, biochemical, and anatomical alterations in various brain centers. Due to its widespread and diverse manifestations, chronic pain is often resistant to classical pharmacological treatment paradigms, prompting the search for alternative treatment approaches that are safe and efficacious. The current review will focus on the following themes: attentional and cognitive interventions, the role of global environmental factors, and the effects of exercise and physical rehabilitation in both chronic pain patients and preclinical pain models. The manuscript will discuss not only the analgesic efficacy of these therapies, but also their ability to reverse pain-related brain neuroplasticity. Finally, we will discuss the potential mechanisms of action for each of the interventions. PMID:28299206

  14. Physical activity and brain plasticity in late adulthood.

    PubMed

    Erickson, Kirk I; Gildengers, Ariel G; Butters, Meryl A

    2013-03-01

    The human brain shrinks with advancing age, but recent research suggests that it is also capable of remarkable plasticity, even in late life. In this review we summarize the research linking greater amounts of physical activity to less cortical atrophy, better brain function, and enhanced cognitive function, and argue that physical activity takes advantage of the brain's natural capacity for plasticity. Further, although the effects of physical activity on the brain are relatively widespread, there is also some specificity, such that prefrontal and hippocampal areas appear to be more influenced than other areas of the brain. The specificity of these effects, we argue, provides a biological basis for understanding the capacity for physical activity to influence neurocognitive and neuropsychiatric disorders such as depression. We conclude that physical activity is a promising intervention that can influence the endogenous pharmacology of the brain to enhance cognitive and emotional function in late adulthood.

  15. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    care for these patients is whole brain radiotherapy (WBRT). WBRT, however, is often associated with neurological complications that preclude...offers an opportunity to selectively radiate tumor cells while sparing normal tissues. The high energy β- emitter, Yttrium-90 (90Y), a FDA approved...11. Penetrate the syringe needle into intercoastal space promptly through skin and muscle layers into the left ventricle under the guidance of

  16. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation.

    PubMed

    Dong, Hongquan; Zhang, Xiang; Wang, Yiming; Zhou, Xiqiao; Qian, Yanning; Zhang, Shu

    2017-03-01

    Brain inflammation has a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells are the "first responder" in the injury rather than microglia. Functional aspects of mast cell-microglia interactions remain poorly understood. Our results demonstrated that site-directed injection of the "mast cell degranulator" compound 48/80 (C48/80) in the hypothalamus induced mast cell degranulation, microglial activation, and inflammatory factor production, which initiated the acute brain inflammatory response. "Mast cell stabilizer" disodium cromoglycate (cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced microglial activation, inhibition of MAPK and AKT pathways, and repression of protein expression of histamine receptor 1 (H1R), histamine receptor 4 (H4R), protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. We also demonstrated that C48/80 had no effect on microglial activation in mast cell-deficient Kit(W-sh/W-sh) mice. These results implicate that activated brain mast cells trigger microglial activation and stabilization of mast cell inhibits microglial activation-induced central nervous system (CNS) inflammation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.

  17. Active debris removal of multiple priority targets

    NASA Astrophysics Data System (ADS)

    Braun, Vitali; Lüpken, A.; Flegel, S.; Gelhaus, J.; Möckel, M.; Kebschull, C.; Wiedemann, C.; Vörsmann, P.

    2013-05-01

    Today's space debris environment shows major concentrations of objects within distinct orbital regions for nearly all size regimes. The most critical region is found at orbital altitudes near 800 km with high declinations. Within this region many satellites are operated in so called sun-synchronous orbits (SSO). Among those, there are Earth observation, communication and weather satellites. Due to the orbital geometry in SSO, head-on encounters with relative velocities of about 15 km/s are most probable and would thus result in highly energetic collisions, which are often referred to as catastrophic collisions, leading to the complete fragmentation of the participating objects. So called feedback collisions can then be triggered by the newly generated fragments, thus leading to a further population increase in the affected orbital region. This effect is known as the Kessler syndrome.Current studies show that catastrophic collisions are not a major problem today, but will become the main process for debris generation within the SSO region in the near future, even without any further launches. In order to avoid this effect, objects with a major impact on collisional cascading have to be actively removed from the critical region after their end of life. Not having the capability to perform an end-of-life maneuver in order to transfer to a graveyard orbit or to de-orbit, many satellites and rocket bodies would have to be de-orbited within a dedicated mission. In such a mission, a service satellite would perform a de-orbit maneuver, after having docked to a specific target.In this paper, chemical and electric propulsion systems were analysed with the main focus on removing multiple targets within one single mission. The targets were chosen from a previously defined priority list in order to enhance the mission efficiency. Total mission time, ΔV and system mass were identified as key parameters to allow for an evaluation of the different concepts. It was shown that it

  18. Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation.

    PubMed

    Johnson, Matthew D; Zhang, Jianyu; Ghosh, Debabrata; McIntyre, Cameron C; Vitek, Jerrold L

    2012-07-01

    Clinical evidence has suggested that subtle changes in deep brain stimulation (DBS) settings can have differential effects on bradykinesia and rigidity in patients with Parkinson's disease. In this study, we first investigated the degree of improvement in bradykinesia and rigidity during targeted globus pallidus DBS in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus macaques. Behavioral outcomes of DBS were then coupled with detailed, subject-specific computational models of neurons in the globus pallidus internus (GPi), globus pallidus externus (GPe), and internal capsule (IC) to determine which neuronal pathways when modulated with high-frequency electrical stimulation best correlate with improvement in motor symptoms. The modeling results support the hypothesis that multiple neuronal pathways can underlie the therapeutic effect of DBS on parkinsonian bradykinesia and rigidity. Across all three subjects, improvements in rigidity correlated most strongly with spread of neuronal activation into IC, driving a small percentage of fibers within this tract (<10% on average). The most robust effect on bradykinesia resulted from stimulating a combination of sensorimotor axonal projections within the GP, specifically at the site of the medial medullary lamina. Thus the beneficial effects of pallidal DBS for parkinsonian symptoms may occur from multiple targets within and near the target nucleus.

  19. Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation

    PubMed Central

    Zhang, Jianyu; Ghosh, Debabrata; McIntyre, Cameron C.; Vitek, Jerrold L.

    2012-01-01

    Clinical evidence has suggested that subtle changes in deep brain stimulation (DBS) settings can have differential effects on bradykinesia and rigidity in patients with Parkinson's disease. In this study, we first investigated the degree of improvement in bradykinesia and rigidity during targeted globus pallidus DBS in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus macaques. Behavioral outcomes of DBS were then coupled with detailed, subject-specific computational models of neurons in the globus pallidus internus (GPi), globus pallidus externus (GPe), and internal capsule (IC) to determine which neuronal pathways when modulated with high-frequency electrical stimulation best correlate with improvement in motor symptoms. The modeling results support the hypothesis that multiple neuronal pathways can underlie the therapeutic effect of DBS on parkinsonian bradykinesia and rigidity. Across all three subjects, improvements in rigidity correlated most strongly with spread of neuronal activation into IC, driving a small percentage of fibers within this tract (<10% on average). The most robust effect on bradykinesia resulted from stimulating a combination of sensorimotor axonal projections within the GP, specifically at the site of the medial medullary lamina. Thus the beneficial effects of pallidal DBS for parkinsonian symptoms may occur from multiple targets within and near the target nucleus. PMID:22514292

  20. Brain-targeted delivery of docetaxel by glutathione-coated nanoparticles for brain cancer.

    PubMed

    Grover, Aditya; Hirani, Anjali; Pathak, Yashwant; Sutariya, Vijaykumar

    2014-12-01

    Gliomas are some of the most aggressive types of cancers but the blood-brain barrier acts as an obstacle to therapeutic intervention in brain-related diseases. The blood-brain barrier blocks the permeation of potentially toxic compounds into neural tissue through the interactions of brain endothelial cells with glial cells (astrocytes and pericytes) which induce the formation of tight junctions in endothelial cells lining the blood capillaries. In the present study, we characterize a glutathione-coated docetaxel-loaded PEG-PLGA nanoparticle, show its in vitro drug release data along with cytotoxicity data in C6 and RG2 cells, and investigate its trans-blood-brain barrier permeation through the establishment of a Transwell cellular co-culture. We show that the docetaxel-loaded nanoparticle's size enables its trans-blood-brain barrier permeation; the nanoparticle exhibits a steady, sustained release of docetaxel; the drug is able to induce cell death in glioma models; and the glutathione-coated nanoparticle is able to permeate through the Transwell in vitro blood-brain barrier model.

  1. Effect of PLGA NP size on efficiency to target traumatic brain injury.

    PubMed

    Cruz, Luis J; Stammes, Marieke A; Que, Ivo; van Beek, Ermond R; Knol-Blankevoort, Vicky T; Snoeks, Thomas J A; Chan, Alan; Kaijzel, Eric L; Löwik, Clemens W G M

    2016-02-10

    Necrotic cell death occurs exclusively under pathological conditions, such as ischemic diseases. Necrosis imaging is of diagnostic value and enables early measurement of treatment efficiency in ischemic patients. Here we explored the targeted delivery of particles, with diameters of approximately 100nm, 200nm and 800nm, consisting of a poly(lactic-co-glycolic acid) (PLGA) nanoparticle (NP) core coated with a polyethylene glycol-lipid (PEG) layer. Targeted delivery was facilitated by coupling the amino end group of the polyethylene glycol-layer to 800CW imaging agent, which specifically binds to intracellular proteins of cells that have lost membrane integrity, thus revealing the extent of the damaged area. We found that smaller NPs (100nm), with an appropriate coating, diffuse throughout the traumatic brain injury (TBI) in mice. Optical imaging revealed that smaller (100-nm) PEG-coated NPs carrying 800CW penetrated deeper into the mouse brain than large 800CW containing NPs (800nm). The importance of the 800CW as a ligand to target the necrotic tissue was further confirmed in living mice. The ability to achieve brain penetration with smaller NPs is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find application in the treatment of stroke, brain tumors, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible.

  2. Supervised learning for neural manifold using spatiotemporal brain activity

    NASA Astrophysics Data System (ADS)

    Kuo, Po-Chih; Chen, Yong-Sheng; Chen, Li-Fen

    2015-12-01

    Objective. Determining the means by which perceived stimuli are compactly represented in the human brain is a difficult task. This study aimed to develop techniques for the construction of the neural manifold as a representation of visual stimuli. Approach. We propose a supervised locally linear embedding method to construct the embedded manifold from brain activity, taking into account similarities between corresponding stimuli. In our experiments, photographic portraits were used as visual stimuli and brain activity was calculated from magnetoencephalographic data using a source localization method. Main results. The results of 10 × 10-fold cross-validation revealed a strong correlation between manifolds of brain activity and the orientation of faces in the presented images, suggesting that high-level information related to image content can be revealed in the brain responses represented in the manifold. Significance. Our experiments demonstrate that the proposed method is applicable to investigation into the inherent patterns of brain activity.

  3. The brain as a target for development of new class of drugs for the treatment of somatic diseases.

    PubMed

    Mravec, Boris

    2012-05-01

    Usually, drugs are designed to modulate at cellular level the activity of peripheral tissues and organs affected by pathological processes. Despite unprecedented investment, the number of newly developed drugs remains low. Therefore, potent new drugs that directly influence and restore activity of peripheral tissues and organs altered by somatic diseases are being released into clinical use at the same rate as seen in the past. The brain has long been known to regulate the function of all tissues and organs in the body. This regulatory influence has also been shown to play an important role during pathological conditions, when the brain triggers protective and adaptive reactions modulating the development and progression of somatic diseases affecting peripheral tissues and organs. Importantly, several drugs recently used for the treatment of somatic diseases (e.g., beta-blockers, sartans, statins) also act at the level of the CNS, where they modulate the protective and adaptive reactions of the brain. Pharmacological modulation of brain structures activities may represent the basis for a new approach towards the treatment of various somatic diseases (e.g., cardiovascular and gastrointestinal diseases). Therefore, brain-targeted therapy of somatic diseases may significantly extend the area for development of new drugs.

  4. Changes in baseball batters' brain activity with increased pitch choice.

    PubMed

    Ryu, Kwangmin; Kim, Jingu; Ali, Asif; Kim, Woojong; Radlo, Steven J

    2015-09-01

    In baseball, one factor necessary for batters to decide whether to swing or not depends on what type of pitch is thrown. Oftentimes batters will look for their pitch (i.e., waiting for a fastball). In general, when a pitcher has many types of pitches in his arsenal, batters will have greater difficulty deciding upon the pitch thrown. Little research has been investigated the psychophysiology of a batters decision-making processes. Therefore, the primary purpose of this study was to determine how brain activation changes according to an increase in the number of alternatives (NA) available. A total of 15 male college baseball players participated in this study. The stimuli used in this experiment were video clips of a right-handed pitcher throwing fastball, curve, and slider pitches. The task was to press a button after selecting the fastball as the target stimulus from two pitch choices (fastball and curve), and then from three possibilities (fastball, curve, and slider). Functional and anatomic image scanning magnetic resonance imaging (MRI) runs took 4 and 5[Formula: see text]min, respectively. According to our analysis, the right precentral gyrus, left medial frontal gyrus, and right fusiform gyrus were activated when the NA was one. The supplementary motor areas (SMA) and primary motor cortex were activated when there were two alternatives to choose from and the inferior orbitofrontal gyrus was specifically activated with three alternatives. Contrary to our expectations, the NA was not a critical factor influencing the activation of related decision making areas when the NA was compared against one another. These findings highlight that specific brain areas related to decision making were activated as the NA increased.

  5. Cerebral blood volume changes during brain activation

    PubMed Central

    Krieger, Steffen Norbert; Streicher, Markus Nikolar; Trampel, Robert; Turner, Robert

    2012-01-01

    Cerebral blood volume (CBV) changes significantly with brain activation, whether measured using positron emission tomography, functional magnetic resonance imaging (fMRI), or optical microscopy. If cerebral vessels are considered to be impermeable, the contents of the skull incompressible, and the skull itself inextensible, task- and hypercapnia-related changes of CBV could produce intolerable changes of intracranial pressure. Because it is becoming clear that CBV may be useful as a well-localized marker of neural activity changes, a resolution of this apparent paradox is needed. We have explored the idea that much of the change in CBV is facilitated by exchange of water between capillaries and surrounding tissue. To this end, we developed a novel hemodynamic boundary-value model and found approximate solutions using a numerical algorithm. We also constructed a macroscopic experimental model of a single capillary to provide biophysical insight. Both experiment and theory model capillary membranes as elastic and permeable. For a realistic change of input pressure, a relative pipe volume change of 21±5% was observed when using the experimental setup, compared with the value of approximately 17±1% when this quantity was calculated from the mathematical model. Volume, axial flow, and pressure changes are in the expected range. PMID:22569192

  6. DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

    PubMed Central

    Sanchez-Mut, Jose V.; Aso, Ester; Panayotis, Nicolas; Lott, Ira; Dierssen, Mara; Rabano, Alberto; Urdinguio, Rocio G.; Fernandez, Agustin F.; Astudillo, Aurora; Martin-Subero, Jose I.; Balint, Balazs; Fraga, Mario F.; Gomez, Antonio; Gurnot, Cecile; Roux, Jean-Christophe; Avila, Jesus; Hensch, Takao K.; Ferrer, Isidre

    2013-01-01

    The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease. PMID:24030951

  7. DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease.

    PubMed

    Sanchez-Mut, Jose V; Aso, Ester; Panayotis, Nicolas; Lott, Ira; Dierssen, Mara; Rabano, Alberto; Urdinguio, Rocio G; Fernandez, Agustin F; Astudillo, Aurora; Martin-Subero, Jose I; Balint, Balazs; Fraga, Mario F; Gomez, Antonio; Gurnot, Cecile; Roux, Jean-Christophe; Avila, Jesus; Hensch, Takao K; Ferrer, Isidre; Esteller, Manel

    2013-10-01

    The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.

  8. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2013-10-01

    www.paneuropeannetworks.com/ST9/#163/z 7 Stafford JH, Hao G, Best AM, Sun X, Thorpe PE. Highly specific PET imaging of prostate tumors in mice with an iodine - 124 ...vascular endothelial cells. • Autoradiography and PET imaging of radioactive iodine labeled PGN635 confirmed the targeting specificity of PGN635 and

  9. Brain activation associated with active and passive lower limb stepping

    PubMed Central

    Jaeger, Lukas; Marchal-Crespo, Laura; Wolf, Peter; Riener, Robert; Michels, Lars; Kollias, Spyros

    2014-01-01

    Reports about standardized and repeatable experimental procedures investigating supraspinal activation in patients with gait disorders are scarce in current neuro-imaging literature. Well-designed and executed tasks are important to gain insight into the effects of gait-rehabilitation on sensorimotor centers of the brain. The present study aims to demonstrate the feasibility of a novel imaging paradigm, combining the magnetic resonance (MR)-compatible stepping robot (MARCOS) with sparse sampling functional magnetic resonance imaging (fMRI) to measure task-related BOLD signal changes and to delineate the supraspinal contribution specific to active and passive stepping. Twenty-four healthy participants underwent fMRI during active and passive, periodic, bilateral, multi-joint, lower limb flexion and extension akin to human gait. Active and passive stepping engaged several cortical and subcortical areas of the sensorimotor network, with higher relative activation of those areas during active movement. Our results indicate that the combination of MARCOS and sparse sampling fMRI is feasible for the detection of lower limb motor related supraspinal activation. Activation of the anterior cingulate and medial frontal areas suggests motor response inhibition during passive movement in healthy participants. Our results are of relevance for understanding the neural mechanisms underlying gait in the healthy. PMID:25389396

  10. A real-time brain-machine interface combining motor target and trajectory intent using an optimal feedback control design.

    PubMed

    Shanechi, Maryam M; Williams, Ziv M; Wornell, Gregory W; Hu, Rollin C; Powers, Marissa; Brown, Emery N

    2013-01-01

    Real-time brain-machine interfaces (BMI) have focused on either estimating the continuous movement trajectory or target intent. However, natural movement often incorporates both. Additionally, BMIs can be modeled as a feedback control system in which the subject modulates the neural activity to move the prosthetic device towards a desired target while receiving real-time sensory feedback of the state of the movement. We develop a novel real-time BMI using an optimal feedback control design that jointly estimates the movement target and trajectory of monkeys in two stages. First, the target is decoded from neural spiking activity before movement initiation. Second, the trajectory is decoded by combining the decoded target with the peri-movement spiking activity using an optimal feedback control design. This design exploits a recursive Bayesian decoder that uses an optimal feedback control model of the sensorimotor system to take into account the intended target location and the sensory feedback in its trajectory estimation from spiking activity. The real-time BMI processes the spiking activity directly using point process modeling. We implement the BMI in experiments consisting of an instructed-delay center-out task in which monkeys are presented with a target location on the screen during a delay period and then have to move a cursor to it without touching the incorrect targets. We show that the two-stage BMI performs more accurately than either stage alone. Correct target prediction can compensate for inaccurate trajectory estimation and vice versa. The optimal feedback control design also results in trajectories that are smoother and have lower estimation error. The two-stage decoder also performs better than linear regression approaches in offline cross-validation analyses. Our results demonstrate the advantage of a BMI design that jointly estimates the target and trajectory of movement and more closely mimics the sensorimotor control system.

  11. Invisible Brain: Knowledge in Research Works and Neuron Activity

    PubMed Central

    Segev, Aviv; Curtis, Dorothy; Jung, Sukhwan; Chae, Suhyun

    2016-01-01

    If the market has an invisible hand, does knowledge creation and representation have an “invisible brain”? While knowledge is viewed as a product of neuron activity in the brain, can we identify knowledge that is outside the brain but reflects the activity of neurons in the brain? This work suggests that the patterns of neuron activity in the brain can be seen in the representation of knowledge-related activity. Here we show that the neuron activity mechanism seems to represent much of the knowledge learned in the past decades based on published articles, in what can be viewed as an “invisible brain” or collective hidden neural networks. Similar results appear when analyzing knowledge activity in patents. Our work also tries to characterize knowledge increase as neuron network activity growth. The results propose that knowledge-related activity can be seen outside of the neuron activity mechanism. Consequently, knowledge might exist as an independent mechanism. PMID:27439199

  12. What goes around comes around: novel pharmacological targets in the gut–brain axis

    PubMed Central

    González-Arancibia, Camila; Escobar-Luna, Jorge; Barrera-Bugueño, Camila; Díaz-Zepeda, Camilo; González-Toro, María P.; Olavarría-Ramírez, Loreto; Zanelli-Massai, Francesca; Gotteland, Martin; Bravo, Javier A.; Julio-Pieper, Marcela

    2016-01-01

    The gut and the brain communicate bidirectionally through anatomic and humoral pathways, establishing what is known as the gut–brain axis. Therefore, interventions affecting one system will impact on the other, giving the opportunity to investigate and develop future therapeutic strategies that target both systems. Alterations in the gut–brain axis may arise as a consequence of changes in microbiota composition (dysbiosis), modifications in intestinal barrier function, impairment of enteric nervous system, unbalanced local immune response and exaggerated responses to stress, to mention a few. In this review we analyze and discuss several novel pharmacological targets within the gut–brain axis, with potential applications to improve intestinal and mental health. PMID:27134664

  13. Contribution of regional brain melanocortin receptor subtypes to elevated activity energy expenditure in lean, active rats

    PubMed Central

    Shukla, Charu; Koch, Lauren G.; Britton, Steven L.; Cai, Minying; Hruby, Victor J.; Bednarek, Maria; Novak, Colleen M.

    2015-01-01

    Physical activity and non-exercise activity thermogenesis (NEAT) are crucial factors accounting for individual differences in body weight, interacting with genetic predisposition. In the brain, a number of neuroendocrine intermediates regulate food intake and energy expenditure (EE); this includes the brain melanocortin (MC) system, consisting of melanocortin peptides as well as their receptors (MCR). MC3R and MC4R have emerged as critical modulators of EE and food intake. To determine how variance in MC signaling may underlie individual differences in physical activity levels, we examined behavioral response to MC receptor agonists and antagonists in rats that show high and low levels of physical activity and NEAT, that is, high- and low-capacity runners (HCR, LCR), developed by artificial selection for differential intrinsic aerobic running capacity. Focusing on the hypothalamus, we identified brain region-specific elevations in expression of MCR 3, 4, and also MC5R, in the highly active, lean HCR relative to the less active and obesity-prone LCR. Further, the differences in activity and associated EE as a result of MCR activation or suppression using specific agonists and antagonists were similarly region-specific and directly corresponded to the differential MCR expression patterns. The agonists and antagonists investigated here did not significantly impact food intake at the doses used, suggesting that the differential pattern of receptor expression may by more meaningful to physical activity than to other aspects of energy balance regulation. Thus, MCR-mediated physical activity may be a key neural mechanism in distinguishing the lean phenotype and a target for enhancing physical activity and NEAT. PMID:26404873

  14. Improved Targeting Through Collaborative Decision-Making and Brain Computer Interfaces

    NASA Technical Reports Server (NTRS)

    Stoica, Adrian; Barrero, David F.; McDonald-Maier, Klaus

    2013-01-01

    This paper reports a first step toward a brain-computer interface (BCI) for collaborative targeting. Specifically, we explore, from a broad perspective, how the collaboration of a group of people can increase the performance on a simple target identification task. To this end, we requested a group of people to identify the location and color of a sequence of targets appearing on the screen and measured the time and accuracy of the response. The individual results are compared to a collective identification result determined by simple majority voting, with random choice in case of drawn. The results are promising, as the identification becomes significantly more reliable even with this simple voting and a small number of people (either odd or even number) involved in the decision. In addition, the paper briefly analyzes the role of brain-computer interfaces in collaborative targeting, extending the targeting task by using a BCI instead of a mechanical response.

  15. Effects of concurrent caffeine and mobile phone exposure on local target probability processing in the human brain.

    PubMed

    Trunk, Attila; Stefanics, Gábor; Zentai, Norbert; Bacskay, Ivett; Felinger, Attila; Thuróczy, György; Hernádi, István

    2015-09-23

    Millions of people use mobile phones (MP) while drinking coffee or other caffeine containing beverages. Little is known about the potential combined effects of MP irradiation and caffeine on cognitive functions. Here we investigated whether caffeine intake and concurrent exposure to Universal Mobile Telecommunications System (UMTS) MP-like irradiation may interactively influence neuro-cognitive function in an active visual oddball paradigm. In a full factorial experimental design, 25 participants performed a simple visual target detection task while reaction time (RT) and electroencephalogram (EEG) was recorded. Target trials were divided into Low and High probability sets based on target-to-target distance. We analyzed single trial RT and alpha-band power (amplitude) in the pre-target interval. We found that RT was shorter in High vs. Low local probability trials, and caffeine further shortened RT in High probability trials relative to the baseline condition suggesting that caffeine improves the efficiency of implicit short-term memory. Caffeine also decreased pre-target alpha amplitude resulting in higher arousal level. Furthermore, pre-target gamma power positively correlated with RT, which may have facilitated target detection. However, in the present pharmacologically validated study UMTS exposure either alone or in combination with caffeine did not alter RT or pre-stimulus oscillatory brain activity.

  16. Effects of concurrent caffeine and mobile phone exposure on local target probability processing in the human brain

    PubMed Central

    Trunk, Attila; Stefanics, Gábor; Zentai, Norbert; Bacskay, Ivett; Felinger, Attila; Thuróczy, György; Hernádi, István

    2015-01-01

    Millions of people use mobile phones (MP) while drinking coffee or other caffeine containing beverages. Little is known about the potential combined effects of MP irradiation and caffeine on cognitive functions. Here we investigated whether caffeine intake and concurrent exposure to Universal Mobile Telecommunications System (UMTS) MP-like irradiation may interactively influence neuro-cognitive function in an active visual oddball paradigm. In a full factorial experimental design, 25 participants performed a simple visual target detection task while reaction time (RT) and electroencephalogram (EEG) was recorded. Target trials were divided into Low and High probability sets based on target-to-target distance. We analyzed single trial RT and alpha-band power (amplitude) in the pre-target interval. We found that RT was shorter in High vs. Low local probability trials, and caffeine further shortened RT in High probability trials relative to the baseline condition suggesting that caffeine improves the efficiency of implicit short-term memory. Caffeine also decreased pre-target alpha amplitude resulting in higher arousal level. Furthermore, pre-target gamma power positively correlated with RT, which may have facilitated target detection. However, in the present pharmacologically validated study UMTS exposure either alone or in combination with caffeine did not alter RT or pre-stimulus oscillatory brain activity. PMID:26395526

  17. Identification of peptide sequences that target to the brain using in vivo phage display.

    PubMed

    Li, Jingwei; Zhang, Qizhi; Pang, Zhiqing; Wang, Yuchen; Liu, Qingfeng; Guo, Liangran; Jiang, Xinguo

    2012-06-01

    Phage display technology could provide a rapid means for the discovery of novel peptides. To find peptide ligands specific for the brain vascular receptors, we performed a modified phage display method. Phages were recovered from mice brain parenchyma after administrated with a random 7-mer peptide library intravenously. A longer circulation time was arranged according to the biodistributive brain/blood ratios of phage particles. Following sequential rounds of isolation, a number of phages were sequenced and a peptide sequence (CTSTSAPYC, denoted as PepC7) was identified. Clone 7-1, which encodes PepC7, exhibited translocation efficiency about 41-fold higher than the random library phage. Immunofluorescence analysis revealed that Clone 7-1 had a significant superiority on transport efficiency into the brain compared with native M13 phage. Clone 7-1 was inhibited from homing to the brain in a dose-dependent fashion when cyclic peptides of the same sequence were present in a competition assay. Interestingly, the linear peptide (ATSTSAPYA, Pep7) and a scrambled control peptide PepSC7 (CSPATSYTC) did not compete with the phage at the same tested concentration (0.2-200 pg). Labeled by Cy5.5, PepC7 exhibited significant brain-targeting capability in in vivo optical imaging analysis. The cyclic conformation of PepC7 formed by disulfide bond, and the correct structure itself play a critical role in maintaining the selectivity and affinity for the brain. In conclusion, PepC7 is a promising brain-target motif never been reported before and it could be applied to targeted drug delivery into the brain.

  18. Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

    PubMed Central

    Salem, Heba F; Ahmed, Sayed M; Hassaballah, Ashraf E; Omar, Mahmoud M

    2015-01-01

    Background The blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain. Methods Glutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency. Results The size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than −65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824. Conclusion Overall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new therapeutic option for the treatment of the brain infections. PMID:26229435

  19. Angiogenesis-targeting microbubbles combined with ultrasound-mediated gene therapy in brain tumors.

    PubMed

    Chang, En-Ling; Ting, Chien-Yu; Hsu, Po-Hong; Lin, Yu-Chun; Liao, En-Chi; Huang, Chiung-Yin; Chang, Yuan-Chih; Chan, Hong-Lin; Chiang, Chi-Shiun; Liu, Hao-Li; Wei, Kuo-Chen; Fan, Ching-Hsiang; Yeh, Chih-Kuang

    2017-04-10

    The major challenges in gene therapy for brain cancer are poor transgene expression due to the blood-brain barrier (BBB) and neurologic damage caused by conventional intracerebral injection. Non-viral gene delivery using ultrasound-targeted microbubble (MB) oscillation via the systematic transvascular route is attractive, but there is currently no high-yielding and targeted gene expression method. In this study, we developed a non-viral and angiogenesis-targeting gene delivery approach for efficient brain tumor gene therapy without brain damage. We developed a VEGFR2-targeted and cationic microbubble (VCMB) gene vector for use with transcranial focused ultrasound (FUS) exposure to allow transient gene delivery. The system was tested in a brain tumor model using the firefly luciferase gene and herpes simplex virus type 1 thymidine kinase/ganciclovir (pHSV-TK/GCV) with VCMBs under FUS exposure for transgene expression and anti-tumor effect. In vitro data showed that VCMBs have a high DNA-loading efficiency and high affinity for cancer cells. In vivo data confirmed that this technique enhanced gene delivery into tumor tissues without affecting normal brain tissues. The VCMB group resulted in higher luciferase expression (3.8 fold) relative to the CMB group (1.9 fold), and the direct injection group. The tumor volume on day 25 was significantly smaller in rats treated with the pHSV-TK/GCV system using VCMBs under FUS (9.7±5.2mm(3)) than in the direct injection group (40.1±4.3mm(3)). We demonstrated the successful use of DNA-loaded VCMBs and FUS for non-viral, non-invasive and targeted gene delivery to brain tumors.

  20. Ultrasound effects on brain-targeting mannosylated liposomes: in vitro and blood–brain barrier transport investigations

    PubMed Central

    Zidan, Ahmed S; Aldawsari, Hibah

    2015-01-01

    Delivering drugs to intracerebral regions can be accomplished by improving the capacity of transport through blood–brain barrier. Using sertraline as model drug for brain targeting, the current study aimed at modifying its liposomal vesicles with mannopyranoside. Box-Behnken design was employed to statistically optimize the ultrasound parameters, namely ultrasound amplitude, time, and temperature, for maximum mannosylation capacity, sertraline entrapment, and surface charge while minimizing vesicular size. Moreover, in vitro blood–brain barrier transport model was established to assess the transendothelial capacity of the optimized mannosylated vesicles. Results showed a dependence of vesicular size, mannosylation capacity, and sertraline entrapment on cavitation and bubble implosion events that were related to ultrasound power amplitude, temperature. However, short ultrasound duration was required to achieve >90% mannosylation with nanosized vesicles (<200 nm) of narrow size distribution. Optimized ultrasound parameters of 65°C, 27%, and 59 seconds for ultrasound temperature, amplitude, and time were elucidated to produce 81.1%, 46.6 nm, and 77.6% sertraline entrapment, vesicular size, and mannosylation capacity, respectively. Moreover, the transendothelial ability was significantly increased by 2.5-fold by mannosylation through binding with glucose transporters. Hence, mannosylated liposomes processed by ultrasound could be a promising approach for manufacturing and scale-up of brain-targeting liposomes. PMID:26244012

  1. Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

    PubMed

    Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

    2015-09-08

    Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain.

  2. Yugoslavia. "Migration" -- programme activities targeting men.

    PubMed

    Dzeletovic, A; Matovic-miljanovic, S

    1999-01-01

    In Yugoslavia, companies send their workers to different parts of the world, including countries with a high incidence of AIDS. It has been noted that it is characteristic for migrants to accommodate themselves to foreign conditions, which subsequently lead to health problems, especially with regards to reproductive and sexual health. Often, in the case of partner separation, men may seek sexual relations with an unknown partner and/or neglect to use proper protection. According to research carried out in Yugoslavia, there are critical gaps in workers' knowledge on sexual and reproductive health. Based on research results, an educational program for migrants, designed to train and strengthen individuals¿ capabilities and modify their risky behavior, was created. Program activities include production of brochures targeting those people travelling to countries with a high incidence of HIV/AIDS. In addition, a process for creating more cooperation between the state and other organizations at regional and local levels was initiated.

  3. Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport.

    PubMed

    Harbi, Ibrahim; Aljaeid, Bader; El-Say, Khalid M; Zidan, Ahmed S

    2016-12-01

    Effectiveness of CNS-acting drugs depends on the localization, targeting, and capacity to be transported through the blood-brain barrier (BBB) which can be achieved by designing brain-targeting delivery vectors. Hence, the objective of this study was to screen the formulation and process variables affecting the performance of sertraline (Ser-HCl)-loaded pegylated and glycosylated liposomes. The prepared vectors were characterized for Ser-HCl entrapment, size, surface charge, release behavior, and in vitro transport through the BBB. Furthermore, the compatibility among liposomal components was assessed using SEM, FTIR, and DSC analysis. Through a thorough screening study, enhancement of Ser-HCl entrapment, nanosized liposomes with low skewness, maximized stability, and controlled drug leakage were attained. The solid-state characterization revealed remarkable interaction between Ser-HCl and the charging agent to determine drug entrapment and leakage. Moreover, results of liposomal transport through mouse brain endothelialpolyoma cells demonstrated greater capacity of the proposed glycosylated liposomes to target the cerebellar due to its higher density of GLUT1 and higher glucose utilization. This transport capacity was confirmed by the inhibiting action of both cytochalasin B and phenobarbital. Using C6 glioma cells model, flow cytometry, time-lapse live cell imaging, and in vivo NIR fluorescence imaging demonstrated that optimized glycosylated liposomes can be transported through the BBB by classical endocytosis, as well as by specific transcytosis. In conclusion, the current study proposed a thorough screening of important formulation and process variabilities affecting brain-targeting liposomes for further scale-up processes.

  4. Prosthetic systems for therapeutic optical activation and silencing of genetically-targeted neurons

    NASA Astrophysics Data System (ADS)

    Bernstein, Jacob G.; Han, Xue; Henninger, Michael A.; Ko, Emily Y.; Qian, Xiaofeng; Talei Franzesi, Giovanni; McConnell, Jackie P.; Stern, Patrick; Desimone, Robert; Boyden, Edward S.

    2008-02-01

    Many neural disorders are associated with aberrant activity in specific cell types or neural projection pathways embedded within the densely-wired, heterogeneous matter of the brain. An ideal therapy would permit correction of activity just in specific target neurons, while leaving other neurons unaltered. Recently our lab revealed that the naturally-occurring light-activated proteins channelrhodopsin-2 (ChR2) and halorhodopsin (Halo/NpHR) can, when genetically expressed in neurons, enable them to be safely, precisely, and reversibly activated and silenced by pulses of blue and yellow light, respectively. We here describe the ability to make specific neurons in the brain light-sensitive, using a viral approach. We also reveal the design and construction of a scalable, fully-implantable optical prosthetic capable of delivering light of appropriate intensity and wavelength to targeted neurons at arbitrary 3-D locations within the brain, enabling activation and silencing of specific neuron types at multiple locations. Finally, we demonstrate control of neural activity in the cortex of the non-human primate, a key step in the translation of such technology for human clinical use. Systems for optical targeting of specific neural circuit elements may enable a new generation of high-precision therapies for brain disorders.

  5. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting.

    PubMed

    Kumar, Mukesh; Misra, Ambikanandan; Mishra, A K; Mishra, Pushpa; Pathak, Kamla

    2008-12-01

    The objective of the present study was to optimize olanzapine nanoemulsion (ONE), for nose-to-brain delivery. The nanoemulsions and olanzapine mucoadhesive nanoemulsions (OMNEs) were prepared using water titration method and characterized for technical and electrokinetic properties. Biodistribution of nanoemulsions and olanzapine solution (OS) in the brain and blood of rats following intranasal (intranasal) and intravenous (intravenous) administrations were examined using optimized technetium-labeled ((99m)Tc-labeled) olanzapine formulations. The brain/blood uptake ratios of 0.45, 0.88, 0.80, and 0.04 of OS (intranasal), ONE (intranasal), OMNE (intranasal), ONE (intravenous), respectively, at 0.5 h are indicative of direct nose-to-brain transport (DTP). Higher % drug targeting efficiency (%DTE) and %DTP for mucoadhesive nanoemulsions indicated effective brain targeting of olanzapine among the prepared nanoemulsions. Gamma scintigraphy imaging of the rat brain conclusively demonstrated rapid and larger extent of transport of olanzapine by OMNE (intranasal), when compared with OS (intranasal), ONE (intranasal), and ONE (intravenous), into the rat brain.

  6. Network-dependent modulation of brain activity during sleep.

    PubMed

    Watanabe, Takamitsu; Kan, Shigeyuki; Koike, Takahiko; Misaki, Masaya; Konishi, Seiki; Miyauchi, Satoru; Miyahsita, Yasushi; Masuda, Naoki

    2014-09-01

    Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy model to brain activity obtained by functional magnetic resonance imaging from sleeping healthy subjects. We found that the brain activity of individual brain regions and functional interactions between pairs of regions significantly increased in the default-mode network during SWS and decreased during REM sleep. In contrast, the network activity of the fronto-parietal and sensory-motor networks showed the opposite pattern. Furthermore, in the three networks, the amount of the activity changes throughout REM sleep was negatively correlated with that throughout SWS. The present findings suggest that the brain activity is dynamically modulated even in a sleep stage and that the pattern of modulation depends on the type of the large-scale brain networks.

  7. Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.

    PubMed

    Mishra, Manoj K; Beaty, Claude A; Lesniak, Wojciech G; Kambhampati, Siva P; Zhang, Fan; Wilson, Mary A; Blue, Mary E; Troncoso, Juan C; Kannan, Sujatha; Johnston, Michael V; Baumgartner, William A; Kannan, Rangaramanujam M

    2014-03-25

    Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer-drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.

  8. Written distractor words influence brain activity during overt picture naming

    PubMed Central

    Diaz, Michele T.; Hogstrom, Larson J.; Zhuang, Jie; Voyvodic, James T.; Johnson, Micah A.; Camblin, C. Christine

    2014-01-01

    Language production requires multiple stages of processing (e.g., semantic retrieval, lexical selection), each of which may involve distinct brain regions. Distractor words can be combined with picture naming to examine factors that influence language production. Phonologically-related distractors have been found to speed picture naming (facilitation), while slower response times and decreased accuracy (interference) generally occur when a distractor is categorically related to the target image. However, other types of semantically-related distractors have been reported to produce a facilitative effect (e.g., associative, part-whole). The different pattern of results for different types of semantically-related distractors raises the question about how the nature of the semantic relation influences the effect of the distractor. To explore the nature of these semantic effects further, we used functional MRI to examine the influence of four types of written distractors on brain activation during overt picture naming. Distractors began with the same sound, were categorically-related, part of the object to be named, or were unrelated to the picture. Phonologically-related trials elicited greater activation than both semantic conditions (categorically-related and part-whole) in left insula and bilateral parietal cortex, regions that have been attributed to phonological aspects of production and encoding, respectively. Semantic conditions elicited greater activation than phonological trials in left posterior MTG, a region that has been linked to concept retrieval and semantic integration. Overall, the two semantic conditions did not differ substantially in their functional activation which suggests a similarity in the semantic demands and lexical competition across these two conditions. PMID:24715859

  9. Antibody-targeted nanovectors for the treatment of brain cancers.

    PubMed

    Sharpe, Martyn A; Marcano, Daniela C; Berlin, Jacob M; Widmayer, Marsha A; Baskin, David S; Tour, James M

    2012-04-24

    Introduced here is the hydrophilic carbon clusters (HCCs) antibody drug enhancement system (HADES), a methodology for cell-specific drug delivery. Antigen-targeted, drug-delivering nanovectors are manufactured by combining specific antibodies with drug-loaded poly(ethylene glycol)-HCCs (PEG-HCCs). We show that HADES is highly modular, as both the drug and antibody component can be varied for selective killing of a range of cultured human primary glioblastoma multiforme. Using three different chemotherapeutics and three different antibodies, without the need for covalent bonding to the nanovector, we demonstrate extreme lethality toward glioma, but minimal toxicity toward human astrocytes and neurons.

  10. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    PubMed

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work.

  11. Decoding Target Distance and Saccade Amplitude from Population Activity in the Macaque Lateral Intraparietal Area (LIP)

    PubMed Central

    Bremmer, Frank; Kaminiarz, Andre; Klingenhoefer, Steffen; Churan, Jan

    2016-01-01

    Primates perform saccadic eye movements in order to bring the image of an interesting target onto the fovea. Compared to stationary targets, saccades toward moving targets are computationally more demanding since the oculomotor system must use speed and direction information about the target as well as knowledge about its own processing latency to program an adequate, predictive saccade vector. In monkeys, different brain regions have been implicated in the control of voluntary saccades, among them the lateral intraparietal area (LIP). Here we asked, if activity in area LIP reflects the distance between fovea and saccade target, or the amplitude of an upcoming saccade, or both. We recorded single unit activity in area LIP of two macaque monkeys. First, we determined for each neuron its preferred saccade direction. Then, monkeys performed visually guided saccades along the preferred direction toward either stationary or moving targets in pseudo-randomized order. LIP population activity allowed to decode both, the distance between fovea and saccade target as well as the size of an upcoming saccade. Previous work has shown comparable results for saccade direction (Graf and Andersen, 2014a,b). Hence, LIP population activity allows to predict any two-dimensional saccade vector. Functional equivalents of macaque area LIP have been identified in humans. Accordingly, our results provide further support for the concept of activity from area LIP as neural basis for the control of an oculomotor brain-machine interface. PMID:27630547

  12. Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: Sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

    SciTech Connect

    Vose, Sarah C.; Holland, Nina T.; Eskenazi, Brenda; Casida, John E.

    2007-10-01

    Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte, and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC{sub 50} values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes, and brain remain to be defined.

  13. Deep Brain Stimulation of the Basolateral Amygdala: Targeting Technique and Electrodiagnostic Findings

    PubMed Central

    Langevin, Jean-Philippe; Chen, James W. Y.; Koek, Ralph J.; Sultzer, David L.; Mandelkern, Mark A.; Schwartz, Holly N.; Krahl, Scott E.

    2016-01-01

    The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety. PMID:27517963

  14. Preliminary brain-targeting studies on intranasal mucoadhesive microemulsions of sumatriptan.

    PubMed

    Vyas, Tushar K; Babbar, A K; Sharma, R K; Singh, Shashi; Misra, Ambikanandan

    2006-03-01

    The aim of this investigation was to prepare microemulsions containing sumatriptan (ST) and sumatriptan succinate (SS) to accomplish rapid delivery of drug to the brain in acute attacks of migraine and perform comparative in vivo evaluation in rats. Sumatriptan microemulsions (SME)/sumatriptan succinate microemulsions (SSME) were prepared using titration method and characterized for drug content, globule size and size distribution, and zeta potential. Biodistribution of SME, SSME, sumatriptan solution (SSS), and marketed product (SMP) in the brain and blood of Swiss albino rats following intranasal and intravenous (IV) administrations were examined using optimized technetium-labeled ((99m)Tc-labeled) ST formulations. The pharmacokinetic parameters, drug targeting efficiency (DTE), and direct drug transport (DTP) were derived. Gamma scintigraphy imaging of rat brain following IV and intranasal administrations were performed to ascertain the localization of drug. SME and SSME were transparent and stable with mean globule size 38±20 nm and zeta potential between -35 to -55 mV. Brain/blood uptake ratios at 0.5 hour following IV administration of SME and intranasal administrations of SME, SMME, and SSS were found to be 0.20, 0.50, 0.60, and 0.26, respectively, suggesting effective transport of drug following intranasal administration of microemulsions. Higher DTE and DTP for mucoadhesive microemulsions indicated more effective targeting following intranasal administration and best brain targeting of ST from mucoadhesive microemulsions. Rat brain scintigraphy endorsed higher uptake of ST into the brain. Studies conclusively demonstrated rapid and larger extent of transport of microemulsion of ST compared with microemulsion of SS, SMP, and SSS into the rat brain. Hence, intranasal delivery of ST microemulsion developed in this investigation can play a promising role in the treatment of acute attacks of migraine.

  15. Microemulsion-based drug delivery system for transnasal delivery of Carbamazepine: preliminary brain-targeting study.

    PubMed

    Patel, Rashmin Bharatbhai; Patel, Mrunali Rashmin; Bhatt, Kashyap K; Patel, Bharat G; Gaikwad, Rajiv V

    2016-01-01

    This study reports the development and evaluation of Carbamazepine (CMP)-loaded microemulsions (CMPME) for intranasal delivery in the treatment of epilepsy. The CMPME was prepared by the spontaneous emulsification method and characterized for physicochemical parameters. All formulations were radiolabeled with (99m)Tc (technetium) and biodistribution of CMP in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rats was also performed to determine the uptake of the CMP into the brain. CMPME were found crystal clear and stable with average globule size of 34.11 ± 1.41 nm. (99m)Tc-labeled CMP solution (CMPS)/CMPME/CMP mucoadhesive microemulsion (CMPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of CMPMME compared to intravenous CMPME was found to be 2- to 3-fold higher signifying larger extent of distribution of the CMP in brain. Drug targeting efficiency and direct drug transport were found to be highest for CMPMME post-intranasal administration compared to intravenous CMP. Rat brain scintigraphy also demonstrated higher intranasal uptake of the CMP into the brain. This investigation demonstrates a prompt and larger extent of transport of CMP into the brain through intranasal CMPMME, which may prove beneficial for treatment of epilepsy.

  16. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications.

    PubMed

    Sudhyadhom, Atchar; Bova, Frank J; Foote, Kelly D; Rosado, Christian A; Kirsch-Darrow, Lindsey; Okun, Michael S

    2007-07-01

    The use of deep brain stimulation (DBS) has recently been expanding for the treatment of many neurologic disorders such as Parkinson disease, dystonia, essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression, and obsessive compulsive disorder. The target structures for DBS include specific segregated territories within limbic, associative, or motor regions of very small subnuclei. In this review, we summarize current clinical techniques for DBS, the cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to functional territories within specific brain targets. Future development of new techniques and technology that may include a more direct visualization of "motor" territories within target structures may prove useful for avoiding side effects that may result from stimulation of associative and limbic regions. Alternatively, newer procedures may choose and specifically target non-motor territories for chronic electrical stimulation.

  17. Transcellular targeting of fiber- and hexon-modified adenovirus vectors across the brain microvascular endothelial cells in vitro.

    PubMed

    Laakkonen, Johanna P; Engler, Tatjana; Romero, Ignacio A; Weksler, Babette; Couraud, Pierre-Olivier; Kreppel, Florian; Kochanek, Stefan

    2012-01-01

    In central nervous system (CNS)-directed gene therapy, efficient targeting of brain parenchyma through the vascular route is prevented by the endothelium and the epithelium of the blood-brain and the blood-cerebrospinal fluid barriers, respectively. In this study, we evaluated the feasibility of the combined genetic and chemical adenovirus capsid modification technology to enable transcellular delivery of targeted adenovirus (Ad) vectors across the blood-brain barrier (BBB) in vitro models. As a proof-of-principle ligand, maleimide-activated full-length human transferrin (hTf) was covalently attached to cysteine-modified Ad serotype 5 vectors either to its fiber or hexon protein. In transcytosis experiments, hTf-coupled vectors were shown to be redirected across the BBB models, the transcytosis activity of the vectors being dependent on the location of the capsid modification and the in vitro model used. The transduction efficiency of hTf-targeted vectors decreased significantly in confluent, polarized cells, indicating that the intracellular route of the vectors differed between unpolarized and polarized cells. After transcellular delivery the majority of the hTf-modified vectors remained intact and partly capable of gene transfer. Altogether, our results demonstrate that i) covalent attachment of a ligand to Ad capsid can mediate transcellular targeting across the cerebral endothelium in vitro, ii) the attachment site of the ligand influences its transcytosis efficiency and iii) combined genetic/chemical modification of Ad vector can be used as a versatile platform for the development of Ad vectors for transcellular targeting.

  18. Recognizing off-target drug effects in the gut and brain: revisiting isotretinoin and depression.

    PubMed

    Kollipara, R; Reisz, C

    2016-04-01

    Clinicians often face complex decisions regarding off-target drug effects, both in diagnosis and treatment. A key component in the formulation of the correct diagnosis is the temporal relationship between drug introduction and adverse effect. The sentinel injury may target the gut and brain. The description of the complaint may vary among providers. Modeling Information visualization for clinicians in real time will require the integration of time-stamped data with organ-specific complaints.

  19. Ionic transporter activity in astrocytes, microglia, and oligodendrocytes during brain ischemia

    PubMed Central

    Annunziato, Lucio; Boscia, Francesca; Pignataro, Giuseppe

    2013-01-01

    Glial cells constitute a large percentage of cells in the nervous system. During recent years, a large number of studies have critically attributed to glia a new role which no longer reflects the long-held view that glia constitute solely a silent and passive supportive scaffolding for brain cells. Indeed, it has been hypothesized that glia, partnering neurons, have a much more actively participating role in brain function. Alteration of intraglial ionic homeostasis in response to ischemic injury has a crucial role in inducing and maintaining glial responses in the ischemic brain. Therefore, glial transporters as potential candidates in stroke intervention are becoming promising targets to enhance an effective and additional therapy for brain ischemia. In this review, we will describe in detail the role played by ionic transporters in influencing astrocyte, microglia, and oligodendrocyte activity and the implications that these transporters have in the progression of ischemic lesion. PMID:23549380

  20. Correspondence between resting state activity and brain gene expression

    PubMed Central

    Wang, Guang-Zhong; Belgard, T. Grant; Mao, Deng; Chen, Leslie; Berto, Stefano; Preuss, Todd M.; Lu, Hanzhang; Geschwind, Daniel H.; Konopka, Genevieve

    2015-01-01

    SUMMARY The relationship between functional brain activity and gene expression has not been fully explored in the human brain. Here, we identify significant correlations between gene expression in the brain and functional activity by comparing fractional Amplitude of Low Frequency Fluctuations (fALFF) from two independent human fMRI resting state datasets to regional cortical gene expression from a newly generated RNA-seq dataset and two additional gene expression datasets to obtain robust and reproducible correlations. We find significantly more genes correlated with fALFF than expected by chance, and identify specific genes correlated with the imaging signals in multiple expression datasets in the default mode network. Together, these data support a population-level relationship between regional steady state brain gene expression and resting state brain activity. PMID:26590343

  1. Cre Fused with RVG Peptide Mediates Targeted Genome Editing in Mouse Brain Cells In Vivo

    PubMed Central

    Zou, Zhiyuan; Sun, Zhaolin; Li, Pan; Feng, Tao; Wu, Sen

    2016-01-01

    Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. However, whether RVG can be used for genome editing in the brain has not been reported. In this work, we combined RVG with Cre recombinase for bacterial expression. The purified RVG-Cre protein cut plasmids in vitro and traversed cell membranes in cultured Neuro2a cells. By tail vein-injecting RVG-Cre into Cre reporter mouse lines mTmG and Rosa26lacZ, we demonstrated that RVG-Cre could target brain cells and achieve targeted somatic genome editing in adult mice. This direct delivery of the gene-editing enzyme protein into mouse brains with RVG is much safer than plasmid- or viral-based methods, holding promise for further applications in the treatment of various brain diseases. PMID:27983648

  2. Olfactory targeting through intranasal delivery of biopharmaceutical drugs to the brain: current development.

    PubMed

    Wen, Ming Ming

    2011-06-01

    Many therapeutic drugs are difficult to reach the central nervous system (CNS) from the systemic blood circulation because the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier which prevents most molecules from passing through. To bypass BBB, drugs can be delivered through olfactory region for nose-to-brain targeting. Peptide and protein drugs have been developed for the treatment of various neurodegenerative diseases. Drug delivery of these therapeutic proteins is facing several challenges because of the instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity. New genetically engineered biotechnology products, such as recombinant human nerve growth factor, human VEGF, and interferons, are now possible to be delivered into the brain from the non-invasive intranasal route. For gene therapy, intranasal route is also a promising alternative method to deliver plasmid DNA to the brain. This review provides an overview of strategies to improve the drug delivery to the brain and the latest development of protein, peptide, and gene intranasal delivery for brain targeting.

  3. Systemic Delivery of Blood-Brain Barrier Targeted Polymeric Nanoparticles Enhances Delivery to Brain Tissue

    PubMed Central

    Saucier-Sawyer, Jennifer K.; Deng, Yang; Seo, Young-Eun; Cheng, Christopher J.; Zhang, Junwei; Quijano, Elias; Saltzman, W. Mark

    2016-01-01

    Delivery of therapeutic agents to the central nervous system is a significant challenge, hindering progress in the treatment of diseases such as glioblastoma. Due to the presence of the blood-brain barrier (BBB), therapeutic agents do not readily transverse the brain endothelium to enter the parenchyma. Previous reports suggest that surface modification of polymer nanoparticles can improve their ability to cross the BBB, but it is unclear whether the observed enhancements in transport are large enough to enhance therapy. In this study, we synthesized two degradable polymer nanoparticle systems surface-modified with ligands previously suggested to improve BBB transport, and tested their ability to cross the BBB after intravenous injection in mice. All nanoparticle preparations were able to cross the BBB, although generally in low amounts (<0.5% of the injected dose), which was consistent with prior reports. One nanoparticle produced significantly higher brain uptake (~0.8% of the injected dose): a block copolymer of polylactic acid and hyperbranched polyglycerol, surface modified with adenosine (PLA-HPG-Ad). PLA-HPG-Ad nanoparticles provided controlled release of camptothecin, killing U87 glioma cells in culture. When administered intravenously in mice with intracranial U87 tumors, they failed to increase survival. These results suggest that enhancing nanoparticle transport across the BBB does not necessarily yield proportional pharmacological effects. PMID:26453169

  4. Caveolins: targeting pro-survival signaling in the heart and brain

    PubMed Central

    Stary, Creed M.; Tsutsumi, Yasuo M.; Patel, Piyush M.; Head, Brian P.; Patel, Hemal H.; Roth, David M.

    2012-01-01

    The present review discusses intracellular signaling moieties specific to membrane lipid rafts (MLRs) and the scaffolding proteins caveolin and introduces current data promoting their potential role in the treatment of pathologies of the heart and brain. MLRs are discreet microdomains of the plasma membrane enriched in gylcosphingolipids and cholesterol that concentrate and localize signaling molecules. Caveolin proteins are necessary for the formation of MLRs, and are responsible for coordinating signaling events by scaffolding and enriching numerous signaling moieties in close proximity. Specifically in the heart and brain, caveolins are necessary for the cytoprotective phenomenon termed ischemic and anesthetic preconditioning. Targeted overexpression of caveolin in the heart and brain leads to induction of multiple pro-survival and pro-growth signaling pathways; thus, caveolins represent a potential novel therapeutic target for cardiac and neurological pathologies. PMID:23060817

  5. Functional Assays for Specific Targeting and Delivery of RNA Nanoparticles to Brain Tumor

    PubMed Central

    Lee, Tae Jin; Haque, Farzin; Vieweger, Mario; Yoo, Ji Young; Kaur, Balveen; Guo, Peixuan; Croce, Carlo M.

    2017-01-01

    Cumulative progress in nanoparticle development has opened a new era of targeted delivery of therapeutics to cancer cells and tissue. However, developing proper detection methods has lagged behind resulting in the lack of precise evaluation and monitoring of the systemically administered nanoparticles. RNA nanoparticles derived from the bacteriophage phi29 DNA packaging motor pRNA have emerged as a new generation of drugs for cancer therapy. Multifunctional RNA nanoparticles can be fabricated by bottom-up self-assembly of engineered RNA fragments harboring targeting (RNA aptamer or chemical ligand), therapeutic (siRNA, miRNA, ribozymes, and small molecule drugs), and imaging (fluorophore, radiolabels) modules. We have recently demonstrated that RNA nanoparticles can reach and target intracranial brain tumors in mice upon systemic injection with little or no accumulation in adjacent healthy brain tissues or in major healthy internal organs. Herein, we describe various functional imaging methods (fluorescence confocal microscopy, flow cytometry, fluorescence whole body imaging, and magnetic resonance imaging) to evaluate and monitor RNA nanoparticle targeting to intracranial brain tumors in mice. Such imaging techniques will allow in-depth evaluation of specifically delivered RNA therapeutics to brain tumors. PMID:25896001

  6. Abnormal brain activation during movement observation in patients with conversion paralysis.

    PubMed

    Burgmer, Markus; Konrad, Carsten; Jansen, Andreas; Kugel, Harald; Sommer, Jens; Heindel, Walter; Ringelstein, Erich B; Heuft, Gereon; Knecht, Stefan

    2006-02-15

    Dissociative paralysis in conversion disorders has variably been attributed to a lack of movement initiation or an inhibition of movement. While psychodynamic theory suggests altered movement conceptualization, brain activation associated with observation and replication of movements has so far not been assessed neurobiologically. Here, we measured brain activation by functional magnetic resonance imaging during observation and subsequent imitative execution of movements in four patients with dissociative hand paralysis. Compared to healthy controls conversion disorder patients showed decreased activation of cortical hand areas during movement observation. This effect was specific to the side of their dissociative paralysis. No brain activation compatible with movement inhibition was observed. These findings indicate that in dissociative paralysis, there is not only derangement of movement initiation but already of movement conceptualization. This raises the possibility that strategies targeted at reestablishing appropriate movement conceptualization may contribute to the therapy of dissociative paralysis.

  7. Neurological disorders and therapeutics targeted to surmount the blood–brain barrier

    PubMed Central

    Kanwar, Jagat R; Sriramoju, Bhasker; Kanwar, Rupinder K

    2012-01-01

    We are now in an aging population, so neurological disorders, particularly the neurodegenerative diseases, are becoming more prevalent in society. As per the epidemiological studies, Europe alone suffers 35% of the burden, indicating an alarming rate of disease progression. Further, treatment for these disorders is a challenging area due to the presence of the tightly regulated blood–brain barrier and its unique ability to protect the brain from xenobiotics. Conventional therapeutics, although effective, remain critically below levels of optimum therapeutic efficacy. Hence, methods to overcome the blood–brain barrier are currently a focus of research. Nanotechnological applications are gaining paramount importance in addressing this question, and yielding some promising results. This review addresses the pathophysiology of the more common neurological disorders and novel drug candidates, along with targeted nanoparticle applications for brain delivery. PMID:22848160

  8. Docosahexaenoic acid-mediated, targeted and sustained brain delivery of curcumin microemulsion.

    PubMed

    Shinde, Rajshree L; Devarajan, Padma V

    2017-11-01

    We disclose microemulsions (ME) of curcumin (CUR) with docosahexaenoic acid (DHA)-rich oil (CUR DHA ME) for targeted delivery to the brain. MEs of CUR (5 mg/mL) with and without DHA-rich oil (CUR Capmul ME) suitable for intravenous and intranasal administration exhibited negative zeta potential, globule size  <20 nm and good stability. Following intravenous delivery MEs exhibited high brain concentration with CUR DHA ME exhibiting a 2.8-fold higher Cmax than CUR solution. Furthermore, high and sustained concentration was demonstrated even at 24 h, which was 8- and 2-fold higher than CUR solution and CUR Capmul ME, respectively. Brain concentrations following intranasal administration were, however, substantially higher as evident from higher Cmax and AUC and sustained compared to corresponding intravenous formulations signifying nose to brain targeting. The high brain concentration of CUR DHA ME is ascribed to the targeting efficiency enabled by DHA-mediated transport across the blood-brain barrier (BBB). Histopathological and nasal toxicity confirmed safety of the MEs. Concentration-dependent cytotoxicity in vitro, on human glioblastoma U-87MG cell line was observed with CUR DHA MEs and with the blank DHA ME, implying anticancer potential of DHA. The dramatically low IC50 value of CUR DHA ME (3.755 ± 0.24 ng/mL) is therefore attributed to the synergistic effect of CUR and DHA in the ME. The CUR concentration achieved with CUR DHA ME at 24  h which translated to  >66-fold(intranasal) and  >21-fold (intravenous) the IC50 value in the U-87MG cell line suggests great promise of CUR DHA ME for therapy of brain cancer by both routes.

  9. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.

    PubMed

    Niessner, Heike; Forschner, Andrea; Klumpp, Bernhard; Honegger, Jürgen B; Witte, Maria; Bornemann, Antje; Dummer, Reinhard; Adam, Annemarie; Bauer, Jürgen; Tabatabai, Ghazaleh; Flaherty, Keith; Sinnberg, Tobias; Beck, Daniela; Leiter, Ulrike; Mauch, Cornelia; Roesch, Alexander; Weide, Benjamin; Eigentler, Thomas; Schadendorf, Dirk; Garbe, Claus; Kulms, Dagmar; Quintanilla-Martinez, Leticia; Meier, Friedegund

    2013-02-01

    Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.

  10. Gamma Knife irradiation method based on dosimetric controls to target small areas in rat brains

    SciTech Connect

    Constanzo, Julie; Paquette, Benoit; Charest, Gabriel; Masson-Côté, Laurence; Guillot, Mathieu

    2015-05-15

    Purpose: Targeted and whole-brain irradiation in humans can result in significant side effects causing decreased patient quality of life. To adequately investigate structural and functional alterations after stereotactic radiosurgery, preclinical studies are needed. The purpose of this work is to establish a robust standardized method of targeted irradiation on small regions of the rat brain. Methods: Euthanized male Fischer rats were imaged in a stereotactic bed, by computed tomography (CT), to estimate positioning variations relative to the bregma skull reference point. Using a rat brain atlas and the stereotactic bregma coordinates obtained from CT images, different regions of the brain were delimited and a treatment plan was generated. A single isocenter treatment plan delivering ≥100 Gy in 100% of the target volume was produced by Leksell GammaPlan using the 4 mm diameter collimator of sectors 4, 5, 7, and 8 of the Gamma Knife unit. Impact of positioning deviations of the rat brain on dose deposition was simulated by GammaPlan and validated with dosimetric measurements. Results: The authors’ results showed that 90% of the target volume received 100 ± 8 Gy and the maximum of deposited dose was 125 ± 0.7 Gy, which corresponds to an excellent relative standard deviation of 0.6%. This dose deposition calculated with GammaPlan was validated with dosimetric films resulting in a dose-profile agreement within 5%, both in X- and Z-axes. Conclusions: The authors’ results demonstrate the feasibility of standardizing the irradiation procedure of a small volume in the rat brain using a Gamma Knife.

  11. Challenges in the design of clinically useful brain-targeted drug nanocarriers.

    PubMed

    Costantino, L; Boraschi, D; Eaton, M

    2014-01-01

    Nowadays, the delivery of drugs by means of intravenously administered nanosized drug carriers - polymerdrug conjugates, liposomes and micelles, is technically possible. These delivery systems are mainly designed for tumour therapy, and accumulate passively into tumours by means of the well known EPR effect. Targeted nanocarriers, that additionally contain ligands for receptors expressed on cell surfaces, are also widely studied but products of this kind are not marketed, and only a few are in clinical trial. Polymeric nanoparticles (Np) able to deliver drugs to the CNS were pioneered in 1995; a number of papers have been published dealing with brain-targeted drug delivery using polymeric Np able to cross the BBB, mainly for the treatment of brain tumours. At present, however, the translation potential of these Np seems to have been exceeded by targeted liposomes, a platform based on a proven technology. This drug delivery system entered clinical trials soon after its discovery, while the challenges in formulation, characterization and manufacturing of brain-targeted polymeric Np and the cost/benefit ratio could be the factors that have prevented their development. A key issue is that it is virtually impossible to define the in vivo fate of polymers, especially in the brain, which is a regulatory requirement; perhaps this is why no progress has been made. The most advanced Np for brain tumours treatment will be compared here with the published data available for those in clinical trial for tumours outside the CNS, to highlight the knowledge gaps that still penalise these delivery systems. At present, new approaches for brain tumours are emerging, such as lipid Np or the use of monoclonal antibody (mAb)-drug conjugates, which avoid polymers. The success or failure in the approval of the polymeric Np currently in clinical trials will certainly affect the field. At present, the chances of their approval appear to be very low.

  12. Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

    PubMed

    Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

    2017-03-15

    Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin αvβ3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

  13. IMAGING BRAIN ACTIVATION: SIMPLE PICTURES OF COMPLEX BIOLOGY

    PubMed Central

    Dienel, Gerald A.; Cruz, Nancy F.

    2009-01-01

    Elucidation of biochemical, physiological, and cellular contributions to metabolic images of brain is important for interpretation of images of brain activation and disease. Discordant brain images obtained with [14C]deoxyglucose (DG) and [1- or 6-14C]glucose were previously ascribed to increased glycolysis and rapid [14C]lactate release from tissue, but direct proof of [14C]lactate release from activated brain structures is lacking. Analysis of factors contributing to images of focal metabolic activity evoked by monotonic acoustic stimulation of conscious rats reveals that labeled metabolites of [1- or 6-14C]glucose are quickly released from activated cells due to decarboxylation reactions, spreading via gap junctions, and efflux via lactate transporters. Label release from activated tissue accounts for most of the additional [14C]glucose consumed during activation compared to rest. Metabolism of [3,4-14C]glucose generates about four times more [14C]lactate compared to 14CO2 in extracellular fluid suggesting that most lactate is not locally oxidized. In brain slices, direct assays of lactate uptake from extracellular fluid demonstrate that astrocytes have faster influx and higher transport capacity than neurons. Also, lactate transfer from a single astrocyte to other gap junction-coupled astrocytes exceeds astrocyte-to-neuron lactate shuttling. Astrocytes and neurons have excess capacities for glycolysis, and oxidative metabolism in both cell types rises during sensory stimulation. The energetics of brain activation is quite complex and the proportion of glucose consumed by astrocytes and neurons, lactate generation by either cell type, and the contributions of both cell types to brain images during brain activation are likely to vary with the stimulus paradigm and activated pathways. PMID:19076439

  14. Therapeutic administration of plasminogen activator inhibitor-1 prevents hypoxic-ischemic brain injury in newborns.

    PubMed

    Yang, Dianer; Nemkul, Niza; Shereen, Ahmed; Jone, Alice; Dunn, R Scott; Lawrence, Daniel A; Lindquist, Diana; Kuan, Chia-Yi

    2009-07-08

    Disruption of the integrity of the blood-brain barrier (BBB) is an important mechanism of cerebrovascular diseases, including neonatal cerebral hypoxia-ischemia (HI). Although both tissue-type plasminogen activator (tPA) and matrix metalloproteinase-9 (MMP-9) can produce BBB damage, their relationship in neonatal cerebral HI is unclear. Here we use a rodent model to test whether the plasminogen activator (PA) system is critical for MMP-9 activation and HI-induced brain injury in newborns. To test this hypothesis, we examined the therapeutic effect of intracerebroventricular injection of plasminogen activator inhibitor-1 (PAI-1) in rat pups subjected to unilateral carotid artery occlusion and systemic hypoxia. We found that the injection of PAI-1 greatly reduced the activity of both tPA and urokinase-type plasminogen activator after HI. It also blocked HI-induced MMP-9 activation and BBB permeability at 24 h of recovery. Furthermore, magnetic resonance imaging and histological analysis showed the PAI-1 treatment reduced brain edema, axonal degeneration, and cortical cell death at 24-48 h of recovery. Finally, the PAI-1 therapy provided a dose-dependent decrease of brain tissue loss at 7 d of recovery, with the therapeutic window at 4 h after the HI insult. Together, these results suggest that the brain PA system plays a pivotal role in neonatal cerebral HI and may be a promising therapeutic target in infants suffering hypoxic-ischemic encephalopathy.

  15. Translocation of LRP1 targeted carbon nanotubes of different diameters across the blood–brain barrier in vitro and in vivo

    PubMed Central

    Kafa, Houmam; Wang, Julie Tzu-Wen; Rubio, Noelia; Klippstein, Rebecca; Costa, Pedro M.; Hassan, Hatem A.F.M.; Sosabowski, Jane K.; Bansal, Sukhvinder S.; Preston, Jane E.; Abbott, N. Joan; Al-Jamal, Khuloud T.

    2016-01-01

    Brain glioblastoma and neurodegenerative diseases are still largely untreated due to the inability of most drugs to cross the blood–brain barrier (BBB). Nanoparticles have emerged as promising tools for drug delivery applications to the brain; in particular carbon nanotubes (CNTs) that have shown an intrinsic ability to cross the BBB in vitro and in vivo. Angiopep-2 (ANG), a ligand for the low-density lipoprotein receptor-related protein-1 (LRP1), has also shown promising results as a targeting ligand for brain delivery using nanoparticles (NPs). Here, we investigate the ability of ANG-targeted chemically-functionalised multi-walled carbon nanotubes (f-MWNTs) to cross the BBB in vitro and in vivo. ANG was conjugated to wide and thin f-MWNTs creating w-MWNT-ANG and t-MWNT-ANG, respectively. All f-MWNTs were radiolabelled to facilitate quantitative analyses by γ-scintigraphy. ANG conjugation to f-MWNTs enhanced BBB transport of w- and t-MWNTs-ANG compared to their non-targeted equivalents using an in vitro co-cultured BBB model consisting of primary porcine brain endothelial cells (PBEC) and primary rat astrocytes. Additionally, following intravenous administration w-MWNTs-ANG showed significantly higher whole brain uptake than the non-targeted w-MWNT in vivo reaching ~ 2% injected dose per g of brain (%ID/g) within the first hour post-injection. Furthermore, using a syngeneic glioma model, w-MWNT-ANG showed enhanced uptake in glioma brain compared to normal brain at 24 h post-injection. t-MWNTs-ANG, on the other hand, showed higher brain accumulation than w-MWNTs. However, no significant differences were observed between t-MWNT and t-MWNT-ANG indicating the importance of f-MWNTs diameter towards their brain accumulation. The inherent brain accumulation ability of f-MWNTs coupled with improved brain-targeting by ANG favours the future clinical applications of f-MWNT-ANG to deliver active therapeutics for brain glioma therapy. PMID:26809004

  16. Nonthermal ablation of deep brain targets: A simulation study on a large animal model

    PubMed Central

    Top, Can Barış; White, P. Jason; McDannold, Nathan J.

    2016-01-01

    Purpose: Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently limited to central brain targets because of heating and other beam effects caused by the presence of the skull. Recently, it was shown that it is possible to ablate tissues without depositing thermal energy by driving intravenously administered microbubbles to inertial cavitation using low-duty-cycle burst sonications. A recent study demonstrated that this ablation method could ablate tissue volumes near the skull base in nonhuman primates without thermally damaging the nearby bone. However, blood–brain disruption was observed in the prefocal region, and in some cases, this region contained small areas of tissue damage. The objective of this study was to analyze the experimental model with simulations and to interpret the cause of these effects. Methods: The authors simulated prior experiments where nonthermal ablation was performed in the brain in anesthetized rhesus macaques using a 220 kHz clinical prototype transcranial MRI-guided FUS system. Low-duty-cycle sonications were applied at deep brain targets with the ultrasound contrast agent Definity. For simulations, a 3D pseudospectral finite difference time domain tool was used. The effects of shear mode conversion, focal steering, skull aberrations, nonlinear propagation, and the presence of skull base on the pressure field were investigated using acoustic and elastic wave propagation models. Results: The simulation results were in agreement with the experimental findings in the prefocal region. In the postfocal region, however, side lobes were predicted by the simulations, but no effects were evident in the experiments. The main beam was not affected by the different simulated scenarios except for a shift of about 1 mm in peak position due to skull aberrations. However, the authors observed differences in the volume, amplitude, and distribution of the side lobes. In the experiments, a single element passive

  17. Permanent genetic access to transiently active neurons via TRAP: targeted recombination in active populations.

    PubMed

    Guenthner, Casey J; Miyamichi, Kazunari; Yang, Helen H; Heller, H Craig; Luo, Liqun

    2013-06-05

    Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed an approach, targeted recombination in active populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreER(T2) is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that express CreER(T2) can only undergo recombination when tamoxifen is present, allowing genetic access to neurons that are active during a time window of less than 12 hr. We show that TRAP can provide selective access to neurons activated by specific somatosensory, visual, and auditory stimuli and by experience in a novel environment. When combined with tools for labeling, tracing, recording, and manipulating neurons, TRAP offers a powerful approach for understanding how the brain processes information and generates behavior.

  18. Targeting modulates audiences' brain and behavioral responses to safe sex video ads.

    PubMed

    Wang, An-Li; Lowen, Steven B; Shi, Zhenhao; Bissey, Bryn; Metzger, David S; Langleben, Daniel D

    2016-10-01

    Video ads promoting condom use are a key component of media campaigns to stem the HIV epidemic. Recent neuroimaging studies in the context of smoking cessation, point to personal relevance as one of the key variables that determine the effectiveness of public health messages. While minority men who have sex with men (MSM) are at the highest risk of HIV infection, most safe-sex ads feature predominantly Caucasian actors in heterosexual scenarios. We compared brain respons of 45 African American MSM to safe sex ads that were matched (i.e. 'Targeted') to participants' sexual orientation and race, and 'Untargeted' ads that were un matched for these characteristics. Ad recall, perceived 'convincingness' and attitudes towards condom use were also assessed. We found that Targeted ads were better remembered than the Untargeted ads but perceived as equally convincing. Targeted ads engaged brain regions involved in self-referential processing and memory, including the amygdala, hippocampus, temporal and medial prefrontal cortices (MPFC) and the precuneus. Connectivity between MPFC and precuneus and middle temporal gyrus was stronger when viewing Targeted ads. Our results suggest that targeting may increase cognitive processing of safe sex ads and justify further prospective studies linking brain response to media public health interventions and clinical outcomes.

  19. Evoked Brain Activity and Personnel Performance

    DTIC Science & Technology

    1987-10-01

    correlation suggests variability. Early papers by Travis and Gottlober (1936, 1937), Davis and Davis (1936), Rubin (1938) and Williams (1939... Gottlober , A. (1936). Do brain waves have individuality? Science, 8^, 532-533. Travis, L.E., &: Gottlober , A. (1937). How consistent are an individual’s

  20. BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks.

    PubMed

    Richiardi, Jonas; Altmann, Andre; Milazzo, Anna-Clare; Chang, Catie; Chakravarty, M Mallar; Banaschewski, Tobias; Barker, Gareth J; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Conrod, Patricia; Fauth-Bühler, Mira; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Lemaître, Hervé; Mann, Karl F; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomáš; Pausova, Zdenka; Rietschel, Marcella; Robbins, Trevor W; Smolka, Michael N; Spanagel, Rainer; Ströhle, Andreas; Schumann, Gunter; Hawrylycz, Mike; Poline, Jean-Baptiste; Greicius, Michael D

    2015-06-12

    During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set. The set of 136 genes we identify is significantly enriched for ion channels. Polymorphisms in this set of genes significantly affect resting-state functional connectivity in a large sample of healthy adolescents. Expression levels of these genes are also significantly associated with axonal connectivity in the mouse. The results provide convergent, multimodal evidence that resting-state functional networks correlate with the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function.

  1. Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: Developmental exposure of rats to 4-methylbenzylidene camphor

    SciTech Connect

    Maerkel, Kirsten; Durrer, Stefan; Henseler, Manuel; Schlumpf, Margret; Lichtensteiger, Walter . E-mail: Walter.Lichtensteiger@access.unizh.ch

    2007-01-15

    The developing neuroendocrine brain represents a potential target for endocrine active chemicals. The UV filter 4-methylbenzylidene camphor (4-MBC) exhibits estrogenic activity, but also interferes with the thyroid axis. We investigated effects of pre- and postnatal exposure to 4-MBC in the same rat offspring at brain and reproductive organ levels. 4-MBC (7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to the offspring until adulthood. mRNA of estrogen target genes involved in control of sexual behavior and gonadal functions was measured by real-time RT-PCR in ventromedial hypothalamic nucleus (VMH) and medial preoptic area (MPO) of adult offspring. 4-MBC exposure affected mRNA levels of ER alpha, progesterone receptor (PR), preproenkephalin (PPE) and insulin-like growth factor-I (IGF-I) in a sex- and region-specific manner. In order to assess possible changes in sensitivity of target genes to estrogens, offspring were gonadectomized on day 70, injected with estradiol (E2, 10 or 50 {mu}g/kg s.c.) or vehicle on day 84, and sacrificed 6 h later. The acute induction of PR mRNA, and repression (at 6 h) of PPE mRNA by E2 was enhanced by 4-MBC in male and female VMH and female MPO, whereas male MPO exhibited reduced responsiveness of both genes. Steroid receptor coactivator SRC-1 mRNA levels were increased in female VMH and MPO. The data indicate profound sex- and region-specific alterations in the regulation of estrogen target genes at brain level. Effect patterns in baseline and E2-induced gene expression differ from those in uterus and prostate.

  2. Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits.

    PubMed

    Hamani, Clement; Amorim, Beatriz O; Wheeler, Anne L; Diwan, Mustansir; Driesslein, Klaus; Covolan, Luciene; Butson, Christopher R; Nobrega, José N

    2014-11-01

    Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regard to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induces distinct changes in regional brain activity and functional connectivity.

  3. Brain Targeting of Temozolomide via the Intranasal Route Using Lipid-Based Nanoparticles: Brain Pharmacokinetic and Scintigraphic Analyses.

    PubMed

    Khan, Anam; Imam, Syed Sarim; Aqil, Mohammed; Ahad, Abdul; Sultana, Yasmin; Ali, Asgar; Khan, Khalid

    2016-11-07

    The aim of the present work was to investigate the efficacy of temozolomide nanostructured lipid carriers (TMZ-NLCs) to enhance brain targeting via nasal route administration. The formulation was optimized by applying a four-factor, three-level Box-Behnken design. The developed formulations and the functional relationships between their independent and dependent variables were observed. The independent variables used in the formulation were gelucire (X1), liquid lipid/total lipid (X2), Tween 80 (X3), and sonication time (X4), and their effects were observed with regard to size (Y1), % drug release (Y2), and drug loading (Y3). The optimized TMZ-NLC was further evaluated for its surface morphology as well as ex vivo permeation and in vivo studies. All TMZ-NLC formulations showed sizes in the nanometer range, with high drug loading and prolonged drug release. The optimized formulation (TMZ-NLCopt) showed an entrapment efficiency of 81.64 ± 3.71%, zeta potential of 15.21 ± 3.11 mV, and polydispersity index of less than 0.2. The enhancement ratio was found to be 2.32-fold that of the control formulation (TMZ-disp). In vivo studies in mice showed that the brain/blood ratio of TMZ-NLCopt was found to be significantly higher compared to that of TMZ-disp (intranasal, intravenous). Scintigraphy images of mouse brain showed the presence of a high concentration of TMZ. The AUC ratio of TMZ-NLCopt to TMZ-disp in the brain was the highest among the organs. The findings of this study substantiate the existence of a direct nose-to-brain delivery route for NLCs.

  4. Visual and audiovisual effects of isochronous timing on visual perception and brain activity.

    PubMed

    Marchant, Jennifer L; Driver, Jon

    2013-06-01

    Understanding how the brain extracts and combines temporal structure (rhythm) information from events presented to different senses remains unresolved. Many neuroimaging beat perception studies have focused on the auditory domain and show the presence of a highly regular beat (isochrony) in "auditory" stimulus streams enhances neural responses in a distributed brain network and affects perceptual performance. Here, we acquired functional magnetic resonance imaging (fMRI) measurements of brain activity while healthy human participants performed a visual task on isochronous versus randomly timed "visual" streams, with or without concurrent task-irrelevant sounds. We found that visual detection of higher intensity oddball targets was better for isochronous than randomly timed streams, extending previous auditory findings to vision. The impact of isochrony on visual target sensitivity correlated positively with fMRI signal changes not only in visual cortex but also in auditory sensory cortex during audiovisual presentations. Visual isochrony activated a similar timing-related brain network to that previously found primarily in auditory beat perception work. Finally, activity in multisensory left posterior superior temporal sulcus increased specifically during concurrent isochronous audiovisual presentations. These results indicate that regular isochronous timing can modulate visual processing and this can also involve multisensory audiovisual brain mechanisms.

  5. Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction

    PubMed Central

    Cui, Hai; Zhu, Qiong; Hua, Xing; Xia, Hongmei; Tan, Kaibin; Gao, Yunhua; Zhao, Jing

    2016-01-01

    Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p < 0.01). Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4 ± 1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery. PMID:27579317

  6. Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction.

    PubMed

    Xu, Yali; Cui, Hai; Zhu, Qiong; Hua, Xing; Xia, Hongmei; Tan, Kaibin; Gao, Yunhua; Zhao, Jing; Liu, Zheng

    2016-01-01

    Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p < 0.01). Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4 ± 1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

  7. Thermo-sensitive gels containing lorazepam microspheres for intranasal brain targeting.

    PubMed

    Jose, S; Ansa, C R; Cinu, T A; Chacko, A J; Aleykutty, N A; Ferreira, S V; Souto, E B

    2013-01-30

    Thermo-sensitive gels containing lorazepam microspheres were developed and characterized for intranasal brain targeting. Pluronics (PF-127 and PF-68) have been selected since they are thermo-reversible polymers with the property of forming a solution at low temperatures (4-5 °C), and a gel at body temperature (37 °C). This property makes them an interesting material to work with, especially in case of controlled release formulations. The present study focuses on the development of an intranasal formulation for lorazepam, as an alternative route of drug delivery to the brain. Direct transport of drugs to the brain circumventing the brain barrier, following intranasal administration, provides a unique feature and better option to target brain. The presence of mucoadhesive microspheres in the gel vehicle via nasal route can achieve a dual purpose of prolonged drug release and enhanced bioavailability. To optimise the microsphere formulation, Box Behnken design was employed by investigating the effect of three factors, polymer concentration (chitosan), emulsifier concentration (Span 80) and cross-linking agent (glutaraldehyde) on the response variable which is the mean particle size. The concentration of 21% PF-127 and 1% PF-68 were found to be promising gel vehicles. The results showed that the release rate followed a prolonged profile dispersion of the microspheres in the viscous media, in comparison to the microspheres alone. Histopathological studies proved that the optimised formulation does not produce any toxic effect on the microscopic structure of nasal mucosa.

  8. Brain-targeted ACE2 overexpression attenuates neurogenic hypertension by inhibiting COX mediated inflammation

    PubMed Central

    Sriramula, Srinivas; Xia, Huijing; Xu, Ping; Lazartigues, Eric

    2014-01-01

    Overactivity of the renin angiotensin system (RAS), oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that Angiotensin-Converting Enzyme 2 (ACE2) overexpression in the brain attenuates the development of DOCA-salt hypertension, a neurogenic hypertension model with enhanced brain RAS and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. DOCA-salt hypertension significantly increased expression of Nox-2 (+61 ±5 %), Nox-4 (+50 ±13 %) and nitrotyrosine (+89 ±32 %) and reduced activity of the antioxidant enzymes, catalase (−29 ±4 %) and SOD (−31 ±7 %), indicating increased oxidative stress in the brain of non-transgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. DOCA-salt-induced reduction of nNOS expression (−26 ±7 %) and phosphorylated eNOS/total eNOS (−30 ±3 %), and enhanced phosphorylation of Akt and ERK1/2 in the paraventricular nucleus (PVN), were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the PVN. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuro-inflammation, ultimately attenuating DOCA-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuro-inflammation, improves anti-oxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension. PMID:25489058

  9. Linking neuronal brain activity to the glucose metabolism

    PubMed Central

    2013-01-01

    Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. Methods First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Results Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. Conclusions The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported. PMID:23988084

  10. Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution.

    PubMed

    El-Setouhy, Doaa Ahmed; Ibrahim, A B; Amin, Maha M; Khowessah, Omneya M; Elzanfaly, Eman S

    2016-09-20

    Haloperidol is a commonly prescribed antipsychotic drug currently administered as oral and injectable preparations. This study aimed to prepare haloperidol intranasal miniemulsion helpful for psychiatric emergencies and exhibiting lower systemic exposure and side effects associated with non-target site delivery. Haloperidol miniemulsions were successfully prepared by spontaneous emulsification adopting 2(3) factorial design. The effect of three independent variables at two levels each namely; oil type (Capmul®-Capryol™90), lipophilic emulsifier type (Span 20-Span 80) and HLB value (12-14) on globule size, PDI and percent locomotor activity inhibition in mice was evaluated. The optimized formula (F4, Capmul®, Tween 80/Span 20, HLB 14) showed globule size of 209.5±0.98nm, PDI of 0.402±0.03 and locomotor inhibition of 83.89±9.15% with desirability of 0.907. Biodistribution study following intranasal and intravenous administration of the radiolabeled (99m)Tc mucoadhesive F4 revealed that intranasal administration achieved 1.72-fold higher and 6 times faster peak brain levels compared with intravenous administration. Drug targeting efficiency percent and brain/blood exposure ratios remained above 100% and 1 respectively after intranasal instillation compared to a maximum brain/blood exposure ratio of 0.8 post intravenous route. Results suggested the CNS delivery of major fraction of haloperidol via direct transnasal to brain pathway that can be a promising alternative to oral and parenteral routes in chronic and acute situations. Haloperidol concentration of 275.6ng/g brain 8h post intranasal instillation, higher than therapeutic concentration range of haloperidol (0.8 to 5.15ng/ml), suggests possible sustained delivery of the drug through nasal route.

  11. Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury.

    PubMed

    Pardo, Luis; Schlüter, Agatha; Valor, Luis M; Barco, Angel; Giralt, Mercedes; Golbano, Arantxa; Hidalgo, Juan; Jia, Peilin; Zhao, Zhongming; Jové, Mariona; Portero-Otin, Manuel; Ruiz, Montserrat; Giménez-Llort, Lydia; Masgrau, Roser; Pujol, Aurora; Galea, Elena

    2016-05-01

    The clinical challenge in acute injury as in traumatic brain injury (TBI) is to halt the delayed neuronal loss that occurs hours and days after the insult. Here we report that the activation of CREB-dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI. The study was performed in a novel bitransgenic mouse in which a constitutively active CREB, VP16-CREB, was targeted to astrocytes with the Tet-Off system. Using histochemistry, qPCR, and gene profiling we found less neuronal death and damage, reduced macrophage infiltration, preserved mitochondria, and rescued expression of genes related to mitochondrial metabolism in bitransgenic mice as compared to wild type littermates. Finally, with meta-analyses using publicly available databases we identified a core set of VP16-CREB candidate target genes that may account for the neuroprotective effect. Enhancing CREB activity in astrocytes thus emerges as a novel avenue in acute brain post-injury therapeutics.

  12. A pathology-based substrate for target definition in radiosurgery of brain metastases

    SciTech Connect

    Baumert, Brigitta G. . E-mail: brigitta.baumert@maastro.nl; Rutten, Isabelle; Dehing-Oberije, Cary M.Sc.; Twijnstra, Albert; Dirx, Miranda J.M.; Debougnoux-Huppertz, Ria M.T.L.; Lambin, Philippe; Kubat, Bela

    2006-09-01

    Purpose: To investigate the need of a margin other than for accuracy reasons in stereotactic radiosurgery (SRS) of brain metastases by means of histopathology. Methods and Materials: Evaluation of 45 patients from two pathology departments having had brain metastases and an autopsy of the brain. Growth patterns were reviewed with a focus on infiltration beyond the metastases boundary and made visible with immunohistochemical staining: the metastasis itself with tumor-specific markers, surrounding normal brain tissue with a glial marker, and a possible capsule with a soft tissue marker. Measurements were corrected by a tissue-shrinkage correction factor taken from literature. Outcomes parameters for infiltration were mean and maximum depths of infiltration and number of measured infiltration sites. Results: In 48 of 76 metastases, an infiltration was present. The largest group of metastases was lung cancer. Small-cell lung cancer (SCLC) and melanoma showed a maximum depth of infiltration of {>=}1 mm, and other histologies <1 mm. For non-small-cell lung cancer (NSCLC), melanoma, and sarcoma, the highest number of infiltrative sites were observed (median, 2; range, 1-8). SCLC showed significantly larger infiltrative growth, compared with other diagnostic groups. In NSCLC, the highest percentage of infiltration was present (70%). Conclusions: Infiltrative growth beyond the border of the brain metastasis was demonstrated in 63% of the cases evaluated. Infiltrative growth, therefore, has an impact in defining the clinical target volume for SRS of brain metastases, and a margin of {approx}1 mm should be added to the visible lesion.

  13. Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease.

    PubMed

    Spetter, Maartje S; Hallschmid, Manfred

    2015-08-03

    Central nervous system control of metabolic function relies on the input of endocrine messengers from the periphery, including the pancreatic hormone insulin and the adipokine leptin. This concept primarily derives from experiments in animals where substances can be directly applied to the brain. A feasible approach to study the impact of peptidergic messengers on brain function in humans is the intranasal (IN) route of administration, which bypasses the blood-brain barrier and delivers neuropeptides to the brain compartment, but induces considerably less, if any, peripheral uptake than other administration modes. Experimental IN insulin administration has been extensively used to delineate the role of brain insulin signaling in the control of energy homeostasis, but also cognitive function in healthy humans. Clinical pilot studies have found beneficial effects of IN insulin in patients with memory deficits, suggesting that the IN delivery of this and other peptides bears some promise for new, selectively brain-targeted pharmaceutical approaches in the treatment of metabolic and cognitive disorders. More recently, experiments relying on the IN delivery of the hypothalamic hormone oxytocin, which is primarily known for its involvement in psychosocial processes, have provided evidence that oxytocin influences metabolic control in humans. The IN administration of leptin has been successfully tested in animal models but remains to be investigated in the human setting. We briefly summarize the literature on the IN administration of insulin, leptin, and oxytocin, with a particular focus on metabolic effects, and address limitations and perspectives of IN neuropeptide administration.

  14. DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors.

    PubMed

    Sin-Chan, Patrick; Huang, Annie

    2014-10-01

    Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.

  15. Theranostic liposomes loaded with quantum dots and apomorphine for brain targeting and bioimaging.

    PubMed

    Wen, Chih-Jen; Zhang, Li-Wen; Al-Suwayeh, Saleh A; Yen, Tzu-Chen; Fang, Jia-You

    2012-01-01

    Quantum dots (QDs) and apomorphine were incorporated into liposomes to eliminate uptake by the liver and enhance brain targeting. We describe the preparation, physicochemical characterization, in vivo bioimaging, and brain endothelial cell uptake of the theranostic liposomes. QDs and the drug were mainly located in the bilayer membrane and inner core of the liposomes, respectively. Spherical vesicles with a mean diameter of ~140 nm were formed. QDs were completely encapsulated by the vesicles. Nearly 80% encapsulation percentage was achieved for apomorphine. A greater fluorescence intensity was observed in mouse brains treated with liposomes compared to free QDs. This result was further confirmed by ex vivo imaging of the organs. QD uptake by the heart and liver was reduced by liposomal incorporation. Apomorphine accumulation in the brain increased by 2.4-fold after this incorporation. According to a hyperspectral imaging analysis, multifunctional liposomes but not the aqueous solution carried QDs into the brain. Liposomes were observed to have been efficiently endocytosed into bEND3 cells. The mechanisms involved in the cellular uptake were clathrin- and caveola-mediated endocytosis, which were energy-dependent. To the best of our knowledge, our group is the first to develop liposomes with a QD-drug hybrid for the aim of imaging and treating brain disorders.

  16. Intranasal administration of carbamazepine to mice: a direct delivery pathway for brain targeting.

    PubMed

    Serralheiro, Ana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2014-08-18

    The currently available antiepileptic drugs are typically administered via oral or intravenous (IV) routes which commonly exhibit high systemic distribution into non-targeted tissues, leading to peripheral adverse effects and limited brain uptake. In order to improve the efficacy and tolerability of the antiepileptic drug therapy, alternative administration strategies have been investigated. The purpose of the present study was to assess the pharmacokinetics of carbamazepine administered via intranasal (IN) and IV routes to mice, and to investigate whether a direct transport of the drug from nose to brain could be involved. The similar pharmacokinetic profiles obtained in all matrices following both administration routes indicate that, after IN delivery, carbamazepine reaches quickly and extensively the bloodstream, achieving the brain predominantly via systemic circulation. However, the uneven biodistribution of carbamazepine through the brain regions with higher concentrations in the olfactory bulb and frontal cortex following IN instillation, in comparison with the homogenous brain distribution pattern after IV injection, strongly suggests the involvement of a direct transport of carbamazepine from nose to brain. Therefore, it seems that IN delivery represents a suitable and promising alternative route to administer carbamazepine not only for the chronically use of the drug but also in emergency conditions.

  17. Multimodality treatment of brain metastases from renal cell carcinoma in the era of targeted therapy

    PubMed Central

    Bassanelli, Maria; Viterbo, Antonella; Roberto, Michela; Giacinti, Silvana; Staddon, Anita; Aschelter, Anna Maria; D’Antonio, Chiara; Marchetti, Paolo

    2016-01-01

    In patients with renal cancer, brain metastasis is associated with poor survival and high morbidity. Poor life expectancy is often associated with widespread extracranial metastases. In such patients, a multidisciplinary approach is paramount. Brain metastases-specific therapies may include surgery, radiosurgery, conventional radiation and targeted therapies (TT) or a combination of these treatments. Some factors are important prognostically when choosing the best strategy: performance status, the number, size and location of brain metastases, the extension of systemic metastases and a well-controlled primary tumour. Failure of chemical therapy has always been attributed to an intact blood–brain barrier and acquired drug resistance by renal cancer cells. Recent studies have demonstrated objective responses with TT in a variety of cancer types, including renal cancer. In most cases, these agents have been used in combination and in conjunction with whole-brain radiation therapy and radiosurgery. Local control appears to be better with the combined method if the patient has a good performance status and may improve overall survival. This review summarizes current literature data on multidisciplinary approach in the management of renal brain metastasis with radiation, surgery and TT with an emphasis on potential better outcomes with a combination of current treatment methods. PMID:27800033

  18. The impact of microglial activation on blood-brain barrier in brain diseases

    PubMed Central

    da Fonseca, Anna Carolina Carvalho; Matias, Diana; Garcia, Celina; Amaral, Rackele; Geraldo, Luiz Henrique; Freitas, Catarina; Lima, Flavia Regina Souza

    2014-01-01

    The blood-brain barrier (BBB), constituted by an extensive network of endothelial cells (ECs) together with neurons and glial cells, including microglia, forms the neurovascular unit (NVU). The crosstalk between these cells guarantees a proper environment for brain function. In this context, changes in the endothelium-microglia interactions are associated with a variety of inflammation-related diseases in brain, where BBB permeability is compromised. Increasing evidences indicate that activated microglia modulate expression of tight junctions, which are essential for BBB integrity and function. On the other hand, the endothelium can regulate the state of microglial activation. Here, we review recent advances that provide insights into interactions between the microglia and the vascular system in brain diseases such as infectious/inflammatory diseases, epilepsy, ischemic stroke and neurodegenerative disorders. PMID:25404894

  19. Antisense-Mediated RNA Targeting: Versatile and Expedient Genetic Manipulation in the Brain

    PubMed Central

    Zalachoras, Ioannis; Evers, Melvin M.; van Roon-Mom, Willeke M. C.; Aartsma-Rus, Annemieke M.; Meijer, Onno C.

    2011-01-01

    A limiting factor in brain research still is the difficulty to evaluate in vivo the role of the increasing number of proteins implicated in neuronal processes. We discuss here the potential of antisense-mediated RNA targeting approaches. We mainly focus on those that manipulate splicing (exon skipping and exon inclusion), but will also briefly discuss mRNA targeting. Classic knockdown of expression by mRNA targeting is only one possible application of antisense oligonucleotides (AON) in the control of gene function. Exon skipping and inclusion are based on the interference of AONs with splicing of pre-mRNAs. These are powerful, specific and particularly versatile techniques, which can be used to circumvent pathogenic mutations, shift splice variant expression, knock down proteins, or to create molecular models using in-frame deletions. Pre-mRNA targeting is currently used both as a research tool, e.g., in models for motor neuron disease, and in clinical trials for Duchenne muscular dystrophy and amyotrophic lateral sclerosis. AONs are particularly promising in relation to brain research, as the modified AONs are taken up extremely fast in neurons and glial cells with a long residence, and without the need for viral vectors or other delivery tools, once inside the blood brain barrier. In this review we cover (1). The principles of antisense-mediated techniques, chemistry, and efficacy. (2) The pros and cons of AON approaches in the brain compared to other techniques of interfering with gene function, such as transgenesis and short hairpin RNAs, in terms of specificity of the manipulation, spatial, and temporal control over gene expression, toxicity, and delivery issues. (3) The potential applications for Neuroscience. We conclude that there is good evidence from animal studies that the central nervous system can be successfully targeted, but the potential of the diverse AON-based approaches appears to be under-recognized. PMID:21811437

  20. Quantitative imaging of protein targets in the human brain with PET

    NASA Astrophysics Data System (ADS)

    Gunn, Roger N.; Slifstein, Mark; Searle, Graham E.; Price, Julie C.

    2015-11-01

    PET imaging of proteins in the human brain with high affinity radiolabelled molecules has a history stretching back over 30 years. During this period the portfolio of protein targets that can be imaged has increased significantly through successes in radioligand discovery and development. This portfolio now spans six major categories of proteins; G-protein coupled receptors, membrane transporters, ligand gated ion channels, enzymes, misfolded proteins and tryptophan-rich sensory proteins. In parallel to these achievements in radiochemical sciences there have also been significant advances in the quantitative analysis and interpretation of the imaging data including the development of methods for image registration, image segmentation, tracer compartmental modeling, reference tissue kinetic analysis and partial volume correction. In this review, we analyze the activity of the field around each of the protein targets in order to give a perspective on the historical focus and the possible future trajectory of the field. The important neurobiology and pharmacology is introduced for each of the six protein classes and we present established radioligands for each that have successfully transitioned to quantitative imaging in humans. We present a standard quantitative analysis workflow for these radioligands which takes the dynamic PET data, associated blood and anatomical MRI data as the inputs to a series of image processing and bio-mathematical modeling steps before outputting the outcome measure of interest on either a regional or parametric image basis. The quantitative outcome measures are then used in a range of different imaging studies including tracer discovery and development studies, cross sectional studies, classification studies, intervention studies and longitudinal studies. Finally we consider some of the confounds, challenges and subtleties that arise in practice when trying to quantify and interpret PET neuroimaging data including motion artifacts

  1. Targeting of deep-brain structures in nonhuman primates using MR and CT Images

    NASA Astrophysics Data System (ADS)

    Chen, Antong; Hines, Catherine; Dogdas, Belma; Bone, Ashleigh; Lodge, Kenneth; O'Malley, Stacey; Connolly, Brett; Winkelmann, Christopher T.; Bagchi, Ansuman; Lubbers, Laura S.; Uslaner, Jason M.; Johnson, Colena; Renger, John; Zariwala, Hatim A.

    2015-03-01

    In vivo gene delivery in central nervous systems of nonhuman primates (NHP) is an important approach for gene therapy and animal model development of human disease. To achieve a more accurate delivery of genetic probes, precise stereotactic targeting of brain structures is required. However, even with assistance from multi-modality 3D imaging techniques (e.g. MR and CT), the precision of targeting is often challenging due to difficulties in identification of deep brain structures, e.g. the striatum which consists of multiple substructures, and the nucleus basalis of meynert (NBM), which often lack clear boundaries to supporting anatomical landmarks. Here we demonstrate a 3D-image-based intracranial stereotactic approach applied toward reproducible intracranial targeting of bilateral NBM and striatum of rhesus. For the targeting we discuss the feasibility of an atlas-based automatic approach. Delineated originally on a high resolution 3D histology-MR atlas set, the NBM and the striatum could be located on the MR image of a rhesus subject through affine and nonrigid registrations. The atlas-based targeting of NBM was compared with the targeting conducted manually by an experienced neuroscientist. Based on the targeting, the trajectories and entry points for delivering the genetic probes to the targets could be established on the CT images of the subject after rigid registration. The accuracy of the targeting was assessed quantitatively by comparison between NBM locations obtained automatically and manually, and finally demonstrated qualitatively via post mortem analysis of slices that had been labelled via Evan Blue infusion and immunohistochemistry.

  2. Intraspinal Rewiring of the Corticospinal Tract Requires Target-Derived Brain-Derived Neurotrophic Factor and Compensates Lost Function after Brain Injury

    ERIC Educational Resources Information Center

    Ueno, Masaki; Hayano, Yasufumi; Nakagawa, Hiroshi; Yamashita, Toshihide

    2012-01-01

    Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery…

  3. Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

    PubMed Central

    Ibi, Daisuke; Yamada, Kiyofumi

    2015-01-01

    Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders. PMID:26633355

  4. Telomerase activity in human brain tumors: astrocytoma and meningioma.

    PubMed

    Kheirollahi, Majid; Mehrazin, Masoud; Kamalian, Naser; Mohammadi-asl, Javad; Mehdipour, Parvin

    2013-05-01

    Somatic cells do not have telomerase activity but immortalized cell lines and more than 85 % of the cancer cells show telomerase activation to prevent the telomere from progressive shortening. The activation of this enzyme has been found in a variety of human tumors and tumor-derived cell lines, but only few studies on telomerase activity in human brain tumors have been reported. Here, we evaluated telomerase activity in different grades of human astrocytoma and meningioma brain tumors. In this study, assay for telomerase activity performed on 50 eligible cases consisted of 26 meningioma, 24 astrocytoma according to the standard protocols. In the brain tissues, telomerase activity was positive in 39 (65 %) of 50 patients. One sample t test showed that the telomerase activity in meningioma and astrocytoma tumors was significantly positive entirely (P < 0.001). Also, grade I of meningioma and low grades of astrocytoma (grades I and II) significantly showed telomerase activity. According to our results, we suggest that activation of telomerase is an event that starts mostly at low grades of brain including meningioma and astrocytoma tumors.

  5. Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis*

    PubMed Central

    Hu, Zhongdong; Wang, Ying; Huang, Fuqiang; Chen, Rongrong; Li, Chunjia; Wang, Fang; Goto, June; Kwiatkowski, David J.; Wdzieczak-Bakala, Joanna; Tu, Pengfei; Liu, Jianmiao; Zha, Xiaojun; Zhang, Hongbing

    2015-01-01

    Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistic target of rapamycin (mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressed X-linked 2 (BEX2) is a novel downstream effector of mTOR. Elevated BEX2 in Tsc2−/− mouse embryonic fibroblasts, Pten−/− mouse embryonic fibroblasts, Tsc2-deficient rat uterine leiomyoma cells, and brains of neuronal specific Tsc1 knock-out mice were abolished by mTOR inhibitor rapamycin. Furthermore, BEX2 was also increased in the liver of a hepatic specific Pten knock-out mouse and the kidneys of Tsc2 heterozygous deletion mice, and a patient with tuberous sclerosis complex (TSC). mTOR up-regulation of BEX2 was mediated in parallel by both STAT3 and NF-κB. BEX2 was involved in mTOR up-regulation of VEGF production and angiogenesis. Depletion of BEX2 blunted the tumorigenesis of cells with activated mTOR. Therefore, enhanced STAT3/NF-κB-BEX2-VEGF signaling pathway contributes to hyperactive mTOR-induced tumorigenesis. BEX2 may be targeted for the treatment of the cancers with aberrantly activated mTOR signaling pathway. PMID:26296882

  6. Brain oxidative stress as basic target of antioxidant traditional oriental medicines.

    PubMed

    Konishi, Tetsuya

    2009-04-01

    Prevention and amelioration of Mibyou (sub-healthy condition) is the critical target for disease prevention including age-related diseases and cancer although the Mibyou condition is not yet pathologically defined. Since the oxidative stress is an underlying basic etiology associated with many diseases and aging, the psychologically induced oxidative stress, especially in the brain was supposed as one of the pathology of Mibyou. Several traditional herbal prescriptions applied for the brain disorder were found effective to prevent cerebral oxidative stress induced by ischemia/reperfusion and also under psychological distress produced by whiskers cut in mice. Shengmai San comprising three herbs, Panax ginseng, Ophiopogon japonicus and Schisandra chinensis is a traditional herbal medicine formula having a long history of using as a remedy and clinical prescription to treat coronal heart diseases. Multifunctional aspect of traditional herbal prescription was discussed in terms of preventing oxidative injury in the brain using Shengmai San as a typical prescription.

  7. Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies.

    PubMed

    Loureiro, Joana A; Gomes, Bárbara; Coelho, Manuel A N; do Carmo Pereira, Maria; Rocha, Sandra

    2014-04-01

    Development of therapeutics for brain disorders is one of the more difficult challenges to be overcome by the scientific community due to the inability of most molecules to cross the blood-brain barrier (BBB). Antibody-conjugated nanoparticles are drug carriers that can be used to target encapsulated drugs to the brain endothelial cells and have proven to be very promising. They significantly improve the accumulation of the drug in pathological sites and decrease the undesirable side effect of drugs in healthy tissues. We review the systems that have demonstrated promising results in crossing the BBB through receptor-mediated endocytic mechanisms for the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

  8. Targeted drug delivery across the blood–brain barrier using ultrasound technique

    PubMed Central

    Deng, Cheri X

    2011-01-01

    Effective delivery of therapeutic agents into the brain can greatly improve the treatments of neurological and neurodegenerative diseases. Application of focused ultrasound facilitated by microbubbles has shown the potential to deliver drugs across the blood–brain barrier into targeted sites within the brain noninvasively. This review provides a summary of the technological background and principle, highlights of recent significant developments and research progress, as well as a critical commentary on the challenges and future directions in the field. This review also outlines and discusses the tasks that researchers face in order to successfully translate the technology into a clinical reality, including obtaining improved understanding of the mechanisms, demonstration of therapeutic efficacy and safety for specific applications, and development of methodology for rational design to achieve optimized and consistent outcome. PMID:21785679

  9. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier.

    PubMed

    Burgess, Alison; Ayala-Grosso, Carlos A; Ganguly, Milan; Jordão, Jessica F; Aubert, Isabelle; Hynynen, Kullervo

    2011-01-01

    Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation.

  10. Physical Activity Affects Brain Integrity in HIV + Individuals

    PubMed Central

    Ortega, Mario; Baker, Laurie M.; Vaida, Florin; Paul, Robert; Basco, Brian; Ances, Beau M.

    2015-01-01

    Prior research has suggested benefits of aerobic physical activity (PA) on cognition and brain volumes in HIV uninfected (HIV−) individuals, however, few studies have explored the relationships between PA and brain integrity (cognition and structural brain volumes) in HIV-infected (HIV +) individuals. Seventy HIV + individuals underwent neuropsychological testing, structural neuroimaging, laboratory tests, and completed a PA questionnaire, recalling participation in walking, running, and jogging activities over the last year. A PA engagement score of weekly metabolic equivalent (MET) hr of activity was calculated using a compendium of PAs. HIV + individuals were classified as physically active (any energy expended above resting expenditure, n = 22) or sedentary (n = 48). Comparisons of neuropsychological performance, grouped by executive and motor domains, and brain volumes were completed between groups. Physically active and sedentary HIV + individuals had similar demographic and laboratory values, but the active group had higher education (14.0 vs. 12.6 years, p = .034). Physically active HIV + individuals performed better on executive (p = .040, unadjusted; p = .043, adjusted) but not motor function (p = .17). In addition, among the physically active group the amount of physical activity (METs) positively correlated with executive (Pearson’s r = 0.45, p = 0.035) but not motor (r = 0.21; p = .35) performance. In adjusted analyses the physically active HIV + individuals had larger putamen volumes (p = .019). A positive relationship exists between PA and brain integrity in HIV + individuals. Results from the present study emphasize the importance to conduct longitudinal interventional investigation to determine if PA improves brain integrity in HIV + individuals. PMID:26581799

  11. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair.

    PubMed

    Lecca, Davide; Trincavelli, Maria Letizia; Gelosa, Paolo; Sironi, Luigi; Ciana, Paolo; Fumagalli, Marta; Villa, Giovanni; Verderio, Claudia; Grumelli, Carlotta; Guerrini, Uliano; Tremoli, Elena; Rosa, Patrizia; Cuboni, Serena; Martini, Claudia; Buffo, Annalisa; Cimino, Mauro; Abbracchio, Maria P

    2008-01-01

    expression of myelin basic protein, confirming progression toward mature oligodendrocytes. Thus, GPR17 may act as a "sensor" that is activated upon brain injury on several embryonically distinct cell types, and may play a key role in both inducing neuronal death inside the ischemic core and in orchestrating the local remodeling/repair response. Specifically, we suggest GPR17 as a novel target for therapeutic manipulation to foster repair of demyelinating wounds, the types of lesions that also occur in patients with multiple sclerosis.

  12. In vivo recordings of brain activity using organic transistors

    PubMed Central

    Khodagholy, Dion; Doublet, Thomas; Quilichini, Pascale; Gurfinkel, Moshe; Leleux, Pierre; Ghestem, Antoine; Ismailova, Esma; Hervé, Thierry; Sanaur, Sébastien; Bernard, Christophe; Malliaras, George G.

    2013-01-01

    In vivo electrophysiological recordings of neuronal circuits are necessary for diagnostic purposes and for brain-machine interfaces. Organic electronic devices constitute a promising candidate because of their mechanical flexibility and biocompatibility. Here we demonstrate the engineering of an organic electrochemical transistor embedded in an ultrathin organic film designed to record electrophysiological signals on the surface of the brain. The device, tested in vivo on epileptiform discharges, displayed superior signal-to-noise ratio due to local amplification compared with surface electrodes. The organic transistor was able to record on the surface low-amplitude brain activities, which were poorly resolved with surface electrodes. This study introduces a new class of biocompatible, highly flexible devices for recording brain activity with superior signal-to-noise ratio that hold great promise for medical applications. PMID:23481383

  13. Human brain activity with functional NIR optical imager

    NASA Astrophysics Data System (ADS)

    Luo, Qingming

    2001-08-01

    In this paper we reviewed the applications of functional near infrared optical imager in human brain activity. Optical imaging results of brain activity, including memory for new association, emotional thinking, mental arithmetic, pattern recognition ' where's Waldo?, occipital cortex in visual stimulation, and motor cortex in finger tapping, are demonstrated. It is shown that the NIR optical method opens up new fields of study of the human population, in adults under conditions of simulated or real stress that may have important effects upon functional performance. It makes practical and affordable for large populations the complex technology of measuring brain function. It is portable and low cost. In cognitive tasks subjects could report orally. The temporal resolution could be millisecond or less in theory. NIR method will have good prospects in exploring human brain secret.

  14. Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer's disease.

    PubMed

    Muntimadugu, Eameema; Dhommati, Raju; Jain, Anjali; Challa, Venu Gopala Swami; Shaheen, M; Khan, Wahid

    2016-09-20

    Poor brain penetration of tarenflurbil (TFB) was one of the major reasons for its failure in phase III clinical trials conducted on Alzheimer's patients. Thus there is a tremendous need of developing efficient delivery systems for TFB. This study was designed with the aim of improving drug delivery to brain through intranasally delivered nanocarriers. TFB was loaded into two different nanocarriers i.e., poly (lactide-co-glycolide) nanoparticles (TFB-NPs) and solid lipid nanoparticles (TFB-SLNs). Particle size of both the nanocarriers (<200nm) as determined by dynamic light scattering technique and transmission electron microscopy, assured transcellular transport across olfactory axons whose diameter was ≈200nm and then paving a direct path to brain. TFB-NPs and TFB-SLNs resulted in 64.11±2.21% and 57.81±5.32% entrapment efficiencies respectively which again asserted protection of drug from chemical and biological degradation in nasal cavity. In vitro release studies proved the sustained release of TFB from TFB-NPs and TFB-SLNs in comparison with pure drug, indicating prolonged residence times of drug at targeting site. Pharmacokinetics suggested improved circulation behavior of nanoparticles and the absolute bioavailabilities followed this order: TFB-NPs (i.n.)>TFB-SLNs (i.n.)>TFB solution (i.n.)>TFB suspension (oral). Brain targeting efficiency was determined in terms of %drug targeting efficiency (%DTE) and drug transport percentage (DTP). The higher %DTE (287.24) and DTP (65.18) were observed for TFB-NPs followed by TFB-SLNs (%DTE: 183.15 and DTP: 45.41) among all other tested groups. These encouraging results proved that therapeutic concentrations of TFB could be transported directly to brain via olfactory pathway after intranasal administration of polymeric and lipidic nanoparticles.

  15. Telomerase Activity is Downregulated Early During Human Brain Development

    PubMed Central

    Ishaq, Abbas; Hanson, Peter S.; Morris, Christopher M.; Saretzki, Gabriele

    2016-01-01

    Changes in hTERT splice variant expression have been proposed to facilitate the decrease of telomerase activity during fetal development in various human tissues. Here, we analyzed the expression of telomerase RNA (hTR), wild type and α-spliced hTERT in developing human fetal brain (post conception weeks, pcw, 6–19) and in young and old cortices using qPCR and correlated it to telomerase activity measured by TRAP assay. Decrease of telomerase activity occurred early during brain development and correlated strongest to decreased hTR expression. The expression of α-spliced hTERT increased between pcw 10 and 19, while that of wild type hTERT remained unchanged. Lack of expression differences between young and old cortices suggests that most changes seem to occur early during human brain development. Using in vitro differentiation of neural precursor stem cells (NPSCs) derived at pcw 6 we found a decrease in telomerase activity but no major expression changes in telomerase associated genes. Thus, they do not seem to model the mechanisms for the decrease in telomerase activity in fetal brains. Our results suggest that decreased hTR levels, as well as transient increase in α-spliced hTERT, might both contribute to downregulation of telomerase activity during early human brain development between 6 and 17 pcw. PMID:27322326

  16. Experiments and models of cortical oscillations as a target for noninvasive brain stimulation.

    PubMed

    Fröhlich, Flavio

    2015-01-01

    Noninvasive brain stimulation is attracting substantial attention due to its potential for safe and effective modulation of brain network dynamics. Promising applications include cognitive enhancement and treatment of disorders of the central nervous system. Recently, targeting of cortical oscillations by brain stimulation with periodic electromagnetic waveforms has emerged as a particularly appealing approach for understanding the causal role of cortical oscillations in human cognition and behavior. Two main approaches exist: repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS); rTMS is more widely used as a research and clinical tool but only recently has it been suggested to selectively engage frequency-matched cortical oscillations. In contrast, tACS is an offspring of transcranial direct current stimulation and has been introduced with the specific aim of engaging cortical oscillations. One of the main lessons that the field of noninvasive brain stimulation has learned over the last few years is that without a mechanistic understanding of how stimulation engages neuronal circuits, little progress can be made toward the rational design of individualized, adaptive stimulation treatments. Computer simulations of cellular and network models from the field of computational neuroscience are a key tool to gain such a mechanistic understanding. However, the insights gained from such modeling strategies can only be fully leveraged when used in tight conjunction with experimental approaches in both human and animal model studies. Here, I provide an in-depth review of the pioneering experimental and computational studies that together provide the basis for understanding how periodic noninvasive brain stimulation targets cortical oscillations to enable the rational design of brain stimulation treatments for disorders associated with specific deficits in cortical oscillations.

  17. Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage

    PubMed Central

    Okada, Takeshi; Suzuki, Hidenori

    2017-01-01

    Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and Toll-like receptor (TLR) 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor (NF)-κB signaling among TLR4 signaling pathways as to the development of early brain injury (EBI) such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κB and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

  18. Daily Physical Activity Is Associated with Subcortical Brain Volume and Cognition in Heart Failure.

    PubMed

    Alosco, Michael L; Brickman, Adam M; Spitznagel, Mary Beth; Sweet, Lawrence H; Josephson, Richard; Griffith, Erica Y; Narkhede, Atul; Hughes, Joel; Gunstad, John

    2015-11-01

    Cognitive impairment in heart failure (HF) is believed to in part stem from structural brain alterations, including shrinkage of subcortical regions. Fortunately, neurocognitive dysfunction in HF can be mitigated by physical activity (PA), though mechanisms for this phenomenon are unclear. PA is protective against age-related cognitive decline that may involve improved structural integrity to brain regions sensitive to aging (e.g., subcortical structures). Yet, no study has examined the benefits of PA on the brain in HF and we sought to do so and clarify related cognitive implications. Fifty older adults with HF completed a neuropsychological battery and wore an accelerometer for 7 days. All participants underwent brain MRI. This study targeted subcortical brain volume given subcortical alterations are often observed in HF and the sensitivity of PA to subcortical structures in other patient populations. Participants averaged 4348.49 (SD=2092.08) steps per day and greater daily steps predicted better attention/executive function, episodic memory, and language abilities, p's<.05. Medical and demographically adjusted regression analyses revealed higher daily steps per day predicted greater subcortical volume, with specific effects for the thalamus and ventral diencephalon, p's<.05. Greater subcortical volume was associated with better attention/executive function, p<.05. Higher daily PA was associated with increased subcortical brain volume and better cognition in older adults with HF. Longitudinal work is needed to clarify whether daily PA can attenuate brain atrophy in HF to reduce accelerated cognitive decline in this population.

  19. Targeted gene delivery in the cricket brain, using in vivo electroporation.

    PubMed

    Matsumoto, Chihiro Sato; Shidara, Hisashi; Matsuda, Koji; Nakamura, Taro; Mito, Taro; Matsumoto, Yukihisa; Oka, Kotaro; Ogawa, Hiroto

    2013-12-01

    The cricket (Gryllus bimaculatus) is a hemimetabolous insect that is emerging as a model organism for the study of neural and molecular mechanisms of behavioral traits. However, research strategies have been limited by a lack of genetic manipulation techniques that target the nervous system of the cricket. The development of a new method for efficient gene delivery into cricket brains, using in vivo electroporation, is described here. Plasmid DNA, which contained an enhanced green fluorescent protein (eGFP) gene, under the control of a G. bimaculatus actin (Gb'-act) promoter, was injected into adult cricket brains. Injection was followed by electroporation at a sufficient voltage. Expression of eGFP was observed within the brain tissue. Localized gene expression, targeted to specific regions of the brain, was also achieved using a combination of local DNA injection and fine arrangement of the electroporation electrodes. Further studies using this technique will lead to a better understanding of the neural and molecular mechanisms that underlie cricket behaviors.

  20. NFL-lipid nanocapsules for brain neural stem cell targeting in vitro and in vivo.

    PubMed

    Carradori, Dario; Saulnier, Patrick; Préat, Véronique; des Rieux, Anne; Eyer, Joel

    2016-09-28

    The replacement of injured neurons by the selective stimulation of neural stem cells in situ represents a potential therapeutic strategy for the treatment of neurodegenerative diseases. The peptide NFL-TBS.40-63 showed specific interactions towards neural stem cells of the subventricular zone. The aim of our work was to produce a NFL-based drug delivery system able to target neural stem cells through the selective affinity between the peptide and these cells. NFL-TBS.40-63 (NFL) was adsorbed on lipid nanocapsules (LNC) whom targeting efficiency was evaluated on neural stem cells from the subventricular zone (brain) and from the central canal (spinal cord). NFL-LNC were incubated with primary neural stem cells in vitro or injected in vivo in adult rat brain (right lateral ventricle) or spinal cord (T10). NFL-LNC interactions with neural stem cells were different depending on the origin of the cells. NFL-LNC showed a preferential uptake by neural stem cells from the brain, while they did not interact with neural stem cells from the spinal cord. The results obtained in vivo correlate with the results observed in vitro, demonstrating that NFL-LNC represent a promising therapeutic strategy to selectively deliver bioactive molecules to brain neural stem cells.

  1. The slowed brain: cortical oscillatory activity in hepatic encephalopathy.

    PubMed

    Butz, Markus; May, Elisabeth S; Häussinger, Dieter; Schnitzler, Alfons

    2013-08-15

    Oscillatory activity of the human brain has received growing interest as a key mechanism of large-scale integration across different brain regions. Besides a crucial role of oscillatory activity in the emergence of other neurological and psychiatric diseases, recent evidence indicates a key role in the pathophysiology of hepatic encephalopathy (HE). This review summarizes the current knowledge on pathological alterations of oscillatory brain activity in association with liver dysfunction and HE in the context of spontaneous brain activity, motor symptoms, sensory processing, and attention. The existing literature demonstrates a prominent slowing of the frequency of oscillatory activity as shown for spontaneous brain activity at rest, with respect to deficits of motor behavior and motor symptoms, and in the context of visual attention processes. The observed slowing extends across different subsystems of the brain and has been confirmed across different frequency bands, providing evidence for ubiquitous changes of oscillatory activity in HE. For example, the frequency of cortico-muscular coherence in HE patients appears at the frequency of the mini-asterixis (⩽12Hz), while cirrhotics without overt signs of HE show coherence similar to healthy subjects, i.e. at 13-30Hz. Interestingly, the so-called critical flicker frequency (CFF) as a measure of the processing of an oscillating visual stimulus has emerged as a useful tool to quantify HE disease severity, correlating with behavioral and neurophysiological alterations. Moreover, the CFF reliably distinguishes patients with manifest HE from cirrhotics without any signs of HE and healthy controls using a cut-off frequency of 39Hz. In conclusion, oscillatory activity is globally slowed in HE in close association with HE symptoms and disease severity. Although the underlying causal mechanisms are not yet understood, these results indicate that pathological changes of oscillatory activity play an important role in the

  2. Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

    PubMed Central

    Chauvier, D; Renolleau, S; Holifanjaniaina, S; Ankri, S; Bezault, M; Schwendimann, L; Rousset, C; Casimir, R; Hoebeke, J; Smirnova, M; Debret, G; Trichet, A-P; Carlsson, Y; Wang, X; Bernard, E; Hébert, M; Rauzier, J-M; Matecki, S; Lacampagne, A; Rustin, P; Mariani, J; Hagberg, H; Gressens, P; Charriaut-Marlangue, C; Jacotot, E

    2011-01-01

    Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia–ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns. PMID:21881605

  3. Targeting Neural Endophenotypes of Eating Disorders with Non-invasive Brain Stimulation

    PubMed Central

    Dunlop, Katharine A.; Woodside, Blake; Downar, Jonathan

    2016-01-01

    The term “eating disorders” (ED) encompasses a wide variety of disordered eating and compensatory behaviors, and so the term is associated with considerable clinical and phenotypic heterogeneity. This heterogeneity makes optimizing treatment techniques difficult. One class of treatments is non-invasive brain stimulation (NIBS). NIBS, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), are accessible forms of neuromodulation that alter the cortical excitability of a target brain region. It is crucial for NIBS to be successful that the target is well selected for the patient population in question. Targets may best be selected by stepping back from conventional DSM-5 diagnostic criteria to identify neural substrates of more basic phenotypes, including behavior related to rewards and punishment, cognitive control, and social processes. These phenotypic dimensions have been recently laid out by the Research Domain Criteria (RDoC) initiative. Consequently, this review is intended to identify potential dimensions as outlined by the RDoC and the underlying behavioral and neurobiological targets associated with ED. This review will also identify candidate targets for NIBS based on these dimensions and review the available literature on rTMS and tDCS in ED. This review systematically reviews abnormal neural circuitry in ED within the RDoC framework, and also systematically reviews the available literature investigating NIBS as a treatment for ED. PMID:26909013

  4. Guidelines to PET measurements of the target occupancy in the brain for drug development.

    PubMed

    Takano, Akihiro; Varrone, Andrea; Gulyás, Balázs; Salvadori, Piero; Gee, Antony; Windhorst, Albert; Vercouillie, Johnny; Bormans, Guy; Lammertsma, Adriaan A; Halldin, Christer

    2016-11-01

    This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.

  5. Fluorescence microscopy studies of a peripheral-benzodiazepine-receptor-targeted molecular probe for brain tumor imaging

    NASA Astrophysics Data System (ADS)

    Marcu, Laura; Vernier, P. Thomas; Manning, H. Charles; Salemi, Sarah; Li, Aimin; Craft, Cheryl M.; Gundersen, Martin A.; Bornhop, Darryl J.

    2003-10-01

    This study investigates the potential of a new multi-modal lanthanide chelate complex for specifically targeting brain tumor cells. We report here results from ongoing studies of up-take, sub-cellular localization and binding specificity of this new molecular imaging probe. Fluorescence microscopy investigations in living rat C6 glioma tumor cells demonstrate that the new imaging agent has affinity for glioma cells and binds to mitochondria.

  6. In Pursuit of Delay-Related Brain Activity for Anticipatory Eye Movements

    PubMed Central

    Burke, Melanie R.; Barnes, Graham R.

    2013-01-01

    How the brain stores motion information and subsequently uses it to follow a moving target is largely unknown. This is mainly due to previous fMRI studies using paradigms in which the eye movements cannot be segregated from the storage of this motion information. To avoid this problem we used a novel paradigm designed in our lab in which we interlaced a delay (2, 4 or 6 seconds) between the 1st and 2nd presentation of a moving stimulus. Using this design we could examine brain activity during a delay period using fMRI and have subsequently found a number of brain areas that reveal sustained activity during predictive pursuit. These areas include, the V5 complex and superior parietal lobe. This study provides new evidence for the network involved in the storage of visual information to generate early motor responses in pursuit. PMID:24039911

  7. Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain.

    PubMed

    Lerchner, W; Corgiat, B; Der Minassian, V; Saunders, R C; Richmond, B J

    2014-03-01

    We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno-associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)- rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly.

  8. Synchronous brain activity across individuals underlies shared psychological perspectives

    PubMed Central

    Lahnakoski, Juha M.; Glerean, Enrico; Jääskeläinen, Iiro P.; Hyönä, Jukka; Hari, Riitta; Sams, Mikko; Nummenmaa, Lauri

    2014-01-01

    For successful communication, we need to understand the external world consistently with others. This task requires sufficiently similar cognitive schemas or psychological perspectives that act as filters to guide the selection, interpretation and storage of sensory information, perceptual objects and events. Here we show that when individuals adopt a similar psychological perspective during natural viewing, their brain activity becomes synchronized in specific brain regions. We measured brain activity with functional magnetic resonance imaging (fMRI) from 33 healthy participants who viewed a 10-min movie twice, assuming once a ‘social’ (detective) and once a ‘non-social’ (interior decorator) perspective to the movie events. Pearson's correlation coefficient was used to derive multisubject voxelwise similarity measures (inter-subject correlations; ISCs) of functional MRI data. We used k-nearest-neighbor and support vector machine classifiers as well as a Mantel test on the ISC matrices to reveal brain areas wherein ISC predicted the participants' current perspective. ISC was stronger in several brain regions—most robustly in the parahippocampal gyrus, posterior parietal cortex and lateral occipital cortex—when the participants viewed the movie with similar rather than different perspectives. Synchronization was not explained by differences in visual sampling of the movies, as estimated by eye gaze. We propose that synchronous brain activity across individuals adopting similar psychological perspectives could be an important neural mechanism supporting shared understanding of the environment. PMID:24936687

  9. Altered Resting-State Brain Activity in Obstructive Sleep Apnea

    PubMed Central

    Zhang, Quan; Wang, Dawei; Qin, Wen; Li, Qiong; Chen, Baoyuan; Zhang, Yunting; Yu, Chunshui

    2013-01-01

    Study Objectives: Structural and functional brain changes may contribute to neural dysfunction in patients with obstructive sleep apnea (OSA). However, the effect of OSA on resting-state brain activity has not been established. The objective of this study was to investigate alterations in resting-state functional connectivity (rsFC) of the common brain networks in patients with OSA and their relationships with changes in gray matter volume (GMV) in the corresponding brain regions. Designs: Resting-state functional and structural MRI data were acquired from patients with OSA and healthy controls. Seven brain networks were identified by independent component analysis. The rsFC in each network was compared between groups and the GMV of brain regions with significant differences in rsFC was also compared. Setting: University hospital. Patients and Participants: Twenty-four male patients with untreated OSA and 21 matched healthy controls. Interventions: N/A. Measurements and Results: OSA specifically affected the cognitive and sensorimotor-related brain networks but not the visual and auditory networks. The medial prefrontal cortex and left dorsolateral prefrontal cortex (DLPFC) showed decreased rsFC and GMV in patients with OSA, suggesting structural and functional deficits. The right DLPFC and left precentral gyrus showed decreased rsFC and unchanged GMV, suggesting a functional deficit. The right posterior cingulate cortex demonstrated increased rsFC and unchanged GMV, suggesting functional compensation. In patients with OSA, the rsFC of the right DLPFC was negatively correlated with the apnea-hypopnea index. Conclusions: OSA specifically affects resting-state functional connectivity in cognitive and sensorimotor-related brain networks, which may be related to the impaired cognitive and motor functions in these patients. Citation: Zhang Q; Wang D; Qin W; Li Q; Chen B; Zhang Y; Yu C. Altered resting-state brain activity in obstructive sleep apnea. SLEEP 2013

  10. Targeting Transporters: Promoting Blood-Brain Barrier Repair in Response to Oxidative Stress Injury

    PubMed Central

    Ronaldson, Patrick T.; Davis, Thomas P.

    2015-01-01

    The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., endogenous transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. PMID:25796436

  11. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

    PubMed

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-06-10

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

  12. Combined strategies of apomorphine diester prodrugs and nanostructured lipid carriers for efficient brain targeting

    NASA Astrophysics Data System (ADS)

    Liu, Kuo-Sheng; Wen, Chih-Jen; Yen, Tzu-Chen; Sung, K. C.; Ku, Ming-Chuan; Wang, Jhi-Joung; Fang, Jia-You

    2012-03-01

    Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

  13. Improved spatial targeting with directionally segmented deep brain stimulation leads for treating essential tremor

    NASA Astrophysics Data System (ADS)

    Keane, Maureen; Deyo, Steve; Abosch, Aviva; Bajwa, Jawad A.; Johnson, Matthew D.

    2012-08-01

    Deep brain stimulation (DBS) in the ventral intermediate nucleus of thalamus (Vim) is known to exert a therapeutic effect on postural and kinetic tremor in patients with essential tremor (ET). For DBS leads implanted near the caudal border of Vim, however, there is an increased likelihood that one will also induce paresthesia side-effects by stimulating neurons within the sensory pathway of the ventral caudal (Vc) nucleus of thalamus. The aim of this computational study was to (1) investigate the neuronal pathways modulated by therapeutic, sub-therapeutic and paresthesia-inducing DBS settings in three patients with ET and (2) determine how much better an outcome could have been achieved had these patients been implanted with a DBS lead containing directionally segmented electrodes (dDBS). Multi-compartment neuron models of the thalamocortical, cerebellothalamic and medial lemniscal pathways were first simulated in the context of patient-specific anatomies, lead placements and programming parameters from three ET patients who had been implanted with Medtronic 3389 DBS leads. The models showed that in these patients, complete suppression of tremor was associated most closely with activating an average of 62% of the cerebellothalamic afferent input into Vim (n = 10), while persistent paresthesias were associated with activating 35% of the medial lemniscal tract input into Vc thalamus (n = 12). The dDBS lead design demonstrated superior targeting of the cerebello-thalamo-cortical pathway, especially in cases of misaligned DBS leads. Given the close proximity of Vim to Vc thalamus, the models suggest that dDBS will enable clinicians to more effectively sculpt current through and around thalamus in order to achieve a more consistent therapeutic effect without inducing side-effects.

  14. Brain acetycholinesterase activity in botulism-intoxicated mallards

    USGS Publications Warehouse

    Rocke, T.E.; Samuel, M.D.

    1991-01-01

    Brain acetylcholinesterase (AChE) activity in captive-reared mallards (Anas platyrhynchos) that died of botulism was compared with euthanized controls. AChE levels for both groups were within the range reported for normal mallards, and there was no significant difference in mean AChE activity between birds that ingested botulism toxin and died and those that did not.

  15. Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke?

    PubMed Central

    Leng, Tiandong; Shi, Yejie; Xiong, Zhi-Gang; Sun, Dandan

    2014-01-01

    Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na+/H+ exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H+-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca2+, Na+, and Zn2+, and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention. PMID:24467911

  16. Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption.

    PubMed

    Huang, Qin; Deng, Jinmu; Wang, Feng; Chen, Song; Liu, Yingjiang; Wang, Zhibiao; Wang, Zhigang; Cheng, Yuan

    2012-01-01

    This study aimed to investigate the feasibility of targeted gene transfer into central nervous system (CNS) by MRI-guided focused ultrasound-induced blood-brain barrier (BBB) disruption. Before each sonication, T2-weighted images were obtained to select the target region. Followed by injecting DNA-loaded microbubbles into the tail vein, sonication was performed. The state of local BBB, distribution of plasmid DNA through the opened BBB, the ultrastructural changes of neurons and BDNF expression were detected. The results showed that MRI-guided focused ultrasound (FUS) could accomplish noninvasive, transient, and local BBB disruption, at 1h after sonication, plasmid DNA across the opened BBB had been internalized into the neurons presenting heterogeneous distribution and numerous transparent vesicles were observed in the cytoplasm of the neurons at the sonicated region, suggesting vesicle-mediated endocytosis. At 48 h after sonication, the expressions of exogenous gene pBDNF-EGFP were observed in the cytoplasm of some neurons, and BDNF expressions were markedly enhanced by the combination of ultrasound and pBDNF-EGFP-loaded microbubbles about 20-fold than that of the control group (P<0.01). The method by using MRI-guided FUS to induce the local BBB disruption could accomplish effective targeted exogenous gene transfer in CNS. This technique may provide a new option for the treatment of various CNS diseases.

  17. Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression.

    PubMed

    Haque, Shadabul; Md, Shadab; Sahni, Jasjeet Kaur; Ali, Javed; Baboota, Sanjula

    2014-01-01

    The purpose of the present study was to investigate the potential of Venlafaxine loaded alginate nanoparticles (VLF AG-NPs) for treatment of depression via intranasal (i.n.) nose to brain delivery route. The VLF AG-NPs were prepared and optimized on the basis of various physio-chemical characteristics. Pharmacodynamic studies of the VLF AG-NPs for antidepressant activity were carried in-vivo by forced swimming test and locomotor activity test on albino Wistar rats. VLF AG-NPsi.n. treatment significantly improved the behavioural analysis parameters i.e. swimming, climbing, and immobility in comparison to the VLF solutioni.n. and VLF tabletoral. The intranasal VLF AG-NPs also improved locomotor activity when compared with VLF solutioni.n. and VLF tabletoral. Confocal laser scanning fluorescence microscopy studies were performed on isolated organs of rats after intravenous and intranasal administrations of Rodamine-123 loaded alginate nanoparticles to determine its efficacy for nose to brain delivery and also for its qualitative distribution to other organs. Brain uptake and pharmacokinetic studies were performed by determination of VLF concentration in blood and brain respectively for VLF AG-NPsi.n., VLF solutioni.n. and VLF solutioni.v. The greater brain/blood ratios for VLF AG-NPsi.n. in comparison to VLF solutioni.n. and VLF solutioni.v. respectively at 30 min are indicative of superiority of alginate nanoparticles for direct nose to brain transport of VLF. Thus, VLF AG-NPsi.n. delivered greater VLF to the brain in comparison to VLF solution which indicates that VLF AG-NPs could be a promising approach for the treatment of depression.

  18. Optogenetic activation of superior colliculus neurons suppresses seizures originating in diverse brain networks

    PubMed Central

    Soper, Colin; Wicker, Evan; Kulick, Catherine V.; N’Gouemo, Prosper; Forcelli, Patrick A.

    2016-01-01

    Because sites of seizure origin may be unknown or multifocal, identifying targets from which activation can suppress seizures originating in diverse networks is essential. We evaluated the ability of optogenetic activation of the deep/intermediate layers of the superior colliculus (DLSC) to fill this role. Optogenetic activation of DLSC suppressed behavioral and electrographic seizures in the pentylenetetrazole (forebrain+brainstem seizures) and Area Tempestas (forebrain/complex partial seizures) models; this effect was specific to activation of DLSC, and not neighboring structures. DLSC activation likewise attenuated seizures evoked by gamma butyrolactone (thalamocortical/absence seizures), or acoustic stimulation of genetically epilepsy prone rates (brainstem seizures). Anticonvulsant effects were seen with stimulation frequencies as low as 5 Hz. Unlike previous applications of optogenetics for the control of seizures, activation of DLSC exerted broad-spectrum anticonvulsant actions, attenuating seizures originating in diverse and distal brain networks. These data indicate that DLSC is a promising target for optogenetic control of epilepsy. PMID:26721319

  19. Protecting Neural Structures and Cognitive Function During Prolonged Space Flight by Targeting the Brain Derived Neurotrophic Factor Molecular Network

    NASA Technical Reports Server (NTRS)

    Schmidt, M. A.; Goodwin, T. J.

    2014-01-01

    Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth

  20. Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide

    PubMed Central

    Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

    2014-01-01

    Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

  1. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

    NASA Astrophysics Data System (ADS)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  2. Brain network activity in monolingual and bilingual older adults.

    PubMed

    Grady, Cheryl L; Luk, Gigi; Craik, Fergus I M; Bialystok, Ellen

    2015-01-01

    Bilingual older adults typically have better performance on tasks of executive control (EC) than do their monolingual peers, but differences in brain activity due to language experience are not well understood. Based on studies showing a relation between the dynamic range of brain network activity and performance on EC tasks, we hypothesized that life-long bilingual older adults would show increased functional connectivity relative to monolinguals in networks related to EC. We assessed intrinsic functional connectivity and modulation of activity in task vs. fixation periods in two brain networks that are active when EC is engaged, the frontoparietal control network (FPC) and the salience network (SLN). We also examined the default mode network (DMN), which influences behavior through reduced activity during tasks. We found stronger intrinsic functional connectivity in the FPC and DMN in bilinguals than in monolinguals. Although there were no group differences in the modulation of activity across tasks and fixation, bilinguals showed stronger correlations than monolinguals between intrinsic connectivity in the FPC and task-related increases of activity in prefrontal and parietal regions. This bilingual difference in network connectivity suggests that language experience begun in childhood and continued throughout adulthood influences brain networks in ways that may provide benefits in later life.

  3. Brain Network Activity in Monolingual and Bilingual Older Adults

    PubMed Central

    Grady, Cheryl L.; Luk, Gigi; Craik, Fergus I.M.; Bialystok, Ellen

    2016-01-01

    Bilingual older adults typically have better performance on tasks of executive control (EC) than do their monolingual peers, but differences in brain activity due to language experience are not well understood. Based on studies showing a relation between the dynamic range of brain network activity and performance on EC tasks, we hypothesized that life-long bilingual older adults would show increased functional connectivity relative to monolinguals in networks related to EC. We assessed intrinsic functional connectivity and modulation of activity in task vs. fixation periods in two brain networks that are active when EC is engaged, the frontoparietal control network (FPC) and the salience network (SLN). We also examined the default mode network (DMN), which influences behavior through reduced activity during tasks. We found stronger intrinsic functional connectivity in the FPC and DMN in bilinguals than in monolinguals. Although there were no group differences in the modulation of activity across tasks and fixation, bilinguals showed stronger correlations than monolinguals between intrinsic connectivity in the FPC and task-related increases of activity in prefrontal and parietal regions. This bilingual difference in network connectivity suggests that language experience begun in childhood and continued throughout adulthood influences brain networks in ways that may provide benefits in later life. PMID:25445783

  4. An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting: The importance of selective blood-brain barrier uptake.

    PubMed

    Bode, Gerard H; Coué, Gregory; Freese, Christian; Pickl, Karin E; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C; Tziveleka, Leto-Aikaterini; Sideratou, Zili; Engbersen, Johan F J; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J G; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M; Kirkpatrick, C James; Steinbusch, Harry W M; Frank, Hans-Georg; Unger, Ronald E; Martinez-Martinez, Pilar

    2016-11-21

    Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood-brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial barriers shows great potential as a therapeutic strategy in a wide variety of diseases. Functionalizing nanoparticles with peptides allows for more efficient targeting to specific organs. We have evaluated the hemocompatibilty, cytotoxicity, endothelial uptake, efficacy of delivery and safety of liposome, hyperbranched polyester, poly(glycidol) and acrylamide-based nanoparticles functionalized with peptides targeting brain endothelial receptors, in vitro and in vivo. We used an ELISA-based method for the detection of nanoparticles in biological fluids, investigating the blood clearance rate and in vivo biodistribution of labeled nanoparticles in the brain after intravenous injection in Wistar rats. Herein, we provide a detailed report of in vitro and in vivo observations.

  5. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route.

    PubMed

    Jain, Darshana S; Bajaj, Amrita N; Athawale, Rajani B; Shikhande, Shruti S; Pandey, Abhijeet; Goel, Peeyush N; Gude, Rajiv P; Patil, Satish; Raut, Preeti

    2016-06-01

    Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB). PLA nanoparticles were developed using solvent evaporation technique. The developed nanoparticles were further dispersed in prepared thermosensitive vehicle of poloxamer 188 and Carbopol 934 to impart the property of increased residence time. The formulated nanoparticles demonstrated no interaction with the simulated nasal fluids (SNF), mucin, serum proteins and erythrocytes which demonstrate the safety of developed formulation for nasal administration. The penetration property of nanoparticles though the nasal mucosa was higher than the pure drug due to low mucociliary clearance. The developed nanoparticles diffused though the membrane pores and rapidly distributed into the brain portions compared to the pure drug. There was detectable and quantifiable amount of drug seen in the brain as demonstrated by in vivo brain distribution studies with considerably low amount of drug deposition in the lungs. The pharmacokinetic parameters demonstrated the enhancement in circulation half life, area under curve (AUC) and Cmax of the drug when administered intranasal in encapsulated form. Thus, the thermosensitive nanodispersions are surely promising delivery systems for delivering anticancer agents though the nasal route for potential treatment of brain tumors.

  6. Brain Hyperglycemia Induced by Heroin: Association with Metabolic Neural Activation.

    PubMed

    Solis, Ernesto; Bola, R Aaron; Fasulo, Bradley J; Kiyatkin, Eugene A

    2017-02-15

    Glucose enters the brain extracellular space from arterial blood, and its proper delivery is essential for metabolic activity of brain cells. By using enzyme-based biosensors coupled with high-speed amperometry in freely moving rats, we previously showed that glucose levels in the nucleus accumbens (NAc) display high variability, increasing rapidly following exposure to various arousing stimuli. In this study, the same technology was used to assess NAc glucose fluctuations induced by intravenous heroin. Heroin passively injected at a low dose optimal for maintaining self-administration behavior (100 μg/kg) induces a rapid but moderate glucose rise (∼150-200 μM or ∼15-25% over resting baseline). When the heroin dose was doubled and tripled, the increase became progressively larger in magnitude and longer in duration. Heroin-induced glucose increases also occurred in other brain structures (medial thalamus, lateral striatum, hippocampus), suggesting that brain hyperglycemia is a whole-brain phenomenon but changes were notably distinct in each structure. While local vasodilation appears to be the possible mechanism underlying the rapid rise in extracellular glucose levels, the driving factor for this vasodilation (central vs peripheral) remains to be clarified. The heroin-induced NAc glucose increases positively correlated with increases in intracerebral heat production determined in separate experiments using multisite temperature recordings (NAc, temporal muscle and skin). However, glucose levels rise very rapidly, preceding much slower increases in brain heat production, a measure of metabolic activation associated with glucose consumption.

  7. Spontaneous brain activity predicts learning ability of foreign sounds.

    PubMed

    Ventura-Campos, Noelia; Sanjuán, Ana; González, Julio; Palomar-García, María-Ángeles; Rodríguez-Pujadas, Aina; Sebastián-Gallés, Núria; Deco, Gustavo; Ávila, César

    2013-05-29

    Can learning capacity of the human brain be predicted from initial spontaneous functional connectivity (FC) between brain areas involved in a task? We combined task-related functional magnetic resonance imaging (fMRI) and resting-state fMRI (rs-fMRI) before and after training with a Hindi dental-retroflex nonnative contrast. Previous fMRI results were replicated, demonstrating that this learning recruited the left insula/frontal operculum and the left superior parietal lobe, among other areas of the brain. Crucially, resting-state FC (rs-FC) between these two areas at pretraining predicted individual differences in learning outcomes after distributed (Experiment 1) and intensive training (Experiment 2). Furthermore, this rs-FC was reduced at posttraining, a change that may also account for learning. Finally, resting-state network analyses showed that the mechanism underlying this reduction of rs-FC was mainly a transfer in intrinsic activity of the left frontal operculum/anterior insula from the left frontoparietal network to the salience network. Thus, rs-FC may contribute to predict learning ability and to understand how learning modifies the functioning of the brain. The discovery of this correspondence between initial spontaneous brain activity in task-related areas and posttraining performance opens new avenues to find predictors of learning capacities in the brain using task-related fMRI and rs-fMRI combined.

  8. Individual Variability in Brain Activity: A Nuisance or an Opportunity?

    PubMed

    Van Horn, John Darrell; Grafton, Scott T; Miller, Michael B

    2008-12-01

    Functional imaging research has been heavily influenced by results based on population-level inference. However, group average results may belie the unique patterns of activity present in the individual that ordinarily are considered random noise. Recent advances in the evolution of MRI hardware have led to significant improvements in the stability and reproducibility of blood oxygen level dependent (BOLD) measurements. These enhancements provide a unique opportunity for closer examination of individual patterns of brain activity. Three objectives can be accomplished by considering brain scans at the individual level; (1) Mapping functional anatomy at a fine grained analysis; (2) Determining if an individual scan is normative with respect to a reference population; and (3) Understanding the sources of intersubject variability in brain activity. In this review, we detail these objectives, briefly discuss their histories and present recent trends in the analyses of individual variability. Finally, we emphasize the unique opportunities and challenges for understanding individual differences through international collaboration among Pacific Rim investigators.

  9. Brain electrical activity analysis using wavelet-based informational tools

    NASA Astrophysics Data System (ADS)

    Rosso, O. A.; Martin, M. T.; Plastino, A.

    2002-10-01

    The traditional way of analyzing brain electrical activity, on the basis of Electroencephalography (EEG) records, relies mainly on visual inspection and years of training. Although it is quite useful, of course, one has to acknowledge its subjective nature that hardly allows for a systematic protocol. In order to overcome this undesirable feature, a quantitative EEG analysis has been developed over the years that introduces objective measures, reflecting not only the characteristics of the brain activity itself but also giving clues concerning the underlying associated neural dynamics. The processing of information by the brain is reflected in dynamical changes of the electrical activity in (i) time, (ii) frequency, and (iii) space. Therefore, the concomitant studies require methods capable of describing the qualitative variation of the signal in both time and frequency. In the present work we introduce new information tools based on the wavelet transform for the assessment of EEG data as adapted to a non-extensive scenario.

  10. Listening to humans walking together activates the social brain circuitry.

    PubMed

    Saarela, Miiamaaria V; Hari, Riitta

    2008-01-01

    Human footsteps carry a vast amount of social information, which is often unconsciously noted. Using functional magnetic resonance imaging, we analyzed brain networks activated by footstep sounds of one or two persons walking. Listening to two persons walking together activated brain areas previously associated with affective states and social interaction, such as the subcallosal gyrus bilaterally, the right temporal pole, and the right amygdala. These areas seem to be involved in the analysis of persons' identity and complex social stimuli on the basis of auditory cues. Single footsteps activated only the biological motion area in the posterior STS region. Thus, hearing two persons walking together involved a more widespread brain network than did hearing footsteps from a single person.

  11. Developmental changes in infant brain activity during naturalistic social experiences.

    PubMed

    Jones, Emily J H; Venema, Kaitlin; Lowy, Rachel; Earl, Rachel K; Webb, Sara Jane

    2015-11-01

    Between 6 and 12 months, typically developing infants undergo a socio-cognitive "revolution." The Interactive Specialization (IS) theory of brain development predicts that these behavioral changes will be underpinned by developmental increases in the power and topographic extent of socially selective cortical responses. To test this hypothesis, we used EEG to examine developmental changes in cortical selectivity for ecologically valid dynamic social versus non-social stimuli in a large cohort of 6- and 12-month-old infants. Consistent with the Interactive Specialization model, results showed that differences in EEG Θ activity between social and non-social stimuli became more pronounced and widespread with age. Differences in EEG activity were most clearly elicited by a live naturalistic interaction, suggesting that measuring brain activity in ecologically valid contexts is central to mapping social brain development in infancy.

  12. Brain feminization requires active repression of masculinization via DNA methylation

    PubMed Central

    Nugent, Bridget M.; Wright, Christopher L.; Shetty, Amol C.; Hodes, Georgia E.; Lenz, Kathryn M.; Mahurkar, Anup; Russo, Scott J.; Devine, Scott E.; McCarthy, Margaret M.

    2015-01-01

    The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually-dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression. Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in females. Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice. RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females. Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation. PMID:25821913

  13. Impaired Brain Creatine Kinase Activity in Huntington's Disease

    PubMed Central

    Zhang, S.F.; Hennessey, T.; Yang, L.; Starkova, N.N.; Beal, M.F.; Starkov, A.A.

    2011-01-01

    Background Huntington's disease (HD) is associated with impaired energy metabolism in the brain. Creatine kinase (CK) catalyzes ATP-dependent phosphorylation of creatine (Cr) into phosphocreatine (PCr), thereby serving as readily available high-capacity spatial and temporal ATP buffering. Objective: Substantial evidence supports a specific role of the Cr/PCr system in neurodegenerative diseases. In the brain, the Cr/PCr ATP-buffering system is established by a concerted operation of the brain-specific cytosolic enzyme BB-CK and ubiquitous mitochondrial uMt-CK. It is not yet established whether the activity of these CK isoenzymes is impaired in HD. Methods We measured PCr, Cr, ATP and ADP in brain extracts of 3 mouse models of HD – R6/2 mice, N171-82Q and HdhQ111 mice – and the activity of CK in cytosolic and mitochondrial brain fractions from the same mice. Results The PCr was significantly increased in mouse HD brain extracts as compared to nontransgenic littermates. We also found an approximately 27% decrease in CK activity in both cytosolic and mitochondrial fractions of R6/2 and N171-82Q mice, and an approximately 25% decrease in the mitochondria from HdhQ111 mice. Moreover, uMt-CK and BB-CK activities were approximately 63% lower in HD human brain samples as compared to nondiseased controls. Conclusion Our findings lend strong support to the role of impaired energy metabolism in HD, and point out the potential importance of impairment of the CK-catalyzed ATP-buffering system in the etiology of HD. PMID:21124007

  14. Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting.

    PubMed

    Mahajan, Hitendra S; Mahajan, Milind S; Nerkar, Pankaj P; Agrawal, Anshuman

    2014-03-01

    The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

  15. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms

    PubMed Central

    Lim, L W; Prickaerts, J; Huguet, G; Kadar, E; Hartung, H; Sharp, T; Temel, Y

    2015-01-01

    Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN. PMID:25826110

  16. Inferring brain-computational mechanisms with models of activity measurements

    PubMed Central

    Diedrichsen, Jörn

    2016-01-01

    High-resolution functional imaging is providing increasingly rich measurements of brain activity in animals and humans. A major challenge is to leverage such data to gain insight into the brain's computational mechanisms. The first step is to define candidate brain-computational models (BCMs) that can perform the behavioural task in question. We would then like to infer which of the candidate BCMs best accounts for measured brain-activity data. Here we describe a method that complements each BCM by a measurement model (MM), which simulates the way the brain-activity measurements reflect neuronal activity (e.g. local averaging in functional magnetic resonance imaging (fMRI) voxels or sparse sampling in array recordings). The resulting generative model (BCM-MM) produces simulated measurements. To avoid having to fit the MM to predict each individual measurement channel of the brain-activity data, we compare the measured and predicted data at the level of summary statistics. We describe a novel particular implementation of this approach, called probabilistic representational similarity analysis (pRSA) with MMs, which uses representational dissimilarity matrices (RDMs) as the summary statistics. We validate this method by simulations of fMRI measurements (locally averaging voxels) based on a deep convolutional neural network for visual object recognition. Results indicate that the way the measurements sample the activity patterns strongly affects the apparent representational dissimilarities. However, modelling of the measurement process can account for these effects, and different BCMs remain distinguishable even under substantial noise. The pRSA method enables us to perform Bayesian inference on the set of BCMs and to recognize the data-generating model in each case. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’. PMID:27574316

  17. Getting the beat: entrainment of brain activity by musical rhythm and pleasantness.

    PubMed

    Trost, Wiebke; Frühholz, Sascha; Schön, Daniele; Labbé, Carolina; Pichon, Swann; Grandjean, Didier; Vuilleumier, Patrik

    2014-12-01

    Rhythmic entrainment is an important component of emotion induction by music, but brain circuits recruited during spontaneous entrainment of attention by music and the influence of the subjective emotional feelings evoked by music remain still largely unresolved. In this study we used fMRI to test whether the metric structure of music entrains brain activity and how music pleasantness influences such entrainment. Participants listened to piano music while performing a speeded visuomotor detection task in which targets appeared time-locked to either strong or weak beats. Each musical piece was presented in both a consonant/pleasant and dissonant/unpleasant version. Consonant music facilitated target detection and targets presented synchronously with strong beats were detected faster. FMRI showed increased activation of bilateral caudate nucleus when responding on strong beats, whereas consonance enhanced activity in attentional networks. Meter and consonance selectively interacted in the caudate nucleus, with greater meter effects during dissonant than consonant music. These results reveal that the basal ganglia, involved both in emotion and rhythm processing, critically contribute to rhythmic entrainment of subcortical brain circuits by music.

  18. Quantitative analysis of axonal fiber activation evoked by deep brain stimulation via activation density heat maps

    PubMed Central

    Hartmann, Christian J.; Chaturvedi, Ashutosh; Lujan, J. Luis

    2015-01-01

    Background: Cortical modulation is likely to be involved in the various therapeutic effects of deep brain stimulation (DBS). However, it is currently difficult to predict the changes of cortical modulation during clinical adjustment of DBS. Therefore, we present a novel quantitative approach to estimate anatomical regions of DBS-evoked cortical modulation. Methods: Four different models of the subthalamic nucleus (STN) DBS were created to represent variable electrode placements (model I: dorsal border of the posterolateral STN; model II: central posterolateral STN; model III: central anteromedial STN; model IV: dorsal border of the anteromedial STN). Axonal fibers of passage near each electrode location were reconstructed using probabilistic tractography and modeled using multi-compartment cable models. Stimulation-evoked activation of local axon fibers and corresponding cortical projections were modeled and quantified. Results: Stimulation at the border of the STN (models I and IV) led to a higher degree of fiber activation and associated cortical modulation than stimulation deeply inside the STN (models II and III). A posterolateral target (models I and II) was highly connected to cortical areas representing motor function. Additionally, model I was also associated with strong activation of fibers projecting to the cerebellum. Finally, models III and IV showed a dorsoventral difference of preferentially targeted prefrontal areas (models III: middle frontal gyrus; model IV: inferior frontal gyrus). Discussion: The method described herein allows characterization of cortical modulation across different electrode placements and stimulation parameters. Furthermore, knowledge of anatomical distribution of stimulation-evoked activation targeting cortical regions may help predict efficacy and potential side effects, and therefore can be used to improve the therapeutic effectiveness of individual adjustments in DBS patients. PMID:25713510

  19. Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.

    PubMed

    Arvanitis, Costas D; Vykhodtseva, Natalia; Jolesz, Ferenc; Livingstone, Margaret; McDannold, Nathan

    2016-05-01

    OBJECT Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an emerging noninvasive alternative to surgery and radiosurgery that is undergoing testing for tumor ablation and functional neurosurgery. The method is currently limited to central brain targets due to skull heating and other factors. An alternative ablative approach combines very low intensity ultrasound bursts and an intravenously administered microbubble agent to locally destroy the vasculature. The objective of this work was to investigate whether it is feasible to use this approach at deep brain targets near the skull base in nonhuman primates. METHODS In 4 rhesus macaques, targets near the skull base were ablated using a clinical TcMRgFUS system operating at 220 kHz. Low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes in conjunction with the ultrasound contrast agent Definity, which was administered as a bolus injection or continuous infusion. The acoustic power level was set to be near the inertial cavitation threshold, which was measured using passive monitoring of the acoustic emissions. The resulting tissue effects were investigated with MRI and with histological analysis performed 3 hours to 1 week after sonication. RESULTS Thirteen targets were sonicated in regions next to the optic tract in the 4 animals. Inertial cavitation, indicated by broadband acoustic emissions, occurred at acoustic pressure amplitudes ranging from 340 to 540 kPa. MRI analysis suggested that the lesions had a central region containing red blood cell extravasations that was surrounded by edema. Blood-brain barrier disruption was observed on contrast-enhanced MRI in the lesions and in a surrounding region corresponding to the prefocal area of the FUS system. In histology, lesions consisting of tissue undergoing ischemic necrosis were found in all regions that were sonicated above the inertial cavitation threshold. Tissue damage in prefocal areas was found in several cases, suggesting that in

  20. Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

    PubMed Central

    Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

    2016-01-01

    The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

  1. On a Mathematical Model of Brain Activities

    SciTech Connect

    Fichtner, K.-H.; Fichtner, L.; Freudenberg, W.; Ohya, M.

    2007-12-03

    The procedure of recognition can be described as follows: There is a set of complex signals stored in the memory. Choosing one of these signals may be interpreted as generating a hypothesis concerning an 'expexted view of the world'. Then the brain compares a signal arising from our senses with the signal chosen from the memory leading to a change of the state of both signals. Furthermore, measurements of that procedure like EEG or MEG are based on the fact that recognition of signals causes a certain loss of excited neurons, i.e. the neurons change their state from 'excited' to 'nonexcited'. For that reason a statistical model of the recognition process should reflect both--the change of the signals and the loss of excited neurons. A first attempt to explain the process of recognition in terms of quantum statistics was given. In the present note it is not possible to present this approach in detail. In lieu we will sketch roughly a few of the basic ideas and structures of the proposed model of the recognition process (Section). Further, we introduce the basic spaces and justify the choice of spaces used in this approach. A more elaborate presentation including all proofs will be given in a series of some forthcoming papers. In this series also the procedures of creation of signals from the memory, amplification, accumulation and transformation of input signals, and measurements like EEG and MEG will be treated in detail.

  2. Adolescent brain activation: dependence on sex, dietary satiation, and restraint.

    PubMed

    Varley-Campbell, Joanna L; Fulford, Jonathan; Moore, Melanie S; Williams, Craig A

    2017-03-30

    The study aimed to explore how both sex and dietary restraint impacts brain activation in response to visual food stimuli in young adolescents (12-13 years) under fed and fasted conditions. Food and non-food images were viewed by 15 boys and 14 girls, while functional magnetic resonance images were acquired. The adolescents were either fasted or in a satiated (fed) state following a randomized crossover study design. When satiation state was not considered, girls showed significantly greater brain activity than boys in regions associated with executive function and decision making, working memory, and self-awareness. In contrast, when either fasted or fed states were considered separately, boys showed significantly increased brain activity in regions linked to executive function, self-awareness, and decision making than the girls. When fasted, compared to unrestrained eaters, restrained individuals showed heightened activation in regions connected to executive function and decision making, with areas associated with self-assessment showing increased activity for unrestrained eaters relative to restrained under fed conditions. These findings highlight important differences in adolescent brain activity and support further investigations to gain greater insight into how these differences might evolve with age.

  3. Modulation of the inter-hemispheric asymmetry of motor-related brain activity using brain-computer interfaces.

    PubMed

    Pereira, Michael; Sobolewski, Aleksander; Millan, Jose Del R

    2015-01-01

    Non-invasive brain stimulation has shown promising results in neurorehabilitation for motor-impaired stroke patients, by rebalancing the relative involvement of each hemisphere in movement generation. Similarly, brain-computer interfaces have been used to successfully facilitate movement-related brain activity spared by the infarct. We propose to merge both approaches by using BCI to train stroke patients to rebalance their motor-related brain activity during motor tasks, through the use of online feedback. In this pilot study, we report results showing that some healthy subjects were able to learn to spontaneously up- and/or down-regulate their ipsilateral brain activity during a single session.

  4. Contralateral targeting of the corpus callosum in normal and pathological brain function.

    PubMed

    Fenlon, Laura R; Richards, Linda J

    2015-05-01

    The corpus callosum connects the two cortical hemispheres of the mammalian brain and is susceptible to structural defects during development, which often result in significant neuropsychological dysfunction. To date, such individuals have been studied primarily with regards to the integrity of the callosal tract at the midline. However, the mechanisms regulating the contralateral targeting of the corpus callosum, after midline crossing has occurred, are less well understood. Recent evidence suggests that defects in contralateral targeting can occur in isolation from midline-tract malformations, and may have significant functional implications. We propose that contralateral targeting is a crucially important and relatively under-investigated event in callosal development, and that defects in this process may constitute an undiagnosed phenotype in several neurological disorders.

  5. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target

    PubMed Central

    Huang, Xi; He, Ye; Dubuc, Adrian M.; Hashizume, Rintaro; Zhang, Wei; Reimand, Jüri; Yang, Huanghe; Wang, Tongfei A.; Stehbens, Samantha J.; Younger, Susan; Barshow, Suzanne; Zhu, Sijun; Cooper, Michael K.; Peacock, John; Ramaswamy, Vijay; Garzia, Livia; Wu, Xiaochong; Remke, Marc; Forester, Craig M.; Kim, Charles C.; Weiss, William A.; James, C. David; Shuman, Marc A.; Bader, Gary D.; Mueller, Sabine; Taylor, Michael D.; Jan, Yuh Nung; Jan, Lily Yeh

    2015-01-01

    Over 20% of the drugs for treating human diseases target ion channels, however, no cancer drug approved by the U.S. Food and Drug Administration (FDA) is intended to target an ion channel. Here, we demonstrate the evolutionarily conserved function of EAG2 potassium channel in promoting brain tumor growth and metastasis, delineate downstream pathways and uncover a mechanism for different potassium channels to functionally corporate and regulate mitotic cell volume and tumor progression. We show that EAG2 potassium channel is enriched at the trailing edge of migrating MB cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identify the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings thus illustrate the potential of targeting ion channels in cancer treatment. PMID:26258683

  6. Interactions between occlusion and human brain function activities.

    PubMed

    Ohkubo, C; Morokuma, M; Yoneyama, Y; Matsuda, R; Lee, J S

    2013-02-01

    There are few review articles in the area of human research that focus on the interactions between occlusion and brain function. This systematic review discusses the effect of occlusion on the health of the entire body with a focus on brain function. Available relevant articles in English from 1999 to 2011 were assessed in an online database and as hard copies in libraries. The selected 19 articles were classified into the following five categories: chewing and tongue movements, clenching and grinding, occlusal splints and occlusal interference, prosthetic rehabilitation, and pain and stimulation. The relationships between the brain activity observed in the motor and sensory cortices and movements of the oral and maxillofacial area, such as those produced by gum chewing, tapping and clenching, were investigated. It was found that the sensorimotor cortex was also affected by the placement of the occlusal interference devices, splints and implant prostheses. Brain activity may change depending on the strength of the movements in the oral and maxillofacial area. Therefore, mastication and other movements stimulate the activity in the cerebral cortex and may be helpful in preventing degradation of a brain function. However, these findings must be verified by evidence gathered from more subjects.

  7. What kind of noise is brain noise: anomalous scaling behavior of the resting brain activity fluctuations

    PubMed Central

    Fraiman, Daniel; Chialvo, Dante R.

    2012-01-01

    The study of spontaneous fluctuations of brain activity, often referred as brain noise, is getting increasing attention in functional magnetic resonance imaging (fMRI) studies. Despite important efforts, much of the statistical properties of such fluctuations remain largely unknown. This work scrutinizes these fluctuations looking at specific statistical properties which are relevant to clarify its dynamical origins. Here, three statistical features which clearly differentiate brain data from naive expectations for random processes are uncovered: First, the variance of the fMRI mean signal as a function of the number of averaged voxels remains constant across a wide range of observed clusters sizes. Second, the anomalous behavior of the variance is originated by bursts of synchronized activity across regions, regardless of their widely different sizes. Finally, the correlation length (i.e., the length at which the correlation strength between two regions vanishes) as well as mutual information diverges with the cluster's size considered, such that arbitrarily large clusters exhibit the same collective dynamics than smaller ones. These three properties are known to be exclusive of complex systems exhibiting critical dynamics, where the spatio-temporal dynamics show these peculiar type of fluctuations. Thus, these findings are fully consistent with previous reports of brain critical dynamics, and are relevant for the interpretation of the role of fluctuations and variability in brain function in health and disease. PMID:22934058

  8. Targeted viral delivery of Cre recombinase induces conditional gene deletion in cardiovascular circuits of the mouse brain.

    PubMed

    Sinnayah, Puspha; Lindley, Timothy E; Staber, Patrick D; Davidson, Beverly L; Cassell, Martin D; Davisson, Robin L

    2004-06-17

    The Cre/loxP system has shown promise for investigating genes involved in nervous system function and pathology, although its application for studying central neural regulation of cardiovascular function and disease has not been explored. Here, we report for the first time that recombination of loxP-flanked genes can be achieved in discrete cardiovascular regulatory nuclei of adult mouse brain using targeted delivery of adenovirus (Ad) or feline immunodeficiency virus (FIV) bearing Cre recombinase (Ad-Cre, FIV-Cre). Single stereotaxic microinjections of Ad-Cre or FIV-Cre into specific nuclei along the subfornical organ-hypothalamic-hypophysial and brain stem-parabrachial axes resulted in robust and highly localized gene deletion as early as 7 days and for as long as 3 wk in a reporter mouse model in which Cre recombinase activates beta-galactosidase expression. An even greater selectivity in Cre-mediated gene deletion could be achieved in unique subpopulations of cells, such as vasopressin-synthesizing magnocellular neurons, by delivering Ad-Cre via retrograde transport. Moreover, Ad-Cre and FIV-Cre induced gene recombination in differential cell populations within these cardiovascular nuclei. FIV-Cre infection resulted in LacZ activation selectively in neurons, whereas both neuronal and glial cell types underwent gene recombination upon infection with Ad-Cre. These results establish the feasibility of using a combination of viral and Cre/loxP technologies to target specific cardiovascular nuclei in the brain for conditional gene modification and suggest the potential of this approach for determining the functional role of genes within these sites.

  9. Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells

    PubMed Central

    Mouhieddine, Tarek H.; Nokkari, Amaly; Itani, Muhieddine M.; Chamaa, Farah; Bahmad, Hisham; Monzer, Alissar; El-Merahbi, Rabih; Daoud, Georges; Eid, Assaad; Kobeissy, Firas H.; Abou-Kheir, Wassim

    2015-01-01

    Background: Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence. Methods: Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines. Results: We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment. Conclusion: Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence. PMID:26635517

  10. A silk platform that enables electrophysiology and targeted drug delivery in brain astroglial cells

    PubMed Central

    Benfenati, Valentina; Toffanin, Stefano; Capelli, Raffaella; Camassa, Laura M. A.; Ferroni, Stefano; Kaplan, David L.; Omenetto, Fiorenzo G.; Muccini, Michele; Zamboni, Roberto

    2010-01-01

    Astroglial cell survival and ion channel activity are relevant molecular targets for the mechanistic study of neural cell interactions with biomaterials and/or electronic interfaces. Astrogliosis is the most typical reaction to in-vivo brain implants and needs to be avoided by developing biomaterials that preserve astroglial cell physiological function. This cellular phenomenon is characterized by a proliferative state and altered expression of astroglial potassium (K+) channels. Silk is a natural polymer with potential for new biomedical applications due to its ability to support in vitro growth and differentiation of many cell types. We report on silk interactions with cultured neocortical astroglial cells. Astrocytes survival is similar when plated on silk-coated glass and on poly-D-lysine (PDL), a well-known polyionic substrate used to promote astroglial cell adhesion to glass surfaces. Comparative analyses of whole-cell and single-cell patch-clamp experiments reveal that silk- and PDL-coated cells display depolarized resting membrane potentials (∼ -40 mV), very high input resistance, and low specific conductance, with values similar to those of undifferentiated glial cells. Analysis of K+ channel conductance reveals that silk-astrocytes express large outwardly delayed rectifying K+ current (KDR). The magnitude of KDR in PDL- and silk-coated astrocytes is similar, indicating that silk does not alter the resting K+ current. We also demonstrate that guanosine-(GUO) embedded silk enables the direct modulation of astroglial K+ conductance in vitro. Astrocytes plated on GUO-embedded silk are more hyperpolarized and express inward rectifying K+ conductance (Kir). The K+ inward current increase and this is paralleled by upregulation and membrane-polarization of Kir4.1 protein signal. Collectively these results indicate that silk is a suitable biomaterial platform for the in vitro studies of astroglial ion channel responses and related physiology. PMID:20688390

  11. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

    PubMed

    Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

    2014-12-15

    Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.

  12. Angiogenesis in refractory depression: A possible phenotypic target to avoid the blood brain barrier.

    PubMed

    Yamada, Maki K

    Major depressive syndrome (so-called depression) is a common but serious mental disease that causes low mood. Most patients are treatable, mainly because of high response rates for medicines such as selective serotonin-reuptake inhibitors (SSRIs). However, there are still a considerable number of patients with refractory or drug-resistant depression. On the other hand, recent findings suggest that angiogenesis, i.e., making new blood vessels, could have an important role in the recovery from depressive disorders, at least in part. It has been reported that the brain capillaries are physiologically capable of undergoing angiogenesis upon stimuli such as exercise and SSRIs seem to accelerate brain angiogenesis. Drugs targeting angiogenesis may possibly be another good concept. In addition, the blood brain barrier (BBB), which is a major obstacle for drug development for the central nervous system, would be circumvented. Here I summarize the reports that relate angiogenesis to a cure for major depression and discuss some of the potential molecular targets.

  13. Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

    PubMed

    Boche, Mithila; Pokharkar, Varsha

    2016-05-20

    To evaluate the possibility of improved drug delivery of quetiapine fumarate (QTP), a nanoemulsion system was developed for intranasal delivery. Effects of different HLBs of Emalex LWIS 10, PEG 400 and Transcutol P, as co-surfactants, were studied on isotropic region of pseudoternary-phase diagrams of nanoemulsion system composed of capmul MCM (CPM) as oil phase, Tween 80 as surfactant and water. Phase behaviour, globule size, transmission electron microscope (TEM) photographs and brain-targeting efficiency of quetiapine nanoemulsion were investigated. In vitro dissolution study of optimised nanoemulsion formulation, with mean diameter 144 ± 0.5 nm, showed more than twofold increase in drug release as compared with pure drug. According to results of in vivo tissue distribution study in Wistar rats, intranasal administration of QTP-loaded nanoemulsion had shorter T max compared with that of intravenous administration. Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion. The nanoemulsion system may be a promising strategy for brain-targeted delivery of QTP.

  14. Non-target adjacent stimuli classification improves performance of classical ERP-based brain computer interface

    NASA Astrophysics Data System (ADS)

    Ceballos, G. A.; Hernández, L. F.

    2015-04-01

    Objective. The classical ERP-based speller, or P300 Speller, is one of the most commonly used paradigms in the field of Brain Computer Interfaces (BCI). Several alterations to the visual stimuli presentation system have been developed to avoid unfavorable effects elicited by adjacent stimuli. However, there has been little, if any, regard to useful information contained in responses to adjacent stimuli about spatial location of target symbols. This paper aims to demonstrate that combining the classification of non-target adjacent stimuli with standard classification (target versus non-target) significantly improves classical ERP-based speller efficiency. Approach. Four SWLDA classifiers were trained and combined with the standard classifier: the lower row, upper row, right column and left column classifiers. This new feature extraction procedure and the classification method were carried out on three open databases: the UAM P300 database (Universidad Autonoma Metropolitana, Mexico), BCI competition II (dataset IIb) and BCI competition III (dataset II). Main results. The inclusion of the classification of non-target adjacent stimuli improves target classification in the classical row/column paradigm. A gain in mean single trial classification of 9.6% and an overall improvement of 25% in simulated spelling speed was achieved. Significance. We have provided further evidence that the ERPs produced by adjacent stimuli present discriminable features, which could provide additional information about the spatial location of intended symbols. This work promotes the searching of information on the peripheral stimulation responses to improve the performance of emerging visual ERP-based spellers.

  15. Language modulates brain activity underlying representation of kinship terms.

    PubMed

    Wu, Haiyan; Ge, Yue; Tang, Honghong; Luo, Yue-Jia; Mai, Xiaoqin; Liu, Chao

    2015-12-21

    Kinship terms have been found to be highly diverse across languages. Here we investigated the brain representation of kinship terms in two distinct populations, native Chinese and Caucasian English speakers, with a five-element kinship identification (FEKI) task. The neuroimaging results showed a common extensive frontal and parietal lobe brain activation pattern for different kinship levels for both Chinese and Caucasian English speakers. Furthermore, Chinese speakers had longer reaction times and elicited more fronto-parietal brain networks activation compared to English speakers in level three (e.g., uncle and nephew) and four (e.g., cousin), including an association between the middle frontal gyrus and superior parietal lobe, which might be associated with higher working memory, attention control, and social distance representation load in Chinese kinship system processing. These results contribute to our understanding of the representation of kinship terms in the two languages.

  16. Identification of hematomas in mild traumatic brain injury using an index of quantitative brain electrical activity.

    PubMed

    Prichep, Leslie S; Naunheim, Rosanne; Bazarian, Jeffrey; Mould, W Andrew; Hanley, Daniel

    2015-01-01

    Rapid identification of traumatic intracranial hematomas following closed head injury represents a significant health care need because of the potentially life-threatening risk they present. This study demonstrates the clinical utility of an index of brain electrical activity used to identify intracranial hematomas in traumatic brain injury (TBI) presenting to the emergency department (ED). Brain electrical activity was recorded from a limited montage located on the forehead of 394 closed head injured patients who were referred for CT scans as part of their standard ED assessment. A total of 116 of these patients were found to be CT positive (CT+), of which 46 patients with traumatic intracranial hematomas (CT+) were identified for study. A total of 278 patients were found to be CT negative (CT-) and were used as controls. CT scans were subjected to quantitative measurements of volume of blood and distance of bleed from recording electrodes by blinded independent experts, implementing a validated method for hematoma measurement. Using an algorithm based on brain electrical activity developed on a large independent cohort of TBI patients and controls (TBI-Index), patients were classified as either positive or negative for structural brain injury. Sensitivity to hematomas was found to be 95.7% (95% CI = 85.2, 99.5), specificity was 43.9% (95% CI = 38.0, 49.9). There was no significant relationship between the TBI-Index and distance of the bleed from recording sites (F = 0.044, p = 0.833), or volume of blood measured F = 0.179, p = 0.674). Results of this study are a validation and extension of previously published retrospective findings in an independent population, and provide evidence that a TBI-Index for structural brain injury is a highly sensitive measure for the detection of potentially life-threatening traumatic intracranial hematomas, and could contribute to the rapid, quantitative evaluation and treatment of such patients.

  17. Inferring deep-brain activity from cortical activity using functional near-infrared spectroscopy.

    PubMed

    Liu, Ning; Cui, Xu; Bryant, Daniel M; Glover, Gary H; Reiss, Allan L

    2015-03-01

    Functional near-infrared spectroscopy (fNIRS) is an increasingly popular technology for studying brain function because it is non-invasive, non-irradiating and relatively inexpensive. Further, fNIRS potentially allows measurement of hemodynamic activity with high temporal resolution (milliseconds) and in naturalistic settings. However, in comparison with other imaging modalities, namely fMRI, fNIRS has a significant drawback: limited sensitivity to hemodynamic changes in deep-brain regions. To overcome this limitation, we developed a computational method to infer deep-brain activity using fNIRS measurements of cortical activity. Using simultaneous fNIRS and fMRI, we measured brain activity in 17 participants as they completed three cognitive tasks. A support vector regression (SVR) learning algorithm was used to predict activity in twelve deep-brain regions using information from surface fNIRS measurements. We compared these predictions against actual fMRI-measured activity using Pearson's correlation to quantify prediction performance. To provide a benchmark for comparison, we also used fMRI measurements of cortical activity to infer deep-brain activity. When using fMRI-measured activity from the entire cortex, we were able to predict deep-brain activity in the fusiform cortex with an average correlation coefficient of 0.80 and in all deep-brain regions with an average correlation coefficient of 0.67. The top 15% of predictions using fNIRS signal achieved an accuracy of 0.7. To our knowledge, this study is the first to investigate the feasibility of using cortical activity to infer deep-brain activity. This new method has the potential to extend fNIRS applications in cognitive and clinical neuroscience research.

  18. Active calibration target for bistatic radar cross-section measurements

    NASA Astrophysics Data System (ADS)

    Pienaar, M.; Odendaal, J. W.; Joubert, J.; Cilliers, J. E.; Smit, J. C.

    2016-05-01

    Either passive calibration targets are expensive and complex to manufacture or their bistatic radar cross section (RCS) levels are significantly lower than the monostatic RCS levels of targets such as spheres, dihedral, and trihedral corner reflectors. In this paper the performance of an active calibration target with relative high bistatic RCS values is illustrated as a reference target for bistatic RCS measurements. The reference target is simple to manufacture, operates over a wide frequency range, and can be configured to calibrate all four polarizations (VV, HH, HV, and VH). Bistatic RCS measurements of canonical targets, performed in a controlled environment, are calibrated with the reference target and the results are compared to simulated results using FEKO.

  19. Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS

    PubMed Central

    2014-01-01

    Background Human immunodeficiency virus type 1(HIV-1) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with accompanying neurological deficits. Induction of inflammasomes causes cleavage and release of IL-1β and IL-18, representing pathogenic processes that underlie inflammatory diseases although their contribution HIV-associated brain disease is unknown. Results Investigation of inflammasome-associated genes revealed that IL-1β, IL-18 and caspase-1 were induced in brains of HIV-infected persons and detected in brain microglial cells. HIV-1 infection induced pro-IL-1β in human microglia at 4 hr post-infection with peak IL-1β release at 24 hr, which was accompanied by intracellular ASC translocation and caspase-1 activation. HIV-dependent release of IL-1β from a human macrophage cell line, THP-1, was inhibited by NLRP3 deficiency and high extracellular [K+]. Exposure of microglia to HIV-1 gp120 caused IL-1β production and similarly, HIV-1 envelope pseudotyped viral particles induced IL-1β release, unlike VSV-G pseudotyped particles. Infection of cultured feline macrophages by the related lentivirus, feline immunodeficiency virus (FIV), also resulted in the prompt induction of IL-1β. In vivo FIV infection activated multiple inflammasome-associated genes in microglia, which was accompanied by neuronal loss in cerebral cortex and neurological deficits. Multivariate analyses of data from FIV-infected and uninfected animals disclosed that IL-1β, NLRP3 and caspase-1 expression in cerebral cortex represented key molecular determinants of neurological deficits. Conclusions NLRP3 inflammasome activation was an early and integral aspect of lentivirus infection of microglia, which was associated with lentivirus-induced brain disease. Inflammasome activation in the brain might represent a potential target for therapeutic interventions in HIV/AIDS. PMID:24886384

  20. The relationship between brain cortical activity and brain oxygenation in the prefrontal cortex during hypergravity exposure.

    PubMed

    Smith, Craig; Goswami, Nandu; Robinson, Ryan; von der Wiesche, Melanie; Schneider, Stefan

    2013-04-01

    Artificial gravity has been proposed as a method to counteract the physiological deconditioning of long-duration spaceflight; however, the effects of hypergravity on the central nervous system has had little study. The study aims to investigate whether there is a relationship between prefrontal cortex brain activity and prefrontal cortex oxygenation during exposure to hypergravity. Twelve healthy participants were selected to undergo hypergravity exposure aboard a short-arm human centrifuge. Participants were exposed to hypergravity in the +Gz axis, starting from 0.6 +Gz for women, and 0.8 +Gz for men, and gradually increasing by 0.1 +Gz until the participant showed signs of syncope. Brain cortical activity was measured using electroencephalography (EEG) and localized to the prefrontal cortex using standard low-resolution brain electromagnetic tomography (LORETA). Prefrontal cortex oxygenation was measured using near-infrared spectroscopy (NIRS). A significant increase in prefrontal cortex activity (P < 0.05) was observed during hypergravity exposure compared with baseline. Prefrontal cortex oxygenation was significantly decreased during hypergravity exposure, with a decrease in oxyhemoglobin levels (P < 0.05) compared with baseline and an increase in deoxyhemoglobin levels (P < 0.05) with increasing +Gz level. No significant correlation was found between prefrontal cortex activity and oxy-/deoxyhemoglobin. It is concluded that the increase in prefrontal cortex activity observed during hypergravity was most likely not the result of increased +Gz values resulting in a decreased oxygenation produced through hypergravity exposure. No significant relationship between prefrontal cortex activity and oxygenation measured by NIRS concludes that brain activity during exposure to hypergravity may be difficult to measure using NIRS. Instead, the increase in prefrontal cortex activity might be attributable to psychological stress, which could pose a problem for the use of a

  1. Targeted Delivery of Drugs to Brain Tumors (LBNL Summer Lecture Series)

    SciTech Connect

    Forte, Trudy

    2007-06-27

    Summer Lecture Series 2007: Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs.

  2. Targeted Delivery of Drugs to Brain Tumors (LBNL Summer Lecture Series)

    ScienceCinema

    Forte, Trudy

    2016-07-12

    Summer Lecture Series 2007: Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs.

  3. Chloride channel-mediated brain glioma targeting of chlorotoxin-modified doxorubicine-loaded liposomes.

    PubMed

    Xiang, Yu; Liang, Liang; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2011-06-30

    The chlorotoxin (ClTx), a scorpion-derived peptide, binding to gliomas with high specificity, was firstly applied to establish the ClTx-modified doxorubicin (DOX)-loaded liposome delivery system for targeting the brain glioma and improving the anticancer efficacy. In vitro physicochemical characterization of the novel liposome system presented satisfactory size of 100 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of both fluorescent probe and anticancer drug. It was demonstrated quantitatively by the spectrophotofluorometry and flow cytometry and qualitatively by the confocal microscopy that ClTx highly facilitated the uptake of liposomes by three glioma cell lines and one endothelial cell line. In vitro cytotoxicity studies proved that the presence of ClTx increased the cytotoxicity against glioma cells and endothelial cells with various levels for different cell lines. In BALB/c mice bearing U87 tumor xenografts, biodistribution of DiR-loaded liposomes by body imaging and anti-glioma pharmacodynamics of DOX-loaded liposomes were investigated. The ClTx-modified liposomes showed more accumulation in the subcutaneous and intracranial tumors, higher tumor growth inhibition and lower blood toxicity in the armpit tumor model. The in vitro and in vivo results exhibited good correlation of glioma targeting of the ClTx-modified liposomes. Significantly, with the ClTx as the targeting ligand, the liposomes might serve as an applicable delivery system for brain glioma therapy or imaging.

  4. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

    PubMed Central

    Howick, Ken; Griffin, Brendan T.; Cryan, John F.; Schellekens, Harriët

    2017-01-01

    Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry. PMID:28134808

  5. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation.

    PubMed

    Howick, Ken; Griffin, Brendan T; Cryan, John F; Schellekens, Harriët

    2017-01-27

    Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrallymediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin's central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.

  6. Alteration of spontaneous brain activity in COPD patients

    PubMed Central

    Zhang, Jiaxing; Chen, Ji; Yu, Qian; Fan, Cunxiu; Zhang, Ran; Lin, Jianzhong; Yang, Tianhe; Fan, Ming

    2016-01-01

    Background and objective Airflow limitation in chronic obstructive pulmonary disease (COPD) results in a decrease in oxygen transport to the brain. The aim of the present study was to explore the alteration of spontaneous brain activity induced by hypoxia in patients with COPD. Patients and methods Twenty-five stable patients with COPD and 25 matching healthy volunteers were investigated. Amplitude of low-frequency fluctuation (ALFF) of blood oxygenation level-dependent signal at resting state in the brain was analyzed using functional magnetic resonance imaging. Results Whole-brain analysis using functional magnetic resonance imaging revealed significant decreases in ALFF in the bilateral posterior cingulate gyri and right lingual gyrus and an increase in ALFF in the left postcentral gyrus of patients with COPD. After controlling for SaO2, patients with COPD only showed an increase in ALFF in the left postcentral gyrus. Region of interest analysis showed a decrease in ALFF in the left precentral gyrus and an increase in ALFF in the left caudate nucleus of patients with COPD. In all subjects, ALFF in the bilateral posterior cingulate gyri and right lingual gyrus showed positive correlations with visual reproduction. Conclusion We demonstrated abnormal spontaneous brain activity of patients with COPD, which may have a pathophysiologic meaning. PMID:27555761

  7. Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling.

    PubMed

    Ponce-Alvarez, Adrián; He, Biyu J; Hagmann, Patric; Deco, Gustavo

    2015-08-01

    How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model's prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information.

  8. Reward anticipation enhances brain activation during response inhibition.

    PubMed

    Rosell-Negre, Patricia; Bustamante, Juan Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Benabarre, Sergio; Barros-Loscertales, Alfonso

    2014-06-01

    The chance to achieve a reward starts up the required neurobehavioral mechanisms to adapt our thoughts and actions in order to accomplish our objective. However, reward does not equally reinforce everybody but depends on interindividual motivational dispositions. Thus, immediate reward contingencies can modulate the cognitive process required for goal achievement, while individual differences in personality can affect this modulation. We aimed to test the interaction between inhibition-related brain response and motivational processing in a stop signal task by reward anticipation and whether individual differences in sensitivity to reward (SR) modulate such interaction. We analyzed the cognitive-motivational interaction between the brain pattern activation of the regions involved in correct and incorrect response inhibition and the association between such brain activations and SR scores. We also analyzed the behavioral effects of reward on both reaction times for the "go" trials before and after correct and incorrect inhibition in order to test error prediction performance and postinhibition adjustment. Our results show enhanced activation during response inhibition under reward contingencies in frontal, parietal, and subcortical areas. Moreover, activation of the right insula and the left putamen positively correlates with the SR scores. Finally, the possibility of reward outcome affects not only response inhibition performance (e.g., reducing stop signal reaction time), but also error prediction performance and postinhibition adjustment. Therefore, reward contingencies improve behavioral performance and enhance brain activation during response inhibition, and SR is related to brain activation. Our results suggest the conditions and factors that subserve cognitive control strategies in cognitive motivational interactions during response inhibition.

  9. Reading cinnamon activates olfactory brain regions.

    PubMed

    González, Julio; Barros-Loscertales, Alfonso; Pulvermüller, Friedemann; Meseguer, Vanessa; Sanjuán, Ana; Belloch, Vicente; Avila, César

    2006-08-15

    Some words immediately and automatically remind us of odours, smells and scents, whereas other language items do not evoke such associations. This study investigated, for the first time, the abstract linking of linguistic and odour information using modern neuroimaging techniques (functional MRI). Subjects passively read odour-related words ('garlic', 'cinnamon', 'jasmine') and neutral language items. The odour-related terms elicited activation in the primary olfactory cortex, which include the piriform cortex and the amygdala. Our results suggest the activation of widely distributed cortical cell assemblies in the processing of olfactory words. These distributed neuron populations extend into language areas but also reach some parts of the olfactory system. These distributed neural systems may be the basis of the processing of language elements, their related conceptual and semantic information and the associated sensory information.

  10. Brain Activation during the Course of Sentence Comprehension

    ERIC Educational Resources Information Center

    Ikuta, Naho; Sugiura, Motoaki; Sassa, Yuko; Watanabe, Jobu; Akitsuki, Yuko; Iwata, Kazuki; Miura, Naoki; Okamoto, Hideyuki; Watanabe, Yoshihiko; Sato, Shigeru; Horie, Kaoru; Matsue, Yoshihiko; Kawashima, Ryuta

    2006-01-01

    The purpose of this study is to determine, by functional magnetic resonance imaging, how the activated regions of the brain change as a Japanese sentence is presented in a grammatically correct order. In this study, we presented constituents of a sentence to Japanese participants one by one at regular intervals. The results showed that the left…

  11. Smart Moves: Powering up the Brain with Physical Activity

    ERIC Educational Resources Information Center

    Conyers, Marcus; Wilson, Donna

    2015-01-01

    The Common Core State Standards emphasize higher-order thinking, problem solving, and the creation, retention, and application of knowledge. Achieving these standards creates greater cognitive demands on students. Recent research suggests that active play and regular exercise have a positive effect on brain regions associated with executive…

  12. Towards a fourth spatial dimension of brain activity.

    PubMed

    Tozzi, Arturo; Peters, James F

    2016-06-01

    Current advances in neurosciences deal with the functional architecture of the central nervous system, paving the way for general theories that improve our understanding of brain activity. From topology, a strong concept comes into play in understanding brain functions, namely, the 4D space of a "hypersphere's torus", undetectable by observers living in a 3D world. The torus may be compared with a video game with biplanes in aerial combat: when a biplane flies off one edge of gaming display, it does not crash but rather it comes back from the opposite edge of the screen. Our thoughts exhibit similar behaviour, i.e. the unique ability to connect past, present and future events in a single, coherent picture as if we were allowed to watch the three screens of past-present-future "glued" together in a mental kaleidoscope. Here we hypothesize that brain functions are embedded in a imperceptible fourth spatial dimension and propose a method to empirically assess its presence. Neuroimaging fMRI series can be evaluated, looking for the topological hallmark of the presence of a fourth dimension. Indeed, there is a typical feature which reveal the existence of a functional hypersphere: the simultaneous activation of areas opposite each other on the 3D cortical surface. Our suggestion-substantiated by recent findings-that brain activity takes place on a closed, donut-like trajectory helps to solve long-standing mysteries concerning our psychological activities, such as mind-wandering, memory retrieval, consciousness and dreaming state.

  13. Early life stress affects limited regional brain activity in depression.

    PubMed

    Du, Lian; Wang, Jingjie; Meng, Ben; Yong, Na; Yang, Xiangying; Huang, Qingling; Zhang, Yan; Yang, Lingling; Qu, Yuan; Chen, Zhu; Li, Yongmei; Lv, Fajin; Hu, Hua

    2016-05-03

    Early life stress (ELS) can alter brain function and increases the risk of major depressive disorder (MDD) in later life. This study investigated whether ELS contributes to differences in regional brain activity between MDD patients and healthy controls (HC), as measured by amplitude of low-frequency fluctuation (ALFF)/fractional (f)ALFF. Eighteen first-episode, treatment-naïve MDD patients and HC were assessed with the Childhood Trauma Questionnaire and resting-state functional magnetic resonance imaging. We compared ALFF/fALFF between MDD patients and HC, with or without controlling for ELS, and determined whether ELS level was correlated with regional brain activity in each group. After regressing out ELS, we found that ALFF increased in bilateral amygdala and left orbital/cerebellum, while fALFF decreased in left inferior temporal and right middle frontal gyri in MDD patients relative to controls. ELS positively correlated with regional activity in the left cerebellum in MDD and in the right post-central/inferior temporal/superior frontal cingulate, inferior frontal gyrus and bilateral cerebellum in HC. Our findings indicate that there is only very limited region showing correlation between ELS and brain activity in MDD, while diverse areas in HC, suggesting ELS has few impacts on MDD patients.

  14. Prefrontal Brain Activity Predicts Temporally Extended Decision-Making Behavior

    ERIC Educational Resources Information Center

    Yarkoni, Tal; Braver, Todd S.; Gray, Jeremy R.; Green, Leonard

    2005-01-01

    Although functional neuroimaging studies of human decision-making processes are increasingly common, most of the research in this area has relied on passive tasks that generate little individual variability. Relatively little attention has been paid to the ability of brain activity to predict overt behavior. Using functional magnetic resonance…

  15. Working Memory Training: Improving Intelligence--Changing Brain Activity

    ERIC Educational Resources Information Center

    Jausovec, Norbert; Jausovec, Ksenija

    2012-01-01

    The main objectives of the study were: to investigate whether training on working memory (WM) could improve fluid intelligence, and to investigate the effects WM training had on neuroelectric (electroencephalography--EEG) and hemodynamic (near-infrared spectroscopy--NIRS) patterns of brain activity. In a parallel group experimental design,…

  16. Early life stress affects limited regional brain activity in depression

    PubMed Central

    Du, Lian; Wang, Jingjie; Meng, Ben; Yong, Na; Yang, Xiangying; Huang, Qingling; Zhang, Yan; Yang, Lingling; Qu, Yuan; Chen, Zhu; Li, Yongmei; Lv, Fajin; Hu, Hua

    2016-01-01

    Early life stress (ELS) can alter brain function and increases the risk of major depressive disorder (MDD) in later life. This study investigated whether ELS contributes to differences in regional brain activity between MDD patients and healthy controls (HC), as measured by amplitude of low-frequency fluctuation (ALFF)/fractional (f)ALFF. Eighteen first-episode, treatment-naïve MDD patients and HC were assessed with the Childhood Trauma Questionnaire and resting-state functional magnetic resonance imaging. We compared ALFF/fALFF between MDD patients and HC, with or without controlling for ELS, and determined whether ELS level was correlated with regional brain activity in each group. After regressing out ELS, we found that ALFF increased in bilateral amygdala and left orbital/cerebellum, while fALFF decreased in left inferior temporal and right middle frontal gyri in MDD patients relative to controls. ELS positively correlated with regional activity in the left cerebellum in MDD and in the right post-central/inferior temporal/superior frontal cingulate, inferior frontal gyrus and bilateral cerebellum in HC. Our findings indicate that there is only very limited region showing correlation between ELS and brain activity in MDD, while diverse areas in HC, suggesting ELS has few impacts on MDD patients. PMID:27138376

  17. Surface modified PLGA nanoparticles for brain targeting of Bacoside-A.

    PubMed

    Jose, S; Sowmya, S; Cinu, T A; Aleykutty, N A; Thomas, S; Souto, E B

    2014-10-15

    The present paper focuses on the development and in vitro/in vivo characterization of nanoparticles composed of poly-(D,L)-Lactide-co-Glycolide (PLGA) loading Bacoside-A, as a new approach for the brain delivery of the neuroprotective drug for the treatment of neurodegenerative disorders (e.g. Alzheimer Disease). Bacoside-A-loaded PLGA nanoparticles were prepared via o/w emulsion solvent evaporation technique. Surface of the nanoparticles were modified by coating with polysorbate 80 to facilitate the crossing of the blood brain barrier (BBB), and the processing parameters (i.e. sonication time, the concentration of polymer (PLGA) and surfactant (polysorbate 80), and drug-polymer ratio) were optimized with the aim to achieve a high production yield. Brain targeting potential of the nanoparticles was evaluated by in vivo studies using Wistar albino rats. The nanoparticles produced by optimal formulation were within the nanosized range (70-200 nm) with relatively low polydispersity index (0.391 ± 1.2). The encapsulation efficiency of Bacoside-A in PLGA nanoparticles was 57.11 ± 7.11%, with a drug loading capacity of 20.5 ± 1.98%. SEM images showed the spherical shape of the PLGA nanoparticles, whereas their low crystallinity was demonstrated by X-ray studies, which also confirmed no chemical interactions between the drug and polymer molecules. The in vitro release of Bacoside-A from the PLGA nanoparticles followed a sustained release pattern with a maximum release of up to 83.04 ± 2.55% in 48 h. When compared to pure drug solution (2.56 ± 1.23 μg/g tissue), in vivo study demonstrated higher brain concentration of Bacoside-A (23.94 ± 1.74 μg/g tissue) suggesting a significant role of surface coated nanoparticles on brain targeting. The results indicate the potential of surface modified PLGA nanoparticles for the delivery of Bacoside-A to the brain.

  18. The Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway as a Discovery Target in Stroke.

    PubMed

    Sun, Jing; Nan, Guangxian

    2016-05-01

    Protein kinases are critical modulators of a variety of intracellular and extracellular signal transduction pathways, and abnormal phosphorylation events can contribute to disease progression in a variety of diseases. As a result, protein kinases have emerged as important new drug targets for small molecule therapeutics. The mitogen-activated protein kinase (MAPK) signaling pathway transmits signals from the cell membrane to the nucleus in response to a variety of different stimuli. Because this pathway controls a broad spectrum of cellular processes, including growth, inflammation, and stress responses, it is accepted as a therapeutic target for cancer and peripheral inflammatory disorders. There is also increasing evidence that MAPK is an important regulator of ischemic and hemorrhagic cerebral vascular disease, raising the possibility that it might be a drug discovery target for stroke. In this review, we discuss the MAPK signaling pathway in association with its activation in stroke-induced brain injury.

  19. Activating PKC-β1 at the blood-brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS.

    PubMed

    Wang, Xueqian; Hawkins, Brian T; Miller, David S

    2011-06-01

    Upregulation of blood-brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-β1 (PKC-β1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-β1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-β1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries and reversed the effect of dioxin on brain uptake of verapamil in dioxin-dosed rats. Thus, targeting BBB PKC-β1 may be an effective strategy to improve drug delivery to the brain, even in drug-resistant individuals.

  20. Blue Light Stimulates Cognitive Brain Activity in Visually Blind Individuals

    PubMed Central

    Vandewalle, Gilles; Collignon, Olivier; Hull, Joseph T.; Daneault, Véronique; Albouy, Geneviève; Lepore, Franco; Phillips, Christophe; Doyon, Julien; Czeisler, Charles A.; Dumont, Marie; Lockley, Steven W.; Carrier, Julie

    2015-01-01

    Light regulates multiple non-image-forming (or non-visual) circadian, neuroendocrine and neurobehavioral functions, via outputs from intrinsically-photosensitive retinal ganglion cells (ipRGCs). Exposure to light directly enhances alertness and performance, so that light is an important regulator of wakefulness and cognition. The roles of rods, cones and ipRGCs in the impact of light on cognitive brain functions remain unclear, however. A small percentage of blind individuals retain non-image-forming photoreception and offer a unique opportunity to investigate light impacts in the absence of conscious vision, presumably through ipRGCs. Here, we show that three such patients were able to choose non-randomly about the presence of light despite their complete lack of sight. Furthermore, 2s of blue light modified EEG activity when administered simultaneously to auditory stimulations. FMRI further showed that, during an auditory working memory task, less than a minute of blue light triggered the recruitment of supplemental prefrontal and thalamic brain regions involved in alertness and cognition regulation, as well as key areas of the default mode network. These results, which have to be considered as a proof of concept, show that non-image-forming photoreception triggers some awareness for light and can have a more rapid impact on human cognition than previously understood, if brain processing is actively engaged. Furthermore, light stimulates higher cognitive brain activity, independently of vision, and engages supplemental brain areas to perform an ongoing cognitive process. To our knowledge, our results constitute the first indication that ipRGC signaling may rapidly affect fundamental cerebral organization, so that it could potentially participate to the regulation of numerous aspects of human brain function. PMID:23859643

  1. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    NASA Astrophysics Data System (ADS)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-05-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. The method presents new opportunities for the use of drugs and for the study of the brain.

  2. A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood–brain barrier, and the transporting mechanism to glioma cells

    PubMed Central

    Liu, Chang; Liu, Xiao-Na; Wang, Gui-Ling; Hei, Yu; Meng, Shuai; Yang, Ling-Fei; Yuan, Lan; Xie, Ying

    2017-01-01

    As the global population ages, cancer rates increase worldwide, and degenerative diseases of the central nervous system (CNS), brain tumors, and inflammation threaten human health more frequently. We designed a dual-mediated (receptor-mediated and adsorption-mediated) liposome, named transferrin–cell penetrating peptide–sterically stabilized liposome (TF-CPP-SSL), to improve therapy for gliomas through combining molecular recognition of transferrin receptors (TF-Rs) on the blood–brain barrier (BBB) and glioma cells with the internalization and lysosomal escaping ability of CPP. Based on the systematic investigation of structure–activity relations on the cellular level, we constructed TF-CPP-SSL rationally by conjugating TF and CPP moieties to the liposomes via PEG3.4K and PEG2.0K, respectively, and found the optimum densities of TF and CPP were 1.8% and 4%, respectively. These liposomes had the highest targeting efficacy for brain microvascular endothelial cell and C6 cell uptake but avoided capture by normal cells. Fluorescence resonance energy transfer technology and coculture models of BBB and glioma C6 cells indicated that TF-CPP-SSL was transported across the BBB without drug leakage, liposome breakup, or cleavage of ligand. TF-CPP-SSL offered advantages for crossing the BBB and entering into glioma C6 cells. Real-time confocal viewing revealed that TF-CPP-SSL was entrapped in endosomes of glioma C6 cells and then escaped from lysosomes successfully to release the liposomal contents into the cytosol. Entrapped contents, such as doxorubicin, could then enter the nucleus to exert pharmacological effects.

  3. Developments of thick solid neon as an active target

    NASA Astrophysics Data System (ADS)

    Kamiguchi, Nagaaki; Moriguchi, Tetsurou; Ozawa, Akira; Isimoto, Sigeru

    2009-10-01

    One of research subjects in our group is to measure reaction cross sections (σR) of RI beams. By measuring σR, we can deduce root mean square radii of unstable nuclei. In the measurements of σR, we usually used a carbon as the reaction targets (a few cm thickness). If we use the reaction target as a detector (active target), there are some advantages in the measurements; (1)The events only colliding with the reaction target can be selected. (2)If position information is available, we may define the colliding point inside the target. (3)If energy information is available, we may measure the energy loss of the beams inside the target. As the active target in the σR measurements, we noticed the solid neon. Since the neon is a noble gas, it is predicted to emit scintillations and work as an ionization chamber for charged particles. Indeed, scintillations from liquid and solid neon have been already observed. We will present production of the thick solid neon (˜30mm thickness), and observations of scintillations and ionization signals from the solid neon. We will also discuss possibility to use the sold neon as the active target in the σR measurements.

  4. Baseline Brain Activity Predicts Response to Neuromodulatory Pain Treatment

    PubMed Central

    Jensen, Mark P.; Sherlin, Leslie H.; Fregni, Felipe; Gianas, Ann; Howe, Jon D.; Hakimian, Shahin

    2015-01-01

    Objectives The objective of this study was to examine the associations between baseline electroencephalogram (EEG)-assessed brain oscillations and subsequent response to four neuromodulatory treatments. Based on available research, we hypothesized that baseline theta oscillations would prospectively predict response to hypnotic analgesia. Analyses involving other oscillations and the other treatments (meditation, neurofeedback, and both active and sham transcranial direct current stimulation) were viewed as exploratory, given the lack of previous research examining brain oscillations as predictors of response to these other treatments. Design Randomized controlled study of single sessions of four neuromodulatory pain treatments and a control procedure. Methods Thirty individuals with spinal cord injury and chronic pain had their EEG recorded before each session of four active treatments (hypnosis, meditation, EEG biofeedback, transcranial direct current stimulation) and a control procedure (sham transcranial direct stimulation). Results As hypothesized, more presession theta power was associated with greater response to hypnotic analgesia. In exploratory analyses, we found that less baseline alpha power predicted pain reduction with meditation. Conclusions The findings support the idea that different patients respond to different pain treatments and that between-person treatment response differences are related to brain states as measured by EEG. The results have implications for the possibility of enhancing pain treatment response by either 1) better patient/treatment matching or 2) influencing brain activity before treatment is initiated in order to prepare patients to respond. Research is needed to replicate and confirm the findings in additional samples of individuals with chronic pain. PMID:25287554

  5. Altered brain activity for phonological manipulation in dyslexic Japanese children.

    PubMed

    Kita, Yosuke; Yamamoto, Hisako; Oba, Kentaro; Terasawa, Yuri; Moriguchi, Yoshiya; Uchiyama, Hitoshi; Seki, Ayumi; Koeda, Tatsuya; Inagaki, Masumi

    2013-12-01

    Because of unique linguistic characteristics, the prevalence rate of developmental dyslexia is relatively low in the Japanese language. Paradoxically, Japanese children have serious difficulty analysing phonological processes when they have dyslexia. Neurobiological deficits in Japanese dyslexia remain unclear and need to be identified, and may lead to better understanding of the commonality and diversity in the disorder among different linguistic systems. The present study investigated brain activity that underlies deficits in phonological awareness in Japanese dyslexic children using functional magnetic resonance imaging. We developed and conducted a phonological manipulation task to extract phonological processing skills and to minimize the influence of auditory working memory on healthy adults, typically developing children, and dyslexic children. Current experiments revealed that several brain regions participated in manipulating the phonological information including left inferior and middle frontal gyrus, left superior temporal gyrus, and bilateral basal ganglia. Moreover, dyslexic children showed altered activity in two brain regions. They showed hyperactivity in the basal ganglia compared with the two other groups, which reflects inefficient phonological processing. Hypoactivity in the left superior temporal gyrus was also found, suggesting difficulty in composing and processing phonological information. The altered brain activity shares similarity with those of dyslexic children in countries speaking alphabetical languages, but disparity also occurs between these two populations. These are initial findings concerning the neurobiological impairments in dyslexic Japanese children.

  6. Repetitive Transcranial Magnetic Stimulation Activates Specific Regions in Rat Brain

    NASA Astrophysics Data System (ADS)

    Ji, Ru-Rong; Schlaepfer, Thomas E.; Aizenman, Carlos D.; Epstein, Charles M.; Qiu, Dike; Huang, Justin C.; Rupp, Fabio

    1998-12-01

    Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique to induce electric currents in the brain. Although rTMS is being evaluated as a possible alternative to electroconvulsive therapy for the treatment of refractory depression, little is known about the pattern of activation induced in the brain by rTMS. We have compared immediate early gene expression in rat brain after rTMS and electroconvulsive stimulation, a well-established animal model for electroconvulsive therapy. Our result shows that rTMS applied in conditions effective in animal models of depression induces different patterns of immediate-early gene expression than does electroconvulsive stimulation. In particular, rTMS evokes strong neural responses in the paraventricular nucleus of the thalamus (PVT) and in other regions involved in the regulation of circadian rhythms. The response in PVT is independent of the orientation of the stimulation probe relative to the head. Part of this response is likely because of direct activation, as repetitive magnetic stimulation also activates PVT neurons in brain slices.

  7. Trying to trust: Brain activity during interpersonal social attitude change.

    PubMed

    Filkowski, Megan M; Anderson, Ian W; Haas, Brian W

    2016-04-01

    Interpersonal trust and distrust are important components of human social interaction. Although several studies have shown that brain function is associated with either trusting or distrusting others, very little is known regarding brain function during the control of social attitudes, including trust and distrust. This study was designed to investigate the neural mechanisms involved when people attempt to control their attitudes of trust or distrust toward another person. We used a novel control-of-attitudes fMRI task, which involved explicit instructions to control attitudes of interpersonal trust and distrust. Control of trust or distrust was operationally defined as changes in trustworthiness evaluations of neutral faces before and after the control-of-attitudes fMRI task. Overall, participants (n = 60) evaluated faces paired with the distrust instruction as being less trustworthy than faces paired with the trust instruction following the control-of-distrust task. Within the brain, both the control-of-trust and control-of-distrust conditions were associated with increased temporoparietal junction, precuneus (PrC), inferior frontal gyrus (IFG), and medial prefrontal cortex activity. Individual differences in the control of trust were associated with PrC activity, and individual differences in the control of distrust were associated with IFG activity. Together, these findings identify a brain network involved in the explicit control of distrust and trust and indicate that the PrC and IFG may serve to consolidate interpersonal social attitudes.

  8. Multi-modal Learning-based Pre-operative Targeting in Deep Brain Stimulation Procedures.

    PubMed

    Liu, Yuan; Dawant, Benoit M

    2016-02-01

    Deep brain stimulation, as a primary surgical treatment for various neurological disorders, involves implanting electrodes to stimulate target nuclei within millimeter accuracy. Accurate pre-operative target selection is challenging due to the poor contrast in its surrounding region in MR images. In this paper, we present a learning-based method to automatically and rapidly localize the target using multi-modal images. A learning-based technique is applied first to spatially normalize the images in a common coordinate space. Given a point in this space, we extract a heterogeneous set of features that capture spatial and intensity contextual patterns at different scales in each image modality. Regression forests are used to learn a displacement vector of this point to the target. The target is predicted as a weighted aggregation of votes from various test samples, leading to a robust and accurate solution. We conduct five-fold cross validation using 100 subjects and compare our method to three indirect targeting methods, a state-of-the-art statistical atlas-based approach, and two variations of our method that use only a single modality image. With an overall error of 2.63±1.37mm, our method improves upon the single modality-based variations and statistically significantly outperforms the indirect targeting ones. Our technique matches state-of-the-art registration methods but operates on completely different principles. Both techniques can be used in tandem in processing pipelines operating on large databases or in the clinical flow for automated error detection.

  9. Active Lessons for Active Brains: Teaching Boys and Other Experiential Learners, Grades 3-10

    ERIC Educational Resources Information Center

    James, Abigail Norfleet; Allison, Sandra Boyd; McKenzie, Caitlin Zimmerman

    2011-01-01

    If you're tired of repeating yourself to students who aren't listening, try a little less talk and a lot more action. The authors follow the best-selling "Teaching the Male Brain and Teaching the Female Brain" with this ready-to-use collection of mathematics, language arts, science, and classroom management strategies. Designed for active,…

  10. Targeting blood–brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery

    PubMed Central

    Ronaldson, Patrick T; Davis, Thomas P

    2012-01-01

    The blood–brain barrier (BBB) is the most significant obstacle to effective CNS drug delivery. It possesses structural and biochemical features (i.e., tight-junction protein complexes and, influx and efflux transporters) that restrict xenobiotic permeation. Pathophysiological stressors (i.e., peripheral inflammatory pain) can alter BBB tight junctions and transporters, which leads to drug-permeation changes. This is especially critical for opioids, which require precise CNS concentrations to be safe and effective analgesics. Recent studies have identified molecular targets (i.e., endogenous transporters and intracellular signaling systems) that can be exploited for optimization of CNS drug delivery. This article summarizes current knowledge in this area and emphasizes those targets that present the greatest opportunity for controlling drug permeation and/or drug transport across the BBB in an effort to achieve optimal CNS opioid delivery. PMID:22468221

  11. Dynamics of tRNA fragments and their targets in aging mammalian brain

    PubMed Central

    Karaiskos, Spyros; Grigoriev, Andrey

    2016-01-01

    Background: The progress of next-generation sequencing technologies has unveiled various non-coding RNAs that have previously been considered products of random degradation and attracted only minimal interest. Among small RNA families, microRNA (miRNAs) have traditionally been considered key post-transcriptional regulators. However, recent studies have reported evidence for widespread presence of fragments of tRNA molecules (tRFs) across a range of organisms and tissues, and of tRF involvement in Argonaute complexes.  Methods:To elucidate potential tRF functionality, we compared available RNA sequencing datasets derived from the brains of young, mid-aged and old rats. Using sliding 7-mer windows along a tRF, we searched for putative seed sequences with high numbers of conserved complementary sites within 3' UTRs of 23 vertebrate genomes. We analyzed Gene Ontology term enrichment of predicted tRF targets and compared their transcript levels with targets of miRNAs in the context of age.  Results and Discussion: We detected tRFs originating from 3’- and 5’-ends of tRNAs in rat brains at significant levels. These fragments showed dynamic changes: 3’ tRFs monotonously increased with age, while 5’ tRFs displayed less consistent patterns. Furthermore, 3’ tRFs showed a narrow size range compared to 5’ tRFs, suggesting a difference in their biogenesis mechanisms. Similar to our earlier results in Drosophila and compatible with other experimental findings, we found “seed” sequence locations on both ends of different tRFs. Putative targets of these fragments were found to be enriched in neuronal and developmental functions. Comparison of tRFs and miRNAs increasing in abundance with age revealed small, but distinct changes in brain target transcript levels for these two types of small RNA, with the higher proportion of tRF targets decreasing with age. We also illustrated the utility of tRF analysis for annotating tRNA genes in sequenced genomes. PMID

  12. Anomalous Light Phenomena vs. Bioelectric Brain Activity

    NASA Astrophysics Data System (ADS)

    Teodorani, M.; Nobili, G.

    We present a research proposal concerning the instrumented investigation of anomalous light phenomena that are apparently correlated with particular mind states, such as prayer, meditation or psi. Previous research by these authors demonstrate that such light phenomena can be monitored and measured quite efficiently in areas of the world where they are reported in a recurrent way. Instruments such as optical equipment for photography and spectroscopy, VLF spectrometers, magnetometers, radar and IR viewers were deployed and used massively in several areas of the world. Results allowed us to develop physical models concerning the structural and time-variable behaviour of light phenomena, and their kinematics. Recent insights and witnesses have suggested to us that a sort of "synchronous connection" seems to exist between plasma-like phenomena and particular mind states of experiencers who seem to trigger a light manifestation which is very similar to the one previously investigated. The main goal of these authors is now aimed at the search for a concrete "entanglement-like effect" between the experiencer's mind and the light phenomena, in such a way that both aspects are intended to be monitored and measured simultaneously using appropriate instrumentation. The goal of this research project is twofold: a) to verify quantitatively the existence of one very particular kind of mind-matter interaction and to study in real time its physical and biophysical manifestations; b) to repeat the same kind of experiment using the same test-subject in different locations and under various conditions of geomagnetic activity.

  13. Breastfeeding, Brain Activation to Own Infant Cry, and Maternal Sensitivity

    PubMed Central

    Kim, Pilyoung; Feldman, Ruth; Mayes, Linda C.; Eicher, Virginia; Thompson, Nancy; Leckman, James F.; Swain, James E.

    2011-01-01

    Background Research points to the importance of breastfeeding for promoting close mother-infant contact and social-emotional development. Recent functional magnetic resonance imaging (fMRI) studies have identified brain regions related to maternal behaviors. However, little research has addressed the neurobiological mechanisms underlying the relationship between breastfeeding and maternal behavior in human mothers. We investigated the associations between breastfeeding, maternal brain response to own infant stimuli, and maternal sensitivity in the early postpartum. Methods Seventeen biological mothers of healthy infants participated in two matched groups according to feeding method – exclusive breastfeeding and exclusive formula-feeding at 2-4 weeks postpartum. fMRI scanning was conducted in the first postpartum month to examine maternal brain activation in response to her own baby's cry versus control baby-cry. Dyadic interactions between mothers and infants at 3-4 months postpartum were videotaped in the home and blindly coded for maternal sensitivity. Results In the first postpartum month, breastfeeding mothers showed greater activations in the superior frontal gyrus, insula, precuneus, striatum, and amygdala while listening to their own baby-cry as compared to formula-feeding mothers. For both breastfeeding and formula-feeding mothers, greater activations in the right superior frontal gyrus and amygdala were associated with higher maternal sensitivity at 3-4 months postpartum. Conclusions Results suggest links between breastfeeding and greater response to infant cues in brain regions implicated in maternal-infant bonding and empathy during the early postpartum. Such brain activations may facilitate greater maternal sensitivity as infants enter their social world. PMID:21501165

  14. Brain temperature fluctuation: a reflection of functional neural activation.

    PubMed

    Kiyatkin, Eugene A; Brown, P Leon; Wise, Roy A

    2002-07-01

    Although it is known that relatively large increases in local brain temperature can occur during behaviour and in response to various novel, stressful and emotionally arousing environmental stimuli, the source of this heat is not clearly established. To clarify this issue, we monitored the temperature in three brain structures (dorsal and ventral striatum, cerebellum) and in arterial blood at the level of the abdominal aorta in freely moving rats exposed to several environmental challenges ranging from traditional stressors to simple sensory stimuli (cage change, tail pinch, exposure to another male rat, a female rat, a mouse or an unexpected sound). We found that brain temperature was consistently higher than arterial blood temperature, and that brain temperature increased prior to, and to a greater extent than, the increase in blood temperature evoked by each test challenge. Thus, the local metabolic consequences of widely correlated neural activity appear to be the primary source of increases in brain temperature and a driving force behind the associated changes in body temperature.

  15. Recombinant Human Adenovirus: Targeting to the Human Transferrin Receptor Improves Gene Transfer to Brain Microcapillary Endothelium

    PubMed Central

    Xia, Haibin; Anderson, Brian; Mao, Qinwen; Davidson, Beverly L.

    2000-01-01

    Some inborn errors of metabolism due to deficiencies of soluble lysosomal enzymes cause global neurodegenerative disease. Representative examples include the infantile and late infantile forms of the ceroid lipofuscinoses (CLN1 or CLN2 deficiency, respectively) and mucopolysaccharidoses type VII (MPS VII), a deficiency of β-glucuronidase. Treatment of the central nervous system component of these disorders will require widespread protein or enzyme replacement, either through dissemination of the protein or through dissemination of a gene encoding it. We hypothesize that transduction of brain microcapillary endothelium (BME) with recombinant viral vectors, with secretion of enzyme product basolaterally, could allow for widespread enzyme dissemination. To achieve this, viruses should be modified to target the BME. This requires (i) identification of a BME-resident target receptor, (ii) identification of motifs targeted to that molecule, (iii) the construction of modified viruses to allow for binding to the target receptor, and (iv) demonstrated transduction of receptor-expressing cells. In proof of principal experiments, we chose the human transferrin receptor (hTfR), a molecule found at high density on human BME. A nonamer phage display library was panned for motifs which could bind hTfR. Forty-three clones were sequenced, most of which contained an AKxxK/R, KxKxPK/R, or KxK motif. Ten peptides representative of the three motifs were cloned into the HI loop of adenovirus type 5 fiber. All motifs tested retained their ability to trimerize and bind transferrin receptor, and seven allowed for recombinant adenovirus production. Importantly, the fiber-modified viruses facilitated increased gene transfer (2- to 34-fold) to hTfR expressing cell lines and human brain microcapillary endothelia expressing high levels of endogenous receptor. Our data indicate that adenoviruses can be modified in the HI loop for expanded tropism to the hTfR. PMID:11070036

  16. Tobramycin variants with enhanced ribosome-targeting activity

    PubMed Central

    Fosso, Marina Y.; Zhu, Hongkun; Green, Keith D.

    2015-01-01

    With the increased evolution of aminoglycoside (AG)-resistant bacterial strains, the need to develop AGs with (i) enhanced antimicrobial activity, (ii) the ability to evade resistance mechanisms, and (iii) the capability of targeting the ribosome with higher efficiency, is more and more pressing. The chemical derivatization of the naturally occurring tobramycin (TOB) by attachment of 37 different thioethers groups at the 6″-position led to the identification of generally poorer substrates of TOB-targeting AG-modifying enzymes (AMEs). Thirteen of these displayed better antibacterial activity than the parental TOB while retaining ribosome-targeting specificity. Analysis of these compounds in vitro shed light on the mechanism by which they act and revealed three with clearly enhanced ribosome-targeting activity. PMID:26033429

  17. Peroxisome proliferator-activated receptor alpha target genes.

    PubMed

    Rakhshandehroo, Maryam; Knoch, Bianca; Müller, Michael; Kersten, Sander

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.

  18. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    PubMed Central

    Rakhshandehroo, Maryam; Knoch, Bianca; Müller, Michael; Kersten, Sander

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well. PMID:20936127

  19. Intuitive operability evaluation of surgical robot using brain activity measurement to determine immersive reality.

    PubMed

    Miura, Satoshi; Kobayashi, Yo; Kawamura, Kazuya; Seki, Masatoshi; Nakashima, Yasutaka; Noguchi, Takehiko; Kasuya, Masahiro; Yokoo, Yuki; Fujie, Masakatsu G

    2012-01-01

    Surgical robots have improved considerably in recent years, but intuitive operability, which represents user inter-operability, has not been quantitatively evaluated. Therefore, for design of a robot with intuitive operability, we propose a method to measure brain activity to determine intuitive operability. The objective of this paper is to determine the master configuration against the monitor that allows users to perceive the manipulator as part of their own body. We assume that the master configuration produces an immersive reality experience for the user of putting his own arm into the monitor. In our experiments, as subjects controlled the hand controller to position the tip of the virtual slave manipulator on a target in a surgical simulator, we measured brain activity through brain-imaging devices. We performed our experiments for a variety of master manipulator configurations with the monitor position fixed. For all test subjects, we found that brain activity was stimulated significantly when the master manipulator was located behind the monitor. We conclude that this master configuration produces immersive reality through the body image, which is related to visual and somatic sense feedback.

  20. Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria.

    PubMed

    Dende, Chaitanya; Meena, Jairam; Nagarajan, Perumal; Panda, Amulya K; Rangarajan, Pundi N; Padmanaban, Govindarajan

    2015-07-31

    Malaria afflicts around 200 million people annually, with a mortality number close to 600,000. The mortality rate in Human Cerebral Malaria (HCM) is unacceptably high (15-20%), despite the availability of artemisinin-based therapy. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. Migration of T cells and parasite-infected RBCs (pRBCs) into the brain are both necessary to precipitate the disease. We have been able to simultaneously target both these parameters of ECM. Curcumin alone was able to reverse all the parameters investigated in this study that govern inflammatory responses, CD8(+) T cell and pRBC sequestration into the brain and blood brain barrier (BBB) breakdown. But the animals eventually died of anemia due to parasite build-up in blood. However, arteether-curcumin (AC) combination therapy even after the onset of symptoms provided complete cure. AC treatment is a promising therapeutic option for HCM.

  1. Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria

    PubMed Central

    Dende, Chaitanya; Meena, Jairam; Nagarajan, Perumal; Panda, Amulya K.; Rangarajan, Pundi N.; Padmanaban, Govindarajan

    2015-01-01

    Malaria afflicts around 200 million people annually, with a mortality number close to 600,000. The mortality rate in Human Cerebral Malaria (HCM) is unacceptably high (15–20%), despite the availability of artemisinin-based therapy. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. Migration of T cells and parasite-infected RBCs (pRBCs) into the brain are both necessary to precipitate the disease. We have been able to simultaneously target both these parameters of ECM. Curcumin alone was able to reverse all the parameters investigated in this study that govern inflammatory responses, CD8+ T cell and pRBC sequestration into the brain and blood brain barrier (BBB) breakdown. But the animals eventually died of anemia due to parasite build-up in blood. However, arteether-curcumin (AC) combination therapy even after the onset of symptoms provided complete cure. AC treatment is a promising therapeutic option for HCM. PMID:26227888

  2. Motor Cortex Microcircuit Simulation Based on Brain Activity Mapping

    PubMed Central

    Chadderdon, George L.; Mohan, Ashutosh; Suter, Benjamin A.; Neymotin, Samuel A.; Kerr, Cliff C.; Francis, Joseph T.; Shepherd, Gordon M. G.; Lytton, William W.

    2016-01-01

    The deceptively simple laminar structure of neocortex belies the complexity of intra- and interlaminar connectivity. We developed a computational model based primarily on a unified set of brain activity mapping studies of mouse M1. The simulation consisted of 775 spiking neurons of 10 cell types with detailed population-to-population connectivity. Static analysis of connectivity with graph-theoretic tools revealed that the corticostriatal population showed strong centrality, suggesting that would provide a network hub. Subsequent dynamical analysis confirmed this observation, in addition to revealing network dynamics that cannot be readily predicted through analysis of the wiring diagram alone. Activation thresholds depended on the stimulated layer. Low stimulation produced transient activation, while stronger activation produced sustained oscillations where the threshold for sustained responses varied by layer: 13% in layer 2/3, 54% in layer 5A, 25% in layer 5B, and 17% in layer 6. The frequency and phase of the resulting oscillation also depended on stimulation layer. By demonstrating the effectiveness of combined static and dynamic analysis, our results show how static brain maps can be related to the results of brain activity mapping. PMID:24708371

  3. Contralateral Cortical Organisation of Information in Visual Short-Term Memory: Evidence from Lateralized Brain Activity during Retrieval

    ERIC Educational Resources Information Center

    Fortier-Gauthier, Ulysse; Moffat, Nicolas; Dell'Acqua, Robert; McDonald, John J.; Jolicoeur, Pierre

    2012-01-01

    We studied brain activity during retention and retrieval phases of two visual short-term memory (VSTM) experiments. Experiment 1 used a balanced memory array, with one color stimulus in each hemifield, followed by a retention interval and a central probe, at the fixation point that designated the target stimulus in memory about which to make a…

  4. Causal interaction following the alteration of target region activation during motor imagery training using real-time fMRI

    PubMed Central

    Zhao, Xiaojie; Zhang, Hang; Song, Sutao; Ye, Qing; Guo, Jia; Yao, Li

    2013-01-01

    Motor imagery training is an effective approach for motor skill learning and motor function rehabilitation. As a novel method of motor imagery training, real-time fMRI (rtfMRI) enables individuals to acquire self-control of localized brain activation, achieving desired changes in behavior. The regulation of target region activation by rtfMRI often alters the activation of related brain regions. However, the interaction between the target region and these related regions is unclear. The Granger causality model (GCM) is a data-driven method that can explore the causal interaction between brain regions. In this study, we employed rtfMRI to train subjects to regulate the activation of the ipsilateral dorsal premotor area (dPMA) during motor imagery training, and we calculated the causal interaction of the dPMA with other motor-related regions based on the GCM. The results demonstrated that as the activity of the dPMA changed during rtfMRI training, the interaction of the target region with other related regions became significantly altered, and behavioral performance was improved after training. The altered interaction primarily exhibited as an increased unidirectional interaction from the dPMA to the other regions. These findings support the dominant role of the dPMA in motor skill learning via rtfMRI training and may indicate how activation of the target region interacts with the activation of other related regions. PMID:24379775

  5. Reduction of Nfia gene expression and subsequent target genes by binge alcohol in the fetal brain.

    PubMed

    Mandal, Chanchal; Park, Ji Hyun; Lee, Hyung Tae; Seo, Hyemyung; Chung, Il Yup; Choi, Ihn Geun; Jung, Kyoung Hwa; Chai, Young Gyu

    2015-06-26

    The objective of the present study was to investigate the changes in gene expression in the fetal brain (forebrain and hippocampus) caused by maternal binge alcohol consumption. Pregnant C57BL/6J mice were treated intragastrically with distilled phosphate-buffered saline (PBS) or ethanol (2.9 g/kg) from embryonic day (ED) 8-12. Microarray analysis revealed that a significant number of genes were altered at ED 18 in the developing brain. Specifically, in hippocampus, nuclear factor one alpha (Nfia) and three N-methyl-D-aspartate (Nmda) receptors (Nmdar1, Nmdar2b, and Nmdar2d) were down-regulated. The transcription factor Nfia controls gliogenesis, cell proliferation and Nmda-induced neuronal survival by regulating the expression of target genes. Some of the Nfia-target gene (Aldh1a, Folh1, Gjb6, Fgf1, Neurod1, Sept4, and Ntsr2) expressions were also altered as expected. These results suggest that the altered expression of Nfia and Nmda receptors may be associated with the etiology of fetal alcohol syndrome (FAS). The data presented in this report will contribute to the understanding of the molecular mechanisms associated with the effects of alcohol in FASD individuals.

  6. Lactoferrin conjugated iron oxide nanoparticles for targeting brain glioma cells in magnetic particle imaging

    NASA Astrophysics Data System (ADS)

    Tomitaka, Asahi; Arami, Hamed; Gandhi, Sonu; Krishnan, Kannan M.

    2015-10-01

    Magnetic Particle Imaging (MPI) is a new real-time imaging modality, which promises high tracer mass sensitivity and spatial resolution directly generated from iron oxide nanoparticles. In this study, monodisperse iron oxide nanoparticles with median core diameters ranging from 14 to 26 nm were synthesized and their surface was conjugated with lactoferrin to convert them into brain glioma targeting agents. The conjugation was confirmed with the increase of the hydrodynamic diameters, change of zeta potential, and Bradford assay. Magnetic particle spectrometry (MPS), performed to evaluate the MPI performance of these nanoparticles, showed no change in signal after lactoferrin conjugation to nanoparticles for all core diameters, suggesting that the MPI signal is dominated by Néel relaxation and thus independent of hydrodynamic size difference or presence of coating molecules before and after conjugations. For this range of core sizes (14-26 nm), both MPS signal intensity and spatial resolution improved with increasing core diameter of nanoparticles. The lactoferrin conjugated iron oxide nanoparticles (Lf-IONPs) showed specific cellular internalization into C6 cells with a 5-fold increase in MPS signal compared to IONPs without lactoferrin, both after 24 h incubation. These results suggest that Lf-IONPs can be used as tracers for targeted brain glioma imaging using MPI.

  7. Spatial decoupling of targets and flashing stimuli for visual brain-computer interfaces

    NASA Astrophysics Data System (ADS)

    Waytowich, Nicholas R.; Krusienski, Dean J.

    2015-06-01

    Objective. Recently, paradigms using code-modulated visual evoked potentials (c-VEPs) have proven to achieve among the highest information transfer rates for noninvasive brain-computer interfaces (BCIs). One issue with current c-VEP paradigms, and visual-evoked paradigms in general, is that they require direct foveal fixation of the flashing stimuli. These interfaces are often visually unpleasant and can be irritating and fatiguing to the user, thus adversely impacting practical performance. In this study, a novel c-VEP BCI paradigm is presented that attempts to perform spatial decoupling of the targets and flashing stimuli using two distinct concepts: spatial separation and boundary positioning. Approach. For the paradigm, the flashing stimuli form a ring that encompasses the intended non-flashing targets, which are spatially separated from the stimuli. The user fixates on the desired target, which is classified using the changes to the EEG induced by the flashing stimuli located in the non-foveal visual field. Additionally, a subset of targets is also positioned at or near the stimulus boundaries, which decouples targets from direct association with a single stimulus. This allows a greater number of target locations for a fixed number of flashing stimuli. Main results. Results from 11 subjects showed practical classification accuracies for the non-foveal condition, with comparable performance to the direct-foveal condition for longer observation lengths. Online results from 5 subjects confirmed the offline results with an average accuracy across subjects of 95.6% for a 4-target condition. The offline analysis also indicated that targets positioned at or near the boundaries of two stimuli could be classified with the same accuracy as traditional superimposed (non-boundary) targets. Significance. The implications of this research are that c-VEPs can be detected and accurately classified to achieve comparable BCI performance without requiring potentially irritating

  8. Targeting the sigma-1 receptor chaperone in the treatment of perinatal brain injury.

    PubMed

    Hashimoto, Kenji

    2015-03-01

    Glutamate-induced excitotoxicity via the N-methyl-d-aspartate (NMDA) receptor is an important factor in the pathogenesis of perinatal brain injury. The sigma-1 receptor on the endoplasmic reticulum (ER) has been known to affect the function of the NMDA receptor. 4-Phenyl-1-(4-phenylbutyl)piperidine (PPBP) has been investigated as a sigma-1 receptor agonist for several decades. An article using PPBP in a model of preterm brain injury was published in Experimental Neurology. The authors reported that PPBP protected against glutamate-induced excitotoxicity in primary hippocampal neurons. Furthermore, the systemic administration of PPBP significantly reduced microglial activation and lesion size in cortical gray and white matter after the excitotoxic insult in neonatal mice. This study suggests that sigma-1 receptor agonists could be potential preventive and therapeutic drugs for perinatal brain injury, although a pharmacological experiment using a sigma-1 receptor antagonist was not performed. This commentary aims to highlights the key findings of this article in a broader context, emphasizing the future potential therapeutic applications in patients with perinatal brain injury.

  9. Fast transient networks in spontaneous human brain activity

    PubMed Central

    Baker, Adam P; Brookes, Matthew J; Rezek, Iead A; Smith, Stephen M; Behrens, Timothy; Probert Smith, Penny J; Woolrich, Mark

    2014-01-01

    To provide an effective substrate for cognitive processes, functional brain networks should be able to reorganize and coordinate on a sub-second temporal scale. We used magnetoencephalography recordings of spontaneous activity to characterize whole-brain functional connectivity dynamics at high temporal resolution. Using a novel approach that identifies the points in time at which unique patterns of activity recur, we reveal transient (100–200 ms) brain states with spatial topographies similar to those of well-known resting state networks. By assessing temporal changes in the occurrence of these states, we demonstrate that within-network functional connectivity is underpinned by coordinated neuronal dynamics that fluctuate much more rapidly than has previously been shown. We further evaluate cross-network interactions, and show that anticorrelation between the default mode network and parietal regions of the dorsal attention network is consistent with an inability of the system to transition directly between two transient brain states. DOI: http://dx.doi.org/10.7554/eLife.01867.001 PMID:24668169

  10. Multivariate Optimization of Rizatriptan Benzoate-Loaded Solid Lipid Nanoparticles for Brain Targeting and Migraine Management.

    PubMed

    Girotra, Priti; Singh, Shailendra Kumar

    2017-02-01

    The present investigation aimed at development of brain-targeted rizatriptan benzoate-loaded solid lipid nanoparticles (RB-SLNs) by design of experiment, for improvement of its anti-migraine potential. Several formulation variables affecting the fabrication of RB-SLNs were screened using the Plackett-Burman design (PBD). The PBD results demonstrated lipid (Precirol® ATO 5) concentration, co-surfactant (Phospholipon® 90 H) concentration and temperature of lipid melt to be the critical variables, having a significant effect on the achievement of minimum particle size, maximum entrapment efficiency coupled with sustained drug release. The interactions between these formulation parameters and the variability between the batches were further explored employing the Box-Behnken design (BBD). The BBD results were validated by fabricating the suggested optimized solution, which yielded 220.4 ± 2.3 nm particle size with a sufficiently high entrapment efficiency of 71.8 ± 1.9% and 45.9 ± 2.7% cumulative drug release in 8 h. The optimized formulation was, thereafter, characterized by FTIR spectroscopy, wide angle XRD, thermal analysis and TEM imaging technique. The in vivo studies revealed the brain uptake potential of optimized RB-SLNs to be 18.43-folds higher with respect to the pure drug in its free form, post 2 h of oral drug administration. The significant anti-migraine efficacy of RB-SLNs was corroborated through the pharmacodynamic studies on adult male Swiss albino mice. The results hence explicate that RB-SLNs have distinctly improved brain target ability and offer an apt approach for the efficient therapeutic management of migraine.

  11. MRI-guided targeted blood-brain barrier disruption with focused ultrasound: histological findings in rabbits.

    PubMed

    McDannold, Nathan; Vykhodtseva, Natalia; Raymond, Scott; Jolesz, Ferenc A; Hynynen, Kullervo

    2005-11-01

    Focused ultrasound offers a method to disrupt the blood-brain barrier (BBB) noninvasively and reversibly at targeted locations. The purpose of this study was to test the safety of this method by searching for ischemia and apoptosis in areas with BBB disruption induced by pulsed ultrasound in the presence of preformed gas bubbles and by looking for delayed effects up to one month after sonication. Pulsed ultrasound exposures (sonications) were performed in the brains of 24 rabbits under monitoring by magnetic resonance imaging (MRI) (ultrasound: frequency = 1.63 MHz, burst length = 100 ms, PRF = 1 Hz, duration = 20 s, pressure amplitude 0.7 to 1.0 MPa). Before sonication, an ultrasound contrast agent (Optison, GE Healthcare, Milwaukee, WI, USA) was injected IV. BBB disruption was confirmed with contrast-enhanced MR images. Whole brain histologic examination was performed using haematoxylin and eosin staining for general histology, vanadium acid fuchsin-toluidine blue staining for ischemic neurons and TUNEL staining for apoptosis. The main effects observed were tiny regions of extravasated red blood cells scattered around the sonicated locations, indicating affected capillaries. Despite these vasculature effects, only a few cells in some of the sonicated areas showed evidence for apoptosis or ischemia. No ischemic or apoptotic regions were detected that would indicate a compromised blood supply was induced by the sonications. No delayed effects were observed either by MRI or histology up to 4 wk after sonication. Ultrasound-induced BBB disruption is possible without inducing substantial vascular damage that would result in ischemic or apoptotic death to neurons. These findings indicate that this method is safe for targeted drug delivery, at least when compared with the currently available invasive methods.

  12. Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase

    SciTech Connect

    Read, David J.; Li Yong; Chao, Moses V.; Cavanagh, John B.; Glynn, Paul

    2010-05-15

    Single doses of organophosphorus compounds (OP) which covalently inhibit neuropathy target esterase (NTE) can induce lower-limb paralysis and distal damage in long nerve axons. Clinical signs of neuropathy are evident 3 weeks post-OP dose in humans, cats and chickens. By contrast, clinical neuropathy in mice following acute dosing with OPs or any other toxic compound has never been reported. Moreover, dosing mice with ethyloctylphosphonofluoridate (EOPF) - an extremely potent NTE inhibitor - causes a different (subacute) neurotoxicity with brain oedema. These observations have raised the possibility that mice are intrinsically resistant to neuropathies induced by acute toxic insult, but may incur brain oedema, rather than distal axonal damage, when NTE is inactivated. Here we provide the first report that hind-limb dysfunction and extensive axonal damage can occur in mice 3 weeks after acute dosing with a toxic compound, bromophenylacetylurea. Three weeks after acutely dosing mice with neuropathic OPs no clinical signs were observed, but distal lesions were present in the longest spinal sensory axons. Similar lesions were evident in undosed nestin-cre:NTEfl/fl mice in which NTE had been genetically-deleted from neural tissue. The extent of OP-induced axonal damage in mice was related to the duration of NTE inactivation and, as reported in chickens, was promoted by post-dosing with phenylmethanesulfonylfluoride. However, phenyldipentylphosphinate, another promoting compound in chickens, itself induced in mice lesions different from the neuropathic OP type. Finally, EOPF induced subacute neurotoxicity with brain oedema in both wild-type and nestin-cre:NTEfl/fl mice indicating that the molecular target for this effect is not neural NTE.

  13. Emotions promote social interaction by synchronizing brain activity across individuals

    PubMed Central

    Nummenmaa, Lauri; Glerean, Enrico; Viinikainen, Mikko; Jääskeläinen, Iiro P.; Hari, Riitta; Sams, Mikko

    2012-01-01

    Sharing others’ emotional states may facilitate understanding their intentions and actions. Here we show that networks of brain areas “tick together” in participants who are viewing similar emotional events in a movie. Participants’ brain activity was measured with functional MRI while they watched movies depicting unpleasant, neutral, and pleasant emotions. After scanning, participants watched the movies again and continuously rated their experience of pleasantness–unpleasantness (i.e., valence) and of arousal–calmness. Pearson’s correlation coefficient was used to derive multisubject voxelwise similarity measures [intersubject correlations (ISCs)] of functional MRI data. Valence and arousal time series were used to predict the moment-to-moment ISCs computed using a 17-s moving average. During movie viewing, participants' brain activity was synchronized in lower- and higher-order sensory areas and in corticolimbic emotion circuits. Negative valence was associated with increased ISC in the emotion-processing network (thalamus, ventral striatum, insula) and in the default-mode network (precuneus, temporoparietal junction, medial prefrontal cortex, posterior superior temporal sulcus). High arousal was associated with increased ISC in the somatosensory cortices and visual and dorsal attention networks comprising the visual cortex, bilateral intraparietal sulci, and frontal eye fields. Seed-voxel–based correlation analysis confirmed that these sets of regions constitute dissociable, functional networks. We propose that negative valence synchronizes individuals’ brain areas supporting emotional sensations and understanding of another’s actions, whereas high arousal directs individuals’ attention to similar features of the environment. By enhancing the synchrony of brain activity across individuals, emotions may promote social interaction and facilitate interpersonal understanding. PMID:22623534

  14. Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route.

    PubMed

    Mittal, Deepti; Md, Shadab; Hasan, Quamrul; Fazil, Mohammad; Ali, Asgar; Baboota, Sanjula; Ali, Javed

    2016-01-01

    The aim of the present study was to prepare and evaluate a rasagiline-loaded chitosan glutamate nanoparticles (RAS-CG-NPs) by ionic gelation of CG with tripolyphosphate anions (TPP). RAS-loaded CG-NPs were characterized for particle size, size distribution, encapsulation efficiency and in vitro drug release. The mean particles size, polydispersity index (PDI) and encapsulation efficiency was found to be 151.1 ± 10.31, 0.380 ± 0.01 and 96.43 ± 4.23, respectively. Biodistribution of RAS formulations in the brain and blood of mice following intranasal (i.n.) and intravenous (i.v.) administration was performed using HPLC analytical method. The drug concentrations in brain following the i.n. of CG-NPs were found to be significantly higher at all the time points compared to both drug (i.n.) and drug CG-NPs (i.v.). The Cmax (999.25 ng/ml) and AUC (2086.60 ng h/ml) of formulation CG-NPs (i.n) were found to be significantly higher than CG-NPs (i.v.) and RAS solution (i.n.). The direct transport percentage (DTP%) values of RAS-loaded CG-NPs (i.n.) as compared to drug solution (i.n.) increased from 66.27 ± 1.8 to 69.27 ± 2.1%. The results showed significant enhancement of bioavailability in brain, after administration of the RAS-loaded CG-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson's disease therapy.

  15. Fate of microbial metabolites of dietary polyphenols in rats: is the brain their target destination?

    PubMed

    Gasperotti, Mattia; Passamonti, Sabina; Tramer, Federica; Masuero, Domenico; Guella, Graziano; Mattivi, Fulvio; Vrhovsek, Urska

    2015-08-19

    Different polyphenol compounds are ingested when consuming a serving of fruits rich in polyphenols, spanning from one-phenol hydroxybenzoic acid to more complex polymeric compounds. Only a minor quantity of the polyphenols (5-10%) is absorbed. The remainder reaches the colon and is extensively metabolized by gut microbiota to low-molecular weight metabolites. Their subsequent tissue distribution is still undefined, although these microbial metabolites are currently believed to play a role in human health and disease states. To fill this knowledge gap, we performed a pharmacokinetics experiment in which a single bolus of 23 polyphenol microbial metabolites (total 2.7 μmol) was administered intravenously to rats to reliably reproduce a physiological postabsorption situation. Tissues and urine were collected shortly thereafter (15 s to 15 min) and were analyzed by UHPLC-MS/MS to quantitatively track these compounds. Remarkably, the brain was found to be a specific target organ for 10 of the 23 polyphenol metabolites injected, which significantly increased in the treated animals. In most cases, their appearance in the brain was biphasic, with an early wave at 2 min (4 compounds) and a second wave starting at 5 min; at 15 min, 9 compounds were still detectable. Most compounds were excreted into the urine. The concentrations in the brain of the treated animals were compared against those of the control group by Student's t test, with p-values < 0.1 considered to be statistically significant. These findings provide new perspectives for understanding the role of diet on brain chemistry. Our experimental approach has enabled us to obtain rich metabolomics information from a single experiment involving a limited number of animals.

  16. Use of Ultrasound Pulses Combined with Definity for Targeted Blood-Brain Barrier Disruption

    NASA Astrophysics Data System (ADS)

    McDannold, Nathan; Vykhodtseva, Natalia; Hynynen, Kullervo

    2007-05-01

    We have developed a method to combine an ultrasound contrast agent (USCA) with low-intensity focused ultrasound pulses combined to produce temporary blood-brain barrier disruption (BBBD), a potential non-invasive means for targeted drug delivery in the brain. All of our previous work used the USCA Optison. The purpose of this work was to test the feasibility of using the USCA Definity for BBBD. Thirty-six non-overlapping locations were sonicated through a craniotomy in experiments in the brains of nine rabbits (4 locations per rabbit; US frequency: 0.69MHz, burst: 10ms, PRF: 1Hz, duration: 20s; pressure amplitude: 0.2-1.5 MPa). Eleven locations were sonicated using Optison at 0.5 MPa. For both agents, the probability for BBBD was estimated to be 50% at 0.4 MPa using probit regression. In histology, small isolated areas of extravasated erythrocytes were observed in some locations. At 0.8 MPa and above, this extravasation was sometimes accompanied by tiny (dimensions of 100 μm or less) regions of damaged brain parenchyma. The magnitude of the BBBD was larger with Optison than with Definity at 0.5 MPa (P=0.04), and more areas with extravasated erythrocytes were observed (P=0.03). We conclude that BBBD is possible using Definity for the dosage of USCA and the acoustic parameters tested in this study. While the probability for BBBD as a function of pressure amplitude and the type of acute tissue effects was similar to findings with Optison, under these experimental conditions, Optison produced a larger effect.

  17. Neuropathology and neurobehavioral alterations in a rat model of traumatic brain injury to occupants of vehicles targeted by underbody blasts.

    PubMed

    Tchantchou, Flaubert; Fourney, William L; Leiste, Ulrich H; Vaughan, Joshua; Rangghran, Parisa; Puche, Adam; Fiskum, Gary

    2017-03-01

    Many victims of blast-induced traumatic brain injury are occupants of military vehicles targeted by land mines. Recently improved vehicle designs protect these individuals against blast overpressure, leaving acceleration as the main force potentially responsible for brain injury. We recently developed a unique rat model of under-vehicle blast-induced hyperacceleration where exposure to acceleration as low as 50G force results in histopathological evidence of diffuse axonal injury and astrocyte activation, with no evidence of neuronal cell death. This study investigated the effects of much higher blast-induced accelerations (1200 to 2800G) on neuronal cell death, neuro-inflammation, behavioral deficits and mortality. Adult male rats were subjected to this range of accelerations, in the absence of exposure to blast overpressure, and evaluated over 28days for working memory (Y maze) and anxiety (elevated plus maze). In addition, brains obtained from rats at one and seven days post-injury were used for neuropathology and neurochemical assays. Sixty seven percent of rats died soon after being subjected to blasts resulting in 2800G acceleration. All rats exposed to 2400G acceleration survived and exhibited transient deficits in working memory and long-term anxiety like behaviors, while those exposed to 1200 acceleration G force only demonstrated increased anxiety. Behavioral deficits were associated with acute microglia/macrophage activation, increased hippocampal neuronal death, and reduced levels of tight junction- and synapse- associated proteins. Taken together, these results suggest that exposure of rats to high underbody blast-induced G forces results in neurologic injury accompanied by neuronal apoptosis, neuroinflammation and evidence for neurosynaptic alterations.

  18. Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders.

    PubMed

    Sommer, Wolfgang H; Saavedra, Juan M

    2008-06-01

    The brain renin-angiotensin system (RAS) participates importantly in the regulation of endocrine, autonomic, and behavioral response to stress. Recent data indicate that central action of AT(1) receptor antagonists can reduce anxiety symptoms in experimental animals. Furthermore, central inhibition of RAS activity decreases ethanol intake in an animal model of alcoholism. Pathological anxiety responses and the development of substance dependence are both critically mediated through corticotrophin-releasing hormone (CRH) systems, and the RAS is positioned to interact both with hypothalamic as well as extrahypothalamic CRH systems. The thesis of this paper is that the RAS is part of the neurochemical dysregulation underlying negative affective states, anxiety disorders, and ethanol dependence and that medications targeting the RAS should be considered to augment the treatment of these disorders.

  19. Improving brain drug targeting through exploitation of the nose-to-brain route: a physiological and pharmacokinetic perspective.

    PubMed

    Badhan, R K S; Kaur, M; Lungare, S; Obuobi, S

    2014-01-01

    With an ageing population and increasing prevalence of central-nervous system (CNS) disorders new approaches are required to sustain the development and successful delivery of therapeutics into the brain and CNS. CNS drug delivery is challenging due to the impermeable nature of the brain microvascular endothelial cells that form the blood-brain barrier (BBB) and which prevent the entry of a wide range of therapeutics into the brain. This review examines the role intranasal delivery may play in achieving direct brain delivery, for small molecular weight drugs, macromolecular therapeutics and cell-based therapeutics, by exploitation of the olfactory and trigeminal nerve pathways. This approach is thought to deliver drugs into the brain and CNS through bypassing the BBB. Details of the mechanism of transfer of administrated therapeutics, the pathways that lead to brain deposition, with a specific focus on therapeutic pharmacokinetics, and examples of successful CNS delivery will be explored.

  20. Brain activity associated with selective attention, divided attention and distraction.

    PubMed

    Salo, Emma; Salmela, Viljami; Salmi, Juha; Numminen, Jussi; Alho, Kimmo

    2017-03-28

    Top-down controlled selective or divided attention to sounds and visual objects, as well as bottom-up triggered attention to auditory and visual distractors, has been widely investigated. However, no study has systematically compared brain activations related to all these types of attention. To this end, we used functional magnetic resonance imaging (fMRI) to measure brain activity in participants performing a tone pitch or a foveal grating orientation discrimination task, or both, distracted by novel sounds not sharing frequencies with the tones or by extrafoveal visual textures. To force focusing of attention to tones or gratings, or both, task difficulty was kept constantly high with an adaptive staircase method. A whole brain analysis of variance (ANOVA) revealed fronto-parietal attention networks for both selective auditory and visual attention. A subsequent conjunction analysis indicated partial overlaps of these networks. However, like some previous studies, the present results also suggest segregation of prefrontal areas involved in the control of auditory and visual attention. The ANOVA also suggested, and another conjunction analysis confirmed, an additional activity enhancement in the left middle frontal gyrus related to divided attention supporting the role of this area in top-down integration of dual task performance. Distractors expectedly disrupted task performance. However, contrary to our expectations, activations specifically related to the distractors were found only in the auditory and visual cortices. This suggests gating of the distractors from further processing perhaps due to strictly focused attention in the current demanding discrimination tasks.

  1. Brain cholinesterase activity of apparently normal wild birds

    USGS Publications Warehouse

    Hill, E.F.

    1988-01-01

    Organophosphorus and carbamate pesticides are potent anticholinesterase substances that have killed large numbers of wild birds of various species. Cause of death is diagnosed by demonstration of depressed brain cholinesterase (ChE) activity in combination with chemical detection of anticholinesterase residue in the affected specimen. ChE depression is determined by comparison of the affected specimen to normal ChE activity for a sample of control specimens of the same species, but timely procurement of controls is not always possible. Therefore, a reference file of normal whole brain ChE activity is provided for 48 species of wild birds from North America representing 11 orders and 23 families for use as emergency substitutes in diagnosis of anticholinesterase poisoning. The ChE values, based on 83 sets of wild control specimens from across the United States, are reproducible provided the described procedures are duplicated. Overall, whole brain ChE activity varied nearly three-fold among the 48 species represented, but it was usually similar for closely related species. However, some species were statistically separable in most families and some species of the same genus differed as much as 50%.

  2. Sleep after spatial learning promotes covert reorganization of brain activity.

    PubMed

    Orban, Pierre; Rauchs, Géraldine; Balteau, Evelyne; Degueldre, Christian; Luxen, André; Maquet, Pierre; Peigneux, Philippe

    2006-05-02

    Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using functional MRI, we mapped regional cerebral activity during place-finding navigation in a virtual town, immediately after learning and 3 days later, in subjects either allowed regular sleep (RS) or totally sleep-deprived (TSD) on the first posttraining night. At immediate and delayed retrieval, place-finding navigation elicited increased brain activity in an extended hippocampo-neocortical network in both RS and TSD subjects. Behavioral performance was equivalent between groups. However, striatal navigation-related activity increased more at delayed retrieval in RS than in TSD subjects. Furthermore, correlations between striatal response and behavioral performance, as well as functional connectivity between the striatum and the hippocampus, were modulated by posttraining sleep. These data suggest that brain activity is restructured during sleep in such a way that navigation in the virtual environment, initially related to a hippocampus-dependent spatial strategy, becomes progressively contingent in part on a response-based strategy mediated by the striatum. Both neural strategies eventually relate to equivalent performance levels, indicating that covert reorganization of brain patterns underlying navigation after sleep is not necessarily accompanied by overt changes in behavior.

  3. High efficiency cell-specific targeting of cytokine activity

    NASA Astrophysics Data System (ADS)

    Garcin, Geneviève; Paul, Franciane; Staufenbiel, Markus; Bordat, Yann; van der Heyden, José; Wilmes, Stephan; Cartron, Guillaume; Apparailly, Florence; de Koker, Stefaan; Piehler, Jacob; Tavernier, Jan; Uzé, Gilles

    2014-01-01

    Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This ‘activity-by-targeting’ concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.

  4. Dopa decarboxylase activity of the living human brain

    SciTech Connect

    Gjedde, A.; Reith, J.; Dyve, S.; Leger, G.; Guttman, M.; Diksic, M.; Evans, A.; Kuwabara, H. )

    1991-04-01

    Monoaminergic neurons use dopa decarboxylase to form dopamine from L-3,4-dihydroxyphenylalanine (L-dopa). We measured regional dopa decarboxylase activity in brains of six healthy volunteers with 6-({sup 18}F)fluoro-L-dopa and positron emission tomography. We calculated the enzyme activity, relative to its Km, with a kinetic model that yielded the relative rate of conversion of 6-({sup 18}F)fluoro-L-dopa to ({sup 18}F)fluorodopamine. Regional values of relative dopa decarboxylase activity ranged from nil in occipital cortex to 1.9 h-1 in caudate nucleus and putamen, in agreement with values obtained in vitro.

  5. The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention

    PubMed Central

    2012-01-01

    A global health problem, traumatic brain injury (TBI) is especially prevalent in the current era of ongoing world military conflicts. Its pathological hallmark is one or more primary injury foci, followed by a spread to initially normal brain areas via cascades of inflammatory cytokines and chemokines resulting in an amplification of the original tissue injury by microglia and other central nervous system immune cells. In some cases this may predispose individuals to later development of Alzheimer’s disease (AD). The inflammatory-based progression of TBI has been shown to be active in humans for up to 17 years post TBI. Unfortunately, all neuroprotective drug trials have failed, and specific treatments remain less than efficacious. These poor results might be explained by too much of a scientific focus on neurons without addressing the functions of microglia in the brain, which are at the center of proinflammatory cytokine generation. To address this issue, we provide a survey of the TBI-related brain immunological mechanisms that may promote progression to AD. We discuss these immune and microglia-based inflammatory mechanisms involved in the progression of post-trauma brain damage to AD. Flavonoid-based strategies to oppose the antigen-presenting cell-like inflammatory phenotype of microglia will also be reviewed. The goal is to provide a rationale for investigations of inflammatory response following TBI which may represent a pathological link to AD. In the end, a better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI to later AD. PMID:22849382

  6. Time delay between cardiac and brain activity during sleep transitions

    NASA Astrophysics Data System (ADS)

    Long, Xi; Arends, Johan B.; Aarts, Ronald M.; Haakma, Reinder; Fonseca, Pedro; Rolink, Jérôme

    2015-04-01

    Human sleep consists of wake, rapid-eye-movement (REM) sleep, and non-REM (NREM) sleep that includes light and deep sleep stages. This work investigated the time delay between changes of cardiac and brain activity for sleep transitions. Here, the brain activity was quantified by electroencephalographic (EEG) mean frequency and the cardiac parameters included heart rate, standard deviation of heartbeat intervals, and their low- and high-frequency spectral powers. Using a cross-correlation analysis, we found that the cardiac variations during wake-sleep and NREM sleep transitions preceded the EEG changes by 1-3 min but this was not the case for REM sleep transitions. These important findings can be further used to predict the onset and ending of some sleep stages in an early manner.

  7. [Correlation of brain electrical activity and motivation in healthy people].

    PubMed

    Bogovin, L V; Nakhamchen, D L; Kolosov, V P; Perel'man, Iu M

    2014-01-01

    Motivation dominates in the structure of the personality and is one of the basic notions which explains the dynamics of the behavior. The literature has little data about neurophysiology of motivation. The aim of the research was to study the correlation between the motivational sphere and electrical activity of the brain at the influence of different provocations. 24 healthy people at the age of 26-36 years were examined. The results of motivation tests turned out to be uniform (the motivation to success was of a moderate or high level, there were mean values of readiness to risk and low motivation to achievement and approval). Multiple correlations between different types of motivation and electrical activity of the brain at rest, at hyperventilation with room temperature air and at isocapnic cold air hyperventilation were revealed.

  8. Noise in brain activity engenders perception and influences discrimination sensitivity.

    PubMed

    Bernasconi, Fosco; De Lucia, Marzia; Tzovara, Athina; Manuel, Aurelie L; Murray, Micah M; Spierer, Lucas

    2011-12-07

    Behavioral and brain responses to identical stimuli can vary with experimental and task parameters, including the context of stimulus presentation or attention. More surprisingly, computational models suggest that noise-related random fluctuations in brain responses to stimuli would alone be sufficient to engender perceptual differences between physically identical stimuli. In two experiments combining psychophysics and EEG in healthy humans, we investigated brain mechanisms whereby identical stimuli are (erroneously) perceived as different (higher vs lower in pitch or longer vs shorter in duration) in the absence of any change in the experimental context. Even though, as expected, participants' percepts to identical stimuli varied randomly, a classification algorithm based on a mixture of Gaussians model (GMM) showed that there was sufficient information in single-trial EEG to reliably predict participants' judgments of the stimulus dimension. By contrasting electrical neuroimaging analyses of auditory evoked potentials (AEPs) to the identical stimuli as a function of participants' percepts, we identified the precise timing and neural correlates (strength vs topographic modulations) as well as intracranial sources of these erroneous perceptions. In both experiments, AEP differences first occurred ~100 ms after stimulus onset and were the result of topographic modulations following from changes in the configuration of active brain networks. Source estimations localized the origin of variations in perceived pitch of identical stimuli within right temporal and left frontal areas and of variations in perceived duration within right temporoparietal areas. We discuss our results in terms of providing neurophysiologic evidence for the contribution of random fluctuations in brain activity to conscious perception.

  9. Brain activity correlates with emotional perception induced by dynamic avatars.

    PubMed

    Goldberg, Hagar; Christensen, Andrea; Flash, Tamar; Giese, Martin A; Malach, Rafael

    2015-11-15

    An accurate judgment of the emotional state of others is a prerequisite for successful social interaction and hence survival. Thus, it is not surprising that we are highly skilled at recognizing the emotions of others. Here we aimed to examine the neuronal correlates of emotion recognition from gait. To this end we created highly controlled dynamic body-movement stimuli based on real human motion-capture data (Roether et al., 2009). These animated avatars displayed gait in four emotional (happy, angry, fearful, and sad) and speed-matched neutral styles. For each emotional gait and its equivalent neutral gait, avatars were displayed at five morphing levels between the two. Subjects underwent fMRI scanning while classifying the emotions and the emotional intensity levels expressed by the avatars. Our results revealed robust brain selectivity to emotional compared to neutral gait stimuli in brain regions which are involved in emotion and biological motion processing, such as the extrastriate body area (EBA), fusiform body area (FBA), superior temporal sulcus (STS), and the amygdala (AMG). Brain activity in the amygdala reflected emotional awareness: for visually identical stimuli it showed amplified stronger response when the stimulus was perceived as emotional. Notably, in avatars gradually morphed along an emotional expression axis there was a parametric correlation between amygdala activity and emotional intensity. This study extends the mapping of emotional decoding in the human brain to the domain of highly controlled dynamic biological motion. Our results highlight an extensive level of brain processing of emotional information related to body language, which relies mostly on body kinematics.

  10. Human brain activity with near-infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Luo, Qingming; Chance, Britton

    1999-09-01

    Human brain activity was studied with a real time functional Near-InfraRed Imager (fNIRI). The imager has 16 measurement channels and covers 4 cm by 9 cm detection area. Brain activities in occipital, motor and prefrontal area were studied with the fNIRI. In prefrontal stimulation, language cognition, analogies, forming memory for new associations, emotional thinking, and mental arithmetic were carried out. Experimental results measured with fNIRI are demonstrated in this paper. It was shown that fNIRI technique is able to reveal the occipital activity during visual stimulation, and co-register well with results of fMRI in the motor cortex activity during finger tapping. In the studies of the effects of left prefrontal lobe on forming memory for new associations, it is shown that left prefrontal lobe activated more under deep conditions than that under shallow encoding, especially the dorsal part. In the studies of emotional thinking, it was shown that the responses were different between positive- negative emotional thinking and negative-positive emotional thinking. In mental arithmetic studies, higher activation was found in the first task than in the second, regardless of the difficulty, and higher activation was measured in subtraction of 17 than in subtraction of 3.

  11. Apparent target size of rat brain benzodiazepine receptor, acetylcholinesterase, and pyruvate kinase is highly influenced by experimental conditions

    SciTech Connect

    Nielsen, M.; Braestrup, C.

    1988-08-25

    Radiation inactivation is a method to determine the apparent target size of molecules. In this report we examined whether radiation inactivation of various enzymes and brain receptors is influenced by the preparation of samples preceding irradiation. The apparent target sizes of endogenous acetylcholinesterase and pyruvate kinase from rat brain and from rabbit muscle and benzodiazepine receptor from rat brain were investigated in some detail. In addition the target sizes of alcohol dehydrogenase (from yeast and horse liver), beta-galactosidase (from Escherichia coli), lactate dehydrogenase (endogenous from rat brain), and 5-HT2 receptors, acetylcholine muscarine receptors, and (/sup 35/S) butyl bicyclophosphorothionate tertiary binding sites from rat brain were determined. The results show that apparent target sizes are highly influenced by the procedure applied for sample preparation before irradiation. The data indicate that irradiation of frozen whole tissue as opposed to lyophilized tissue or frozen tissue homogenates will estimate the smallest and most relevant functional target size of a receptor or an enzyme.

  12. Changes in spontaneous brain activity in early Parkinson's disease.

    PubMed

    Yang, Hong; Zhou, Xiaohong Joe; Zhang, Min-Ming; Zheng, Xu-Ning; Zhao, Yi-Lei; Wang, Jue

    2013-08-09

    Resting state brain activity can provide valuable insights into the pathophysiology of Parkinson's disease (PD). The purpose of the present study was (a) to investigate abnormal spontaneous neuronal activity in early PD patients using resting-state functional MRI (fMRI) with a regional homogeneity (ReHo) method and (b) to demonstrate the potential of using changes in abnormal spontaneous neuronal activity for monitoring the progression of PD during its early stages. Seventeen early PD patients were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr disability scale and the Mini-mental State Examination (MMSE) were compared with seventeen gender- and age-matched healthy controls. All subjects underwent MRI scans using a 1.5T General Electric Signa Excite II scanner. The MRI scan protocol included whole-brain volumetric imaging using a 3D inversion recovery prepared (IR-Prep) fast spoiled gradient-echo pulse sequence and 2D multi-slice (22 axial slices covering the whole brain) resting-state fMRI using an echo planar imaging (EPI) sequence. Images were analyzed in SPM5 together with a ReHo algorithm using the in-house software program REST. A corrected threshold of p<0.05 was determined by AlphaSim and used in statistical analysis. Compared with the healthy controls, the early PD group showed significantly increased ReHo in a number of brain regions, including the left cerebellum, left parietal lobe, right middle temporal lobe, right sub-thalamic nucleus areas, right superior frontal gyrus, middle frontal gyrus (MFG), right inferior parietal lobe (IPL), right precuneus lobe, left MFG and left IPL. Additionally, significantly reduced ReHo was also observed in the early PD patients in the following brain regions: the left putamen, left inferior frontal gyrus, right hippocampus, right anterior cingulum, and bilateral lingual gyrus. Moreover, in PD patients, ReHo in the left putamen was negatively correlated with the UPDRS scores (r=-0

  13. Brain activation to cocaine cues and motivation/treatment status.

    PubMed

    Prisciandaro, James J; McRae-Clark, Aimee L; Myrick, Hugh; Henderson, Scott; Brady, Kathleen T

    2014-03-01

    Motivation to change is believed to be a key factor in therapeutic success in substance use disorders; however, the neurobiological mechanisms through which motivation to change impacts decreased substance use remain unclear. Existing research is conflicting, with some investigations supporting decreased and others reporting increased frontal activation to drug cues in individuals seeking treatment for substance use disorders. The present study investigated the relationship between motivation to change cocaine use and cue-elicited brain activity in cocaine-dependent individuals using two conceptualizations of 'motivation to change': (1) current treatment status (i.e. currently receiving versus not receiving outpatient treatment for cocaine dependence) and (2) self-reported motivation to change substance use, using the Stages of Change Readiness and Treatment Eagerness Scale. Thirty-eight cocaine-dependent individuals (14 currently in treatment) completed a diagnostic assessment and an fMRI cocaine cue-reactivity task. Whole-brain analyses demonstrated that both treatment-seeking and motivated participants had lower activation to cocaine cues in a wide variety of brain regions in the frontal, occipital, temporal and cingulate cortices relative to non-treatment-seeking and less motivated participants. Future research is needed to explain the mechanism by which treatment and/or motivation impacts neural cue reactivity, as such work could potentially aid in the development of more effective therapeutic techniques for substance-dependent patients.

  14. How networks communicate: propagation patterns in spontaneous brain activity.

    PubMed

    Mitra, Anish; Raichle, Marcus E

    2016-10-05

    Initially regarded as 'noise', spontaneous (intrinsic) activity accounts for a large portion of the brain's metabolic cost. Moreover, it is now widely known that infra-slow (less than 0.1 Hz) spontaneous activity, measured using resting state functional magnetic resonance imaging of the blood oxygen level-dependent (BOLD) signal, is correlated within functionally defined resting state networks (RSNs). However, despite these advances, the temporal organization of spontaneous BOLD fluctuations has remained elusive. By studying temporal lags in the resting state BOLD signal, we have recently shown that spontaneous BOLD fluctuations consist of remarkably reproducible patterns of whole brain propagation. Embedded in these propagation patterns are unidirectional 'motifs' which, in turn, give rise to RSNs. Additionally, propagation patterns are markedly altered as a function of state, whether physiological or pathological. Understanding such propagation patterns will likely yield deeper insights into the role of spontaneous activity in brain function in health and disease.This article is part of the themed issue 'Interpreting blood oxygen level-dependent: a dialogue between cognitive and cellular neuroscience'.

  15. Movement preparation and execution: differential functional activation patterns after traumatic brain injury.

    PubMed

    Gooijers, Jolien; Beets, Iseult A M; Albouy, Genevieve; Beeckmans, Kurt; Michiels, Karla; Sunaert, Stefan; Swinnen, Stephan P

    2016-09-01

    Years following the insult, patients with traumatic brain injury often experience persistent motor control problems, including bimanual coordination deficits. Previous studies revealed that such deficits are related to brain structural white and grey matter abnormalities. Here, we assessed, for the first time, cerebral functional activation patterns during bimanual movement preparation and performance in patients with traumatic brain injury, using functional magnetic resonance imaging. Eighteen patients with moderate-to-severe traumatic brain injury (10 females; aged 26.3 years, standard deviation = 5.2; age range: 18.4-34.6 years) and 26 healthy young adults (15 females; aged 23.6 years, standard deviation = 3.8; age range: 19.5-33 years) performed a complex bimanual tracking task, divided into a preparation (2 s) and execution (9 s) phase, and executed either in the presence or absence of augmented visual feedback. Performance on the bimanual tracking task, expressed as the average target error, was impaired for patients as compared to controls (P < 0.001) and for trials in the absence as compared to the presence of augmented visual feedback (P < 0.001). At the cerebral level, movement preparation was characterized by reduced neural activation in the patient group relative to the control group in frontal (bilateral superior frontal gyrus, right dorsolateral prefrontal cortex), parietal (left inferior parietal lobe) and occipital (right striate and extrastriate visual cortex) areas (P's < 0.05). During the execution phase, however, the opposite pattern emerged, i.e. traumatic brain injury patients showed enhanced activations compared with controls in frontal (left dorsolateral prefrontal cortex, left lateral anterior prefrontal cortex, and left orbitofrontal cortex), parietal (bilateral inferior parietal lobe, bilateral superior parietal lobe, right precuneus, right primary somatosensory cortex), occipital (right striate and extrastriate visual cortices), and

  16. Early Oxygen-Utilization and Brain Activity in Preterm Infants

    PubMed Central

    de Vries, Linda S.; Groenendaal, Floris; Toet, Mona C.; Lemmers, Petra M. A.; Vosse van de, Renè E.; van Bel, Frank; Benders, Manon J. N. L.

    2015-01-01

    The combined monitoring of oxygen supply and delivery using Near-InfraRed spectroscopy (NIRS) and cerebral activity using amplitude-integrated EEG (aEEG) could yield new insights into brain metabolism and detect potentially vulnerable conditions soon after birth. The relationship between NIRS and quantitative aEEG/EEG parameters has not yet been investigated. Our aim was to study the association between oxygen utilization during the first 6 h after birth and simultaneously continuously monitored brain activity measured by aEEG/EEG. Forty-four hemodynamically stable babies with a GA < 28 weeks, with good quality NIRS and aEEG/EEG data available and who did not receive morphine were included in the study. aEEG and NIRS monitoring started at NICU admission. The relation between regional cerebral oxygen saturation (rScO2) and cerebral fractional tissue oxygen extraction (cFTOE), and quantitative measurements of brain activity such as number of spontaneous activity transients (SAT) per minute (SAT rate), the interval in seconds (i.e. time) between SATs (ISI) and the minimum amplitude of the EEG in μV (min aEEG) were evaluated. rScO2 was negatively associated with SAT rate (β=-3.45 [CI=-5.76- -1.15], p=0.004) and positively associated with ISI (β=1.45 [CI=0.44-2.45], p=0.006). cFTOE was positively associated with SAT rate (β=0.034 [CI=0.009-0.059], p=0.008) and negatively associated with ISI (β=-0.015 [CI=-0.026- -0.004], p=0.007). Oxygen delivery and utilization, as indicated by rScO2 and cFTOE, are directly related to functional brain activity, expressed by SAT rate and ISI during the first hours after birth, showing an increase in oxygen extraction in preterm infants with increased early electro-cerebral activity. NIRS monitored oxygenation may be a useful biomarker of brain vulnerability in high-risk infants. PMID:25965343

  17. The brain in micro- and hypergravity: the effects of changing gravity on the brain electrocortical activity.

    PubMed

    Marušič, Uroš; Meeusen, Romain; Pišot, Rado; Kavcic, Voyko

    2014-01-01

    Understanding the effects of increased and decreased gravity on central nervous system is essential for developing proper physical and cognitive countermeasures to assure safe and effective space missions and human survival in space. This short review covers the available literature on the brain electrocortical activity effects of decreased and increased gravitational force comparing to the 1g Earth conditions. Among all neuroimaging methods such as functional magnetic resonance imaging (fMRI), positron-emission tomography (PET), diffusion tensor imaging (DTI), the electroencephalography (EEG) was found to be suitable method to monitor brain electrocortical activity in the extreme environments. Due to complexity and high cost of space flight missions, ground-based models have been employed to simulate microgravity effects on human body. Surprisingly, there is very limited number of publications reporting gravity-dependent EEG spectral changes. With increased gravity there are initially increased EEG activity in higher frequencies and at around 4 g appears loss of consciousness with accompanying slowing of EEG due to hypoxia. In microgravity, the most prevalent changes in EEG are faster frequencies such as alpha and beta. The results from simulated microgravity (bed rest) are pointing to changes in theta and alpha, representing signs of cortical inhibition. The changes in EEG activity in space flight are attributed to a decreased sensorimotor input while in parabolic flights short and fast transitions from hyper to microgravity presumably reflect lower arousal levels and emotional processes in microgravity. Thus, based on limited research about gravity-related changes in EEG from different environments it is difficult to draw any unequivocal conclusions. Additional systematic studies about electrocortical activity in space and parabolic flights, as well as longer bed rest studies are needed in order to advance knowledge about brain functioning in extreme conditions

  18. Characteristics of sequential targeting of brain glioma for transferrin-modified cisplatin liposome.

    PubMed

    Lv, Qing; Li, Li-Min; Han, Min; Tang, Xin-Jiang; Yao, Jin-Na; Ying, Xiao-Ying; Li, Fan-Zhu; Gao, Jian-Qing

    2013-02-28

    Methods on how to improve the sequential targeting of glioma subsequent to passing of drug through the blood-brain barrier (BBB) have been occasionally reported. However, the characteristics involved are poorly understood. In the present study, cisplatin (Cis) liposome (lipo) was modified with transferrin (Tf) to investigate the characteristics of potential sequential targeting to glioma. In bEnd3/C6 co-culture BBB models, higher transport efficiency across the BBB and cytotoxicity in basal C6 cells induced by Cis-lipo(Tf) than Cis-lipo and Cis-solution, suggest its sequential targeting effect. Interestingly, similar liposomal morphology as that of donor compartment was first demonstrated in the receptor solution of BBB models. Meanwhile, a greater acquisition in the lysosome of bEnd3, distributed sequentially into the nucleus of C6 cells were found for the Cis-lipo(Tf). Pre-incubation of chlorpromazine and Tf inhibited this process, indicating that a clathrin-dependent endocytosis is involved in the transport of Cis-lipo(Tf) across the BBB.

  19. Transcriptionally active genome regions are preferred targets for retrovirus integration.

    PubMed Central

    Scherdin, U; Rhodes, K; Breindl, M

    1990-01-01

    We have analyzed the transcriptional activity of cellular target sequences for Moloney murine leukemia virus integration in mouse fibroblasts. At least five of the nine random, unselected integration target sequences studied showed direct evidence for transcriptional activity by hybridization to nuclear run-on transcripts prepared from uninfected cells. At least four of the sequences contained multiple recognition sites for several restriction enzymes that cut preferentially in CpG-rich islands, indicating integration into 5' or 3' ends or flanking regions of genes. Assuming that only a minor fraction (less than 20%) of the genome is transcribed in mammalian cells, we calculated the probability that this association of retroviral integration sites with transcribed sequences is due to chance to be very low (1.6 x 10(-2]. Thus, our results strongly suggest that transcriptionally active genome regions are preferred targets for retrovirus integration. Images PMID:2296087

  20. An active contour-based atlas registration model applied to automatic subthalamic nucleus targeting on MRI: method and validation.

    PubMed

    Duay, Valérie; Bresson, Xavier; Castro, Javier Sanchez; Pollo, Claudio; Cuadra, Meritxell Bach; Thiran, Jean-Philippe

    2008-01-01

    This paper presents a new non parametric atlas registration framework, derived from the optical flow model and the active contour theory, applied to automatic subthalamic nucleus (STN) targeting in deep brain stimulation (DBS) surgery. In a previous work, we demonstrated that the STN position can be predicted based on the position of surrounding visible structures, namely the lateral and third ventricles. A STN targeting process can thus be obtained by registering these structures of interest between a brain atlas and the patient image. Here we aim to improve the results of the state of the art targeting methods and at the same time to reduce the computational time. Our simultaneous segmentation and registration model shows mean STN localization errors statistically similar to the most performing registration algorithms tested so far and to the targeting expert's variability. Moreover, the computational time of our registration method is much lower, which is a worthwhile improvement from a clinical point of view.

  1. Neuroimaging and Neuroenergetics: Brain Activations as Information-Driven Reorganization of Energy Flows

    ERIC Educational Resources Information Center

    Strelnikov, Kuzma

    2010-01-01

    There is increasing focus on the neurophysiological underpinnings of brain activations, giving birth to an emerging branch of neuroscience--neuroenergetics. However, no common definition of "brain activation" exists thus far. In this article, we define brain activation as the information-driven reorganization of energy flows in a population of…

  2. Effects of cannabinoids on the activities of mouse brain lipases.

    PubMed

    Hunter, S A; Burstein, S; Renzulli, L

    1986-09-01

    Cannabinoids were found to augment phospholipase activities and modify lipid levels of mouse brain synaptosomes, myelin and mitochondria. Delta-1-tetra-hydrocannabinol (delta 1-THC) and several of its metabolites induced a dose-dependent (0.32-16 microM) stimulation of phospholipase A2 (PLA2) activity resulting in the increased release of free arachidonic acid from exogenous [1-14C]phosphatidylcholine (PC). The potencies of the cannabinoids in modulating PLA2 activity were approximately of the order: 7-OH-delta 1-THC greater than delta 1-THC greater than 7-oxo-delta 1-THC greater than delta 1-THC-7-oic acid = 6 alpha OH-delta 1-THC much greater than 6 beta-OH-delta 1-THC. The hydrolysis of phosphatidylinositol (PI) by synaptosomal phospholipase C (PLC) was enhanced significantly by delta 1-THC and promoted diacylglyceride levels by greater than 100 percent compared to control values. In contrast, arachidonate was the major product resulting from phospholipase activities of a 20,000 g pellet. Synaptosomal diacylglyceride lipase activity was inhibited by delta 1-THC. [1-14C]Arachidonic acid was readily incorporated into subcellular membrane phospholipids and after exposure to cannabinoids led to diminished phosphoglyceride levels and concomitant increases in released neutral lipid products. These data suggest that cannabinoids control phospholipid turnover and metabolism in mouse brain preparations by the activation of phospholipases and, through this mechanism, may exert some of their effects.

  3. Development of an improved active gas target design for ANASEN

    NASA Astrophysics Data System (ADS)

    Schill, Sabina; Blackmon, J. C.; Deibel, C. M.; Macon, K. T.; Rasco, B. C.; Wiedenhoever, I.

    2014-09-01

    The Array for Nuclear Astrophysics and Structure with Exotic Nuclei (ANASEN) is a charged particle detector array with an active gas target-detector capability for sensitive measurements using radioactive ion beams. One of the main goals is to improve our understanding of nuclear reactions important in stellar explosions. Following initial experimental campaigns with ANASEN, we have been developing an improved active gas target design for ANASEN that incorporates an innovative cylindrical gas ionization detector for heavy ions surrounding the beam axis inside of the other ANASEN charged particle detectors. The detection of heavy ions in coincidence with lighter ions in a redesigned proportional counter will provide greater discriminating power. The new active gas target design will be presented, and its simulated performance will be compared with test data. The Array for Nuclear Astrophysics and Structure with Exotic Nuclei (ANASEN) is a charged particle detector array with an active gas target-detector capability for sensitive measurements using radioactive ion beams. One of the main goals is to improve our understanding of nuclear reactions important in stellar explosions. Following initial experimental campaigns with ANASEN, we have been developing an improved active gas target design for ANASEN that incorporates an innovative cylindrical gas ionization detector for heavy ions surrounding the beam axis inside of the other ANASEN charged particle detectors. The detection of heavy ions in coincidence with lighter ions in a redesigned proportional counter will provide greater discriminating power. The new active gas target design will be presented, and its simulated performance will be compared with test data. This work was supported by the U.S. National Science Foundation and the Dept of Energy's Office of Science.

  4. Laterality of Brain Activation for Risk Factors of Addiction

    PubMed Central

    Gordon, Harold W.

    2015-01-01

    Background Laterality of brain activation is reported for tests of risk factors of addiction—impulsivity and craving—but authors rarely address the potential significance of those asymmetries. Objective The purpose of this study is to demonstrate this laterality and discuss its relevance to cognitive and neurophysiological asymmetries associated with drug abuse vulnerability in order to provide new insights for future research in drug abuse. Method From published reports, brain areas of activation for two tests of response inhibition or craving for drugs of abuse were compiled from fMRI activation peaks were tabulated for eight sections (octants) in each hemisphere. Percent asymmetries were calculated (R−L/R+L) across studies for each area. Results For impulsivity, most activation peaks favored the right hemisphere. Overall, the percent difference was 32% (Χ2 = 16.026; p < .0001) with the greater asymmetry for anterior peaks (46.8%; Χ2 = 17.329; p < .0001). The asymmetries for cue-induced craving were opposite, favoring the left hemisphere by 6.7% (Χ2 = 4.028; p < .05). The consistency of left asymmetry was found for almost all drugs. For nicotine, studies where subjects were not allowed to smoke (deprived) prior to measurement had the same left hemisphere activation but those who smoked (satiated) before the fMRI measure showed right asymmetry. Conclusions Brain activation studies demonstrate different left/right hemispheric contributions for impulsivity versus craving—factors related to addiction. Failure to take laterality into consideration is a missed opportunity in designing studies and gaining insight into the etiology of drug abuse and pathways for treatment. PMID:26674074

  5. Altered Spontaneous Brain Activity in Betel Quid Dependence

    PubMed Central

    Liu, Tao; Li, Jian-jun; Zhao, Zhong-yan; Yang, Guo-shuai; Pan, Meng-jie; Li, Chang-qing; Pan, Su-yue; Chen, Feng

    2016-01-01

    Abstract It has been suggested by the first voxel-based morphometry investigation that betel quid dependence (BQD) individuals are presented with brain structural changes in previous reports, and there may be a neurobiological basis for BQD individuals related to an increased risk of executive dysfunction and disinhibition, subjected to the reward system, cognitive system, and emotion system. However, the effects of BQD on neural activity remain largely unknown. Individuals with impaired cognitive control of behavior often reveal altered spontaneous cerebral activity in resting-state functional magnetic resonance imaging and those changes are usually earlier than structural alteration. Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy control participants (n = 32) in an resting-state functional magnetic resonance imaging study to observe brain function alterations associated with the severity of BQD. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were both evaluated to stand for spontaneous cerebral activity. Gray matter volumes of these participants were also calculated for covariate. In comparison with healthy controls, BQD individuals demonstrated dramatically decreased ALFF and ReHo values in the prefrontal gurus along with left fusiform, and increased ALFF and ReHo values in the primary motor cortex area, temporal lobe as well as some regions of occipital lobe. The betel quid dependence scores (BQDS) were negatively related to decreased activity in the right anterior cingulate. The abnormal spontaneous cerebral activity revealed by ALFF and ReHo calculation excluding the structural differences in patients with BQD may help us probe into the neurological pathophysiology underlying BQD-related executive dysfunction and disinhibition. Diminished spontaneous brain activity in the right anterior cingulate cortex may, therefore, represent a biomarker of BQD individuals. PMID

  6. Spatiotemporal dynamics of large-scale brain activity

    NASA Astrophysics Data System (ADS)

    Neuman, Jeremy

    Understanding the dynamics of large-scale brain activity is a tough challenge. One reason for this is the presence of an incredible amount of complexity arising from having roughly 100 billion neurons connected via 100 trillion synapses. Because of the extremely high number of degrees of freedom in the nervous system, the question of how the brain manages to properly function and remain stable, yet also be adaptable, must be posed. Neuroscientists have identified many ways the nervous system makes this possible, of which synaptic plasticity is possibly the most notable one. On the other hand, it is vital to understand how the nervous system also loses stability, resulting in neuropathological diseases such as epilepsy, a disease which affects 1% of the population. In the following work, we seek to answer some of these questions from two different perspectives. The first uses mean-field theory applied to neuronal populations, where the variables of interest are the percentages of active excitatory and inhibitory neurons in a network, to consider how the nervous system responds to external stimuli, self-organizes and generates epileptiform activity. The second method uses statistical field theory, in the framework of single neurons on a lattice, to study the concept of criticality, an idea borrowed from physics which posits that in some regime the brain operates in a collectively stable or marginally stable manner. This will be examined in two different neuronal networks with self-organized criticality serving as the overarching theme for the union of both perspectives. One of the biggest problems in neuroscience is the question of to what extent certain details are significant to the functioning of the brain. These details give rise to various spatiotemporal properties that at the smallest of scales explain the interaction of single neurons and synapses and at the largest of scales describe, for example, behaviors and sensations. In what follows, we will shed some

  7. Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain.

    PubMed

    Zarebkohan, Amir; Najafi, Farhood; Moghimi, Hamid Reza; Hemmati, Mohammad; Deevband, Mohammad Reza; Kazemi, Bahram

    2015-10-12

    Blood-brain barrier inhibits most of drugs and genetic materials from reaching the brain. So, developing high efficiency carriers for gene and drug delivery to the brain, is the challenging area in pharmaceutical sciences. This investigation aimed to target DNA to brain using Serine-Arginine-Leucine (SRL) functionalized PAMAM dendrimers as a novel gene delivery system. The SRL peptide was linked on G4 PAMAM dendrimers using bifunctional PEG. DNA was then loaded in these functionalized nanoparticles and their physicochemical properties and cellular uptake/distribution evaluated by AFM, NMR, FTIR and fluorescence and confocal microscopy. Also, biodistribution and brain localization of nanoparticles were studied after IV injection of nanoparticles into rat tail. Unmodified nanoparticles were used as control in all evaluations. In vitro studies showed that SRL-modified nanoparticles have good transfection efficacy and low toxicity. Results also showed that SRL is a LRP ligand and SRL-modified nanoparticles internalized by clathrin/caveolin energy-dependent endocytosis to brain capillary endothelial cells. After intravenous administration, the SRL-modified nanoparticles were able to cross the blood-brain barrier and enter the brain parenchyma. Our result showed that, SRL-modified nanoparticles provide a safe and effective nanocarrier for brain gene delivery.

  8. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    PubMed Central

    Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

    2014-01-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

  9. Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer's Disease

    PubMed Central

    de la Monte, Suzanne M

    2012-01-01

    Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades. PMID:22329651

  10. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors.

    PubMed

    Sampson, John H; Akabani, Gamal; Archer, Gerald E; Berger, Mitchel S; Coleman, R Edward; Friedman, Allan H; Friedman, Henry S; Greer, Kim; Herndon, James E; Kunwar, Sandeep; McLendon, Roger E; Paolino, Alison; Petry, Neil A; Provenzale, James M; Reardon, David A; Wong, Terence Z; Zalutsky, Michael R; Pastan, Ira; Bigner, Darell D

    2008-06-01

    The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

  11. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors

    PubMed Central

    Sampson, John H.; Akabani, Gamal; Archer, Gerald E.; Berger, Mitchel S.; Coleman, R. Edward; Friedman, Allan H.; Friedman, Henry S.; Greer, Kim; Herndon, James E.; Kunwar, Sandeep; McLendon, Roger E.; Paolino, Alison; Petry, Neil A.; Provenzale, James M.; Reardon, David A.; Wong, Terence Z.; Zalutsky, Michael R.; Pastan, Ira; Bigner, Darell D.

    2008-01-01

    The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of 123I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused 123I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5–102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of 123I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses ≤100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients. PMID:18403491

  12. Alterations in Cholinergic Pathways and Therapeutic Strategies Targeting Cholinergic System after Traumatic Brain Injury

    PubMed Central

    Shin, Samuel S.

    2015-01-01

    Abstract Traumatic brain injury (TBI) results in varying degrees of disability in a significant number of persons annually. The mechanisms of cognitive dysfunction after TBI have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noradrenergic dysfunction has been described in many previous reports. In addition, cholinergic dysfunction has also been a familiar topic among TBI researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in previous studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction after TBI. In addition, we describe studies that use both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies. PMID:25646580

  13. A target-specific electrode and lead design for internal globus pallidus deep brain stimulation.

    PubMed

    Vasques, Xavier; Cif, Laura; Mennessier, Gérard; Coubes, Philippe

    2010-01-01

    In nearly all deep brain stimulation (DBS) applications, the same quadripolar electrode design is used for different anatomical targets even if shape and volume differences exist between nuclei. Taking into account the electrode location within the internal globus pallidus (GPi) and the size of the GPi, 2 electrodes were designed in order to improve the therapeutic benefit, to minimize side effects from DBS and to obtain a more homogeneous electric field distribution. The electrodes were evaluated numerically by using a stereotactic model measuring the correlation between the electric field and the GPi. The model was applied to 26 dystonodyskinetic patients who underwent surgery for a bilateral lead implantation into the posteroventral part of the GPi. The designed electrodes produced a more homogeneous distribution of the electric field than the quadripolar electrode.

  14. Cross validation of experts versus registration methods for target localization in deep brain stimulation.

    PubMed

    Sánchez Castro, F Javier; Pollo, Claudio; Meuli, Reto; Maeder, Philippe; Cuadra, Meritxell Bach; Cuisenaire, Olivier; Villemure, Jean-Guy; Thiran, Jean-Philippe

    2005-01-01

    In the last five years, Deep Brain Stimulation (DBS) has become the most popular and effective surgical technique for the treatent of Parkinson's disease (PD). The Subthalamic Nucleus (STN) is the usual target involved when applying DBS. Unfortunately, the STN is in general not visible in common medical imaging modalities. Therefore, atlas-based segmentation is commonly considered to locate it in the images. In this paper, we propose a scheme that allows both, to perform a comparison between different registration algorithms and to evaluate their ability to locate the STN automatically. Using this scheme we can evaluate the expert variability against the error of the algorithms and we demonstrate that automatic STN location is possible and as accurate as the methods currently used.

  15. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    NASA Astrophysics Data System (ADS)

    Hsu, Shu-Hui; Wen, Chih-Jen; Al-Suwayeh, S. A.; Chang, Hui-Wen; Yen, Tzu-Chen; Fang, Jia-You

    2010-10-01

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  16. Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease.

    PubMed

    Aliev, Gjumrakch; Palacios, Hector H; Walrafen, Brianna; Lipsitt, Amanda E; Obrenovich, Mark E; Morales, Ludis

    2009-10-01

    Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense "hypoxic" mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.

  17. Targeted delivery of GDNF through the blood-brain barrier by MRI-guided focused ultrasound.

    PubMed

    Wang, Feng; Shi, Yu; Lu, Lin; Liu, Li; Cai, Youli; Zheng, Hairong; Liu, Xin; Yan, Fei; Zou, Chao; Sun, Chengyu; Shi, Jie; Lu, Shukun; Chen, Yun

    2012-01-01

    Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), are promising therapeutic agents for neurodegenerative diseases. However, the application of GDNF to treat these diseases effectively is limited because the blood-brain barrier (BBB) prevents the local delivery of macromolecular therapeutic agents from entering the central nervous system (CNS). Focused ultrasound combined with microbubbles (MBs) using appropriate parameters has been previously demonstrated to be able to open the BBB locally and noninvasively. This study investigated the targeted delivery of GDNF MBs through the BBB by magnetic resonance imaging (MRI)-guided focused ultrasound. Evans Blue extravasation and histological examination were used to determine the optimum focused ultrasound parameters. Enzyme-linked immunosorbent assay was performed to verify the effects of GDNF bound on MBs using a biotin-avidin bridging chemistry method to promote GDNF delivery into the brain. The results showed that GDNF can be delivered locally and noninvasively into the CNS through the BBB using MRI-guided focused ultrasound combined with MBs under optimum parameters. MBs that bind GDNF combined with MRI-guided focused ultrasound may be an effective way of delivering neurotrophic factors directly into the CNS. The method described herein provides a potential means of treating patients with CNS diseases.

  18. Efficacy of surface charge in targeting pegylated nanoparticles of sulpiride to the brain.

    PubMed

    Parikh, Tapan; Bommana, Murali Mohan; Squillante, Emilio

    2010-03-01

    The objective of the study was to formulate sulpiride-loaded nanoparticles (NPs) that can improve bioretention and achieve dose reduction by passively targeting the drug near the site of action. Methoxy PEG-PLA and maleimide PEG-PLA were synthesized via ring opening polymerization of L-lactide and used to prepare pegylated nanoparticles (NPs) loaded with sulpiride by emulsification and solvent evaporation method. Thiolated cationized bovine serum albumin (CBSA) was conjugated through the maleimide function to the NPs. Rhodamine B and Alexa Fluor 488 were used as fluorescent markers for nanoparticle uptake studies. The nanoparticles were characterized for particle size, zeta potential and drug loading. Sprague Dawley rats were administered with each of CBSA-NPs, BSA-NPs and uncoated NPs (10mg/kg) via tail vein; plasma and urine concentrations were measured and tissue sections were observed under fluorescence microscope. Characterized particles (mean particle size 329+/-44 nm) indicated the conjugation of cationic albumin to NPs (zeta potential shift from -39 mV to -19 mV). Fluorescence showed a high accumulation of CBSA-NPs in brain compared to that of BSA-NPs and uncoated NPs supported by plasma and urine profile. The significant results proved that CBSA-NPs could be a promising brain drug delivery for sulpiride.

  19. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness.

    PubMed

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood-retinal barrier and blood-cochlear barrier, which have a comparable structure to the blood-brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.

  20. Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis

    PubMed Central

    Cassano, Paolo; Petrie, Samuel R.; Hamblin, Michael R.; Henderson, Theodore A.; Iosifescu, Dan V.

    2016-01-01

    Abstract. We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: “near-infrared radiation,” “NIR,” “low-level light therapy,” “low-level laser therapy,” or “LLLT” plus “depression.” We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD. PMID:26989758

  1. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

    PubMed Central

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood–retinal barrier and blood–cochlear barrier, which have a comparable structure to the blood–brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration. PMID:25995632