Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2012-11-01

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

Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

DTIC Science & Technology

2015-12-01

response. e. Correlate imaging findings with histological studies of vascular damage, tumor cell and endothelial cell apoptosis or necrosis and vascular ...phosphatidylserine (PS) is exposed exclusively on tumor vascular endothelium of brain metastases in mouse models. A novel PS-targeting antibody, PGN635... vascular endothelial cells in multi-focal brain metastases throughout the whole mouse brain. Vascular endothelium in normal brain tissues is negative

Higher-order Brain Areas Associated with Real-time Functional MRI Neurofeedback Training of the Somato-motor Cortex.

PubMed

Auer, Tibor; Dewiputri, Wan Ilma; Frahm, Jens; Schweizer, Renate

2018-05-15

Neurofeedback (NFB) allows subjects to learn self-regulation of neuronal brain activation based on information about the ongoing activation. The implementation of real-time functional magnetic resonance imaging (rt-fMRI) for NFB training now facilitates the investigation into underlying processes. Our study involved 16 control and 16 training right-handed subjects, the latter performing an extensive rt-fMRI NFB training using motor imagery. A previous analysis focused on the targeted primary somato-motor cortex (SMC). The present study extends the analysis to the supplementary motor area (SMA), the next higher brain area within the hierarchy of the motor system. We also examined transfer-related functional connectivity using a whole-volume psycho-physiological interaction (PPI) analysis to reveal brain areas associated with learning. The ROI analysis of the pre- and post-training fMRI data for motor imagery without NFB (transfer) resulted in a significant training-specific increase in the SMA. It could also be shown that the contralateral SMA exhibited a larger increase than the ipsilateral SMA in the training and the transfer runs, and that the right-hand training elicited a larger increase in the transfer runs than the left-hand training. The PPI analysis revealed a training-specific increase in transfer-related functional connectivity between the left SMA and frontal areas as well as the anterior midcingulate cortex (aMCC) for right- and left-hand trainings. Moreover, the transfer success was related with training-specific increase in functional connectivity between the left SMA and the target area SMC. Our study demonstrates that NFB training increases functional connectivity with non-targeted brain areas. These are associated with the training strategy (i.e., SMA) as well as with learning the NFB skill (i.e., aMCC and frontal areas). This detailed description of both the system to be trained and the areas involved in learning can provide valuable information

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

PubMed Central

Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.

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 un-targeted 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. PMID:25519743

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential

PubMed Central

Wang, Lulu; Habib, Amyn A.; Mintz, Akiva; Li, King C.; Zhao, Dawen

2017-01-01

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood–brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors. PMID:28654387

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential.

PubMed

Wang, Lulu; Habib, Amyn A; Mintz, Akiva; Li, King C; Zhao, Dawen

2017-01-01

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood-brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors.

Natural distribution of environmental radon daughters in the different brain areas of an Alzheimer disease victim.

PubMed

Momcilović, Berislav; Lykken, Glenn I; Cooley, Marvin

2006-09-11

Radon is a ubiquitous noble gas in the environment and a primary source of harmful radiation exposure for humans; it decays in a cascade of daughters (RAD) by releasing the cell damaging high energy alpha particles. We studied natural distribution of RAD 210Po and 210Bi in the different parts of the postmortem brain of 86-year-old woman who had suffered from Alzheimer's disease (AD). A distinct brain map emerged, since RAD distribution was different among the analyzed brain areas. The highest RAD irradiation (mSv x year(-1)) occurred in the decreasing order of magnitude: amygdala (Amy) > hippocampus (Hip) > temporal lobe (Tem) approximately = frontal lobe (Fro) > occipital lobe (Occ) approximately = parietal lobe (Par) > substantia nigra (SN) > locus ceruleus (LC) approximately = nucleus basalis (NB); generally more RAD accumulated in the proteins than lipids of gray and white (gray > white) brain matter. Amy and Hip are particularly vulnerable brain structure targets to significant RAD internal radiation damage in AD (5.98 and 1.82 mSv x year(-1), respectively). Next, naturally occurring RAD radiation for Tem and Fro, then Occ and Par, and SN was an order of magnitude higher than that in LC and NB; the later was within RAD we observed previously in the healthy control brains. Naturally occurring environmental RAD exposure may dramatically enhance AD deterioration by selectively targeting brain areas of emotions (Amy) and memory (Hip).

Natural distribution of environmental radon daughters in the different brain areas of an Alzheimer Disease victim

PubMed Central

Momčilović, Berislav; Lykken, Glenn I; Cooley, Marvin

2006-01-01

Background Radon is a ubiquitous noble gas in the environment and a primary source of harmful radiation exposure for humans; it decays in a cascade of daughters (RAD) by releasing the cell damaging high energy alpha particles. Results We studied natural distribution of RAD 210Po and 210Bi in the different parts of the postmortem brain of 86-year-old woman who had suffered from Alzheimer's disease (AD). A distinct brain map emerged, since RAD distribution was different among the analyzed brain areas. The highest RAD irradiation (mSv·year-1) occurred in the decreasing order of magnitude: amygdale (Amy) >> hippocampus (Hip) > temporal lobe (Tem) ~ frontal lobe (Fro) > occipital lobe (Occ) ~ parietal lobe (Par) > substantia nigra (SN) >> locus ceruleus (LC) ~ nucleus basalis (NB); generally more RAD accumulated in the proteins than lipids of gray and white (gray > white) brain matter. Amy and Hip are particularly vulnerable brain structure targets to significant RAD internal radiation damage in AD (5.98 and 1.82 mSv·year-1, respectively). Next, naturally occurring RAD radiation for Tem and Fro, then Occ and Par, and SN was an order of magnitude higher than that in LC and NB; the later was within RAD we observed previously in the healthy control brains. Conclusion Naturally occurring environmental RAD exposure may dramatically enhance AD deterioration by selectively targeting brain areas of emotions (Amy) and memory (Hip). PMID:16965619

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.

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

Improving resolution of dynamic communities in human brain networks through targeted node removal

PubMed Central

Turner, Benjamin O.; Miller, Michael B.; Carlson, Jean M.

2017-01-01

Current approaches to dynamic community detection in complex networks can fail to identify multi-scale community structure, or to resolve key features of community dynamics. We propose a targeted node removal technique to improve the resolution of community detection. Using synthetic oscillator networks with well-defined “ground truth” communities, we quantify the community detection performance of a common modularity maximization algorithm. We show that the performance of the algorithm on communities of a given size deteriorates when these communities are embedded in multi-scale networks with communities of different sizes, compared to the performance in a single-scale network. We demonstrate that targeted node removal during community detection improves performance on multi-scale networks, particularly when removing the most functionally cohesive nodes. Applying this approach to network neuroscience, we compare dynamic functional brain networks derived from fMRI data taken during both repetitive single-task and varied multi-task experiments. After the removal of regions in visual cortex, the most coherent functional brain area during the tasks, community detection is better able to resolve known functional brain systems into communities. In addition, node removal enables the algorithm to distinguish clear differences in brain network dynamics between these experiments, revealing task-switching behavior that was not identified with the visual regions present in the network. These results indicate that targeted node removal can improve spatial and temporal resolution in community detection, and they demonstrate a promising approach for comparison of network dynamics between neuroscientific data sets with different resolution parameters. PMID:29261662

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.

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets.

PubMed

Lang, Patrick Y; Gershon, Timothy R

2018-05-01

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. © 2018 WILEY Periodicals, Inc.

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. ©2013 AACR.

Quantitative targeted proteomics for understanding the blood-brain barrier: towards pharmacoproteomics.

PubMed

Ohtsuki, Sumio; Hirayama, Mio; Ito, Shingo; Uchida, Yasuo; Tachikawa, Masanori; Terasaki, Tetsuya

2014-06-01

The blood-brain barrier (BBB) is formed by brain capillary endothelial cells linked together via complex tight junctions, and serves to prevent entry of drugs into the brain. Multiple transporters are expressed at the BBB, where they control exchange of materials between the circulating blood and brain interstitial fluid, thereby supporting and protecting the CNS. An understanding of the BBB is necessary for efficient development of CNS-acting drugs and to identify potential drug targets for treatment of CNS diseases. Quantitative targeted proteomics can provide detailed information on protein expression levels at the BBB. The present review highlights the latest applications of quantitative targeted proteomics in BBB research, specifically to evaluate species and in vivo-in vitro differences, and to reconstruct in vivo transport activity. Such a BBB quantitative proteomics approach can be considered as pharmacoproteomics.

Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma.

PubMed

Johnsen, Kasper Bendix; Burkhart, Annette; Melander, Fredrik; Kempen, Paul Joseph; Vejlebo, Jonas Bruun; Siupka, Piotr; Nielsen, Morten Schallburg; Andresen, Thomas Lars; Moos, Torben

2017-09-04

Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain.

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.

Identification of clinical target areas in the brainstem of prion‐infected mice

PubMed Central

Mirabile, Ilaria; Jat, Parmjit S.; Brandner, Sebastian

2015-01-01

Aims While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas. Method We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset). Results We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre‐Bötzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem. Conclusions Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre‐Bötzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt–Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases. PMID:25311251

Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier.

PubMed

Lajoie, Jason M; Shusta, Eric V

2015-01-01

Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence the therapeutic potential of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo.

[Blood-brain barrier part III: therapeutic approaches to cross the blood-brain barrier and target the brain].

PubMed

Weiss, N; Miller, F; Cazaubon, S; Couraud, P-O

2010-03-01

Over the last few years, the blood-brain barrier has come to be considered as the main limitation for the treatment of neurological diseases caused by inflammatory, tumor or neurodegenerative disorders. In the blood-brain barrier, the close intercellular contact between cerebral endothelial cells due to tight junctions prevents the passive diffusion of hydrophilic components from the bloodstream into the brain. Several specific transport systems (via transporters expressed on cerebral endothelial cells) are implicated in the delivery of nutriments, ions and vitamins to the brain; other transporters expressed on cerebral endothelial cells extrude endogenous substances or xenobiotics, which have crossed the cerebral endothelium, out of the brain and into the bloodstream. Recently, several strategies have been proposed to target the brain, (i) by by-passing the blood-brain barrier by central drug administration, (ii) by increasing permeability of the blood-brain barrier, (iii) by modulating the expression and/or the activity of efflux transporters, (iv) by using the physiological receptor-dependent blood-brain barrier transport, and (v) by creating new viral or chemical vectors to cross the blood-brain barrier. This review focuses on the illustration of these different approaches. Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.

Enhanced permeability of blood-brain barrier and targeting function of brain via borneol-modified chemically solid lipid nanoparticle.

PubMed

Song, Hui; Wei, Man; Zhang, Nan; Li, He; Tan, Xiaochuan; Zhang, Yujia; Zheng, Wensheng

2018-01-01

The incidence of central nervous system disease has increased in recent years. However, the transportation of drug is restricted by the blood-brain barrier, contributing to the poor therapeutic effect in the brain. Therefore, the development of a new brain-targeting drug delivery system has become the hotspot of pharmacy. Borneol, a simple bicyclic monoterpene extracted from Dryobalanops aromatica , can direct drugs to the upper body parts according to the theory of traditional Chinese medicine. Dioleoyl phosphoethanolamine (DOPE) was chemically modified by borneol as one of the lipid materials of solid lipid nanoparticle (SLN) in the present study. The borneol-modified chemically solid lipid nanoparticle (BO-SLN/CM), borneol-modified physically solid lipid nanoparticle (BO-SLN/PM), and SLN have similar diameter (of about 87 nm) and morphological characteristics. However, BO-SLN/CM has a lower cytotoxicity, higher cell uptake, and better blood-brain barrier permeability compared with BO-SLN/PM and SLN. BO-SLN/CM has a remarkable targeting function to the brain, while BO-SLN/ PM and SLNs are concentrated at the lung. The present study provides an excellent drug delivery carrier, BO-SLN/CM, having the application potential of targeting to the brain and permeating to the blood-brain barrier.

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

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.

Human endogenous retrovirus W in brain lesions: Rationale for targeted therapy in multiple sclerosis.

PubMed

van Horssen, Jack; van der Pol, Susanne; Nijland, Philip; Amor, Sandra; Perron, Hervé

2016-07-01

Attempts to identify a causative agent of Multiple Sclerosis (MS) among environmental viruses have consistently failed suggesting that development of MS is a result from gene-environment interactions. A new pathogenic player within human genes, a human endogenous retrovirus (HERV) was identified from MS cells, named MS-associated retrovirus element (MSRV) and unveiled homologous multicopy HERVs (HERV-W). As independent studies revealed biological features of HERV-W on immune-mediated inflammation and on remyelinating cells, the present study characterized the presence of HERV-W envelope protein (MSRV-Env) at the cellular level, in different MS lesion stages to extend and validate previous studies. Immunohistological analysis of HERV-W envelope cellular expression in different lesion stages from a cohort of MS brains versus controls, using well-characterized and highly specific monoclonal antibodies. HERV-W envelope protein was detected in all MS brains and quite essentially in lesions. Immunohistochemistry showed dominant expression in macrophages and microglia, coinciding with areas of active demyelination, spread over the active lesions, or limited to the rim of active microglia in chronic active lesions or in few surviving astrocytes of inactive plaques. Weak expression was seen in MS normal appearing white matter. In active plaques, few lymphoid cells and astrocytes were also stained. This HERV-W expression was not observed in control brains. HERV-W was expressed in demyelinated lesions from MS brains, which were all positive for this endogenous pathogenic protein. Pronounced HERV-W immunoreactivity in active MS lesions was intimately associated with areas of active demyelination throughout the successive stages of lesion evolution in MS brains. Based on its pathogenic potential, this HERV-W (MSRV) endogenous toxin thus appears to be a novel therapeutic target in MS. It also has a unique positioning as an early and lifelong expressed pathogenic agonist, acting

Lesion Analysis of the Brain Areas Involved in Language Comprehension

ERIC Educational Resources Information Center

Dronkers, Nina F.; Wilkins, David P.; Van Valin, Robert D., Jr.; Redfern, Brenda B.; Jaeger, Jeri J.

2004-01-01

The cortical regions of the brain traditionally associated with the comprehension of language are Wernicke's area and Broca's area. However, recent evidence suggests that other brain regions might also be involved in this complex process. This paper describes the opportunity to evaluate a large number of brain-injured patients to determine which…

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

Optimization of brain metabolism using metabolic-targeted therapeutic hypothermia can reduce mortality from traumatic brain injury.

PubMed

Feng, Jin-Zhou; Wang, Wen-Yuan; Zeng, Jun; Zhou, Zhi-Yuan; Peng, Jin; Yang, Hao; Deng, Peng-Chi; Li, Shi-Jun; Lu, Charles D; Jiang, Hua

2017-08-01

Therapeutic hypothermia is widely used to treat traumatic brain injuries (TBIs). However, determining the best hypothermia therapy strategy remains a challenge. We hypothesized that reducing the metabolic rate, rather than reaching a fixed body temperature, would be an appropriate target because optimizing metabolic conditions especially the brain metabolic environment may enhance neurologic protection. A pilot single-blind randomized controlled trial was designed to test this hypothesis, and a nested metabolomics study was conducted to explore the mechanics thereof. Severe TBI patients (Glasgow Coma Scale score, 3-8) were randomly divided into the metabolic-targeted hypothermia treatment (MTHT) group, 50% to 60% rest metabolic ratio as the hypothermia therapy target, and the body temperature-targeted hypothermia treatment (BTHT) control group, hypothermia therapy target of 32°C to 35°C body temperature. Brain and circulatory metabolic pool blood samples were collected at baseline and on days 1, 3, and 7 during the hypothermia treatment, which were selected randomly from a subgroup of MTHT and BTHT groups. The primary outcome was mortality. Using H nuclear magnetic resonance technology, we tracked and located the disturbances of metabolic networks. Eighty-eight severe TBI patients were recruited and analyzed from December 2013 to December 2014, 44 each were assigned in the MTHT and BTHT groups (median age, 42 years; 69.32% men; mean Glasgow Coma Scale score, 6.17 ± 1.02). The mortality was significantly lower in the MTHT than the BTHT group (15.91% vs. 34.09%; p = 0.049). From these, eight cases of MTHT and six cases from BTHT group were enrolled for metabolomics analysis, which showed a significant difference between the brain and circulatory metabolic patterns in MTHT group on day 7 based on the model parameters and scores plots. Finally, metabolites representing potential neuroprotective monitoring parameters for hypothermia treatment were identified through

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

[Therapeutic strategies targeting brain tumor stem cells].

PubMed

Toda, Masahiro

2009-07-01

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Targeted transport of nanocarriers into brain for theranosis with rabies virus glycoprotein-derived peptide.

PubMed

Fu, Chen; Xiang, Yonggang; Li, Xiaorong; Fu, Ailing

2018-06-01

For successful theranosis of brain diseases, limited access of therapeutic molecules across blood-brain barrier (BBB) needs be overcome in brain delivery. Currently, peptide derivatives of rabies virus glycoprotein (RVG) have been exploited as delivery ligands to transport nanocarriers across BBB and specifically into the brain. The targeting peptides usually conjugate to the nanocarrier surface, and the cargoes, including siRNA, miRNA, DNA, proteins and small molecular chemicals, are complexed or encapsulated in the nanocarriers. The peptide ligand of the RVG-modified nanocarriers introduces the conjugated targeted-delivery into the brain, and the cargoes are involved in disease theranosis. The peptide-modified nanocarriers have been applied to diagnose and treat various brain diseases, such as glioma, Alzheimer's disease, ischemic injury, protein misfolding diseases etc. Since the targeting delivery system has displayed good biocompatibility and desirable therapeutic effect, it will raise a potential application in treating brain diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting

PubMed Central

Clementino, Adryana; Buttini, Francesca; Colombo, Gaia; Pescina, Silvia; Stanisçuaski Guterres, Silvia; Nicoli, Sara

2018-01-01

In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer’s disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose’s upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery. PMID:29543755

Intranasal Administration of PACAP: Uptake by Brain and Brain Region Targeting with Cyclodextrins

PubMed Central

Nonaka, Naoko; Farr, Susan A.; Nakamachi, Tomoya; Morley, John E.; Nakamura, Masanori; Shioda, Seiji; Banks, William A.

2012-01-01

Pituitary adenylate cyclase activating polypeptide (PACAP) is a potent neurotrophic and neuroprotectant that is transported across the blood-brain barrier in amounts sufficient to affect brain function. However, its short half-life in blood makes it difficult to administer peripherally. Here, we determined whether the radioactively labeled 38 amino acid form of PACAP can enter the brain after intranasal (i.n.) administration. Occipital cortex and striatum were the regions with the highest uptake, peaking at levels of about 2-4 percent of the injected dose per g of brain region. Inclusion of unlabeled PACAP greatly increased retention of I-PACAP by brain probably because of inhibition of the brain-to-blood efflux transporter for PACAP located at the blood-brain barrier. Sufficient amounts of PACAP could be delivered to the brain to affect function as shown by improvement of memory in aged SAMP8 mice, a model of Alzheimer’s disease. We found that each of three cyclodextrins when included in the i.n. injection produced a unique distribution pattern of I-PACAP among brain regions. As examples, β-cyclodextrin greatly increased uptake by the occipital cortex and hypothalamus, α-cyclodextrin increased uptake by the olfactory bulb and decreased uptake by the occipital cortex and striatum, and (2-hydropropyl)-β-cyclodextrin increased uptake by the thalamus and decreased uptake by the striatum. These results show that therapeutic amounts of PACAP can be delivered to the brain by intranasal administration and that cyclodextrins may be useful in the therapeutic targeting of peptides to specific brain regions. PMID:22687366

Selective Targeting of Brain Tumors with Gold Nanoparticle-Induced Radiosensitization

PubMed Central

Joh, Daniel Y.; Sun, Lova; Stangl, Melissa; Al Zaki, Ajlan; Murty, Surya; Santoiemma, Phillip P.; Davis, James J.; Baumann, Brian C.; Alonso-Basanta, Michelle; Bhang, Dongha; Kao, Gary D.; Tsourkas, Andrew; Dorsey, Jay F.

2013-01-01

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ∼1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature. PMID:23638079

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies.

PubMed

Mangraviti, Antonella; Gullotti, David; Tyler, Betty; Brem, Henry

2016-10-28

Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation. Copyright © 2016 Elsevier B.V. All rights reserved.

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. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Traumatic brain injury: preferred methods and targets for resuscitation.

PubMed

Scaife, Eric R; Statler, Kimberly D

2010-06-01

Severe traumatic brain injury (TBI) is the most common cause of death and disability in pediatric trauma. This review looks at the strategies to treat TBI in a temporal fashion. We examine the targets for resuscitation from field triage to definitive care in the pediatric ICU. Guidelines for the management of pediatric TBI exist. The themes of contemporary clinical research have been compliance with these guidelines and refinement of treatment recommendations developing a more sophisticated understanding of the pathophysiology of the injured brain. In the field, the aim has been to achieve routine compliance with the resuscitation goals. In the hospital, efforts have been directed at improving our ability to monitor the injured brain, developing techniques that limit brain swelling, and customizing brain perfusion. As our understanding of pediatric TBI evolves, the ambition is that age-specific and perhaps individual brain injury strategies based upon feedback from continuous monitors will be defined. In addition, vogue methods such as hypothermia, hypertonic saline, and aggressive surgical decompression may prove to impact brain swelling and outcomes.

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.

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.

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

PubMed

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.

Body distributioin of RGD-mediated liposome in brain-targeting drug delivery.

PubMed

Qin, Jing; Chen, DaWei; Hu, Haiyang; Qiao, MingXi; Zhao, XiuLi; Chen, Baoyu

2007-09-01

RGD conjugation liposomes (RGD-liposomes) were evaluated for brain-targeting drug delivery. The flow cytometric in vitro study demonstrated that RGD-liposomes could bind to monocytes and neutrophils effectively. Ferulic acid (4-hydroxy-3-methoxycinnamic, FA) was loaded into liposomes. Rats were subjected to intrastriatal microinjections of 100 units of human recombinant IL-1beta to produce brain inflammation and caudal vein injection of three formulations (FA solution, FA liposome and RGD-coated FA liposome). Animals were sacrificed 15, 30, 60 and 120 min after administration to study the body distribution of the FA in the three formulations. HPLC was used to determine the concentration of FA in vivo with salicylic acid as internal standard. The results of body distribution indicated that RGD-coated liposomes could be mediated into the brain with a 6-fold FA concentration compared to FA solution and 3-fold in comparison to uncoated liposome. Brain targeted delivery was achieved and a reduction in dosage might be allowed.

Brain activation in parietal area during manipulation with a surgical robot simulator.

PubMed

Miura, Satoshi; Kobayashi, Yo; Kawamura, Kazuya; Nakashima, Yasutaka; Fujie, Masakatsu G

2015-06-01

we present an evaluation method to qualify the embodiment caused by the physical difference between master-slave surgical robots by measuring the activation of the intraparietal sulcus in the user's brain activity during surgical robot manipulation. We show the change of embodiment based on the change of the optical axis-to-target view angle in the surgical simulator to change the manipulator's appearance in the monitor in terms of hand-eye coordination. The objective is to explore the change of brain activation according to the change of the optical axis-to-target view angle. In the experiments, we used a functional near-infrared spectroscopic topography (f-NIRS) brain imaging device to measure the brain activity of the seven subjects while they moved the hand controller to insert a curved needle into a target using the manipulator in a surgical simulator. The experiment was carried out several times with a variety of optical axis-to-target view angles. Some participants showed a significant peak (P value = 0.037, F-number = 2.841) when the optical axis-to-target view angle was 75°. The positional relationship between the manipulators and endoscope at 75° would be the closest to the human physical relationship between the hands and eyes.

Nanobiotechnology-based drug delivery in brain targeting.

PubMed

Dinda, Subas C; Pattnaik, Gurudutta

2013-01-01

Blood brain barrier (BBB) found to act as rate limiting factor in drug delivery to brain in combating the central nervous system (CNS) disorders. Such limiting physiological factors include the reticuloendothelial system and protein opsonization, which present across BBB, play major role in reducing the passage of drug. Several approaches employed to improve the drug delivery across the BBB. Nanoparticles (NP) are the solid colloidal particle ranges from 1 to 1000 nm in size utilized as career for drug delivery. At present NPs are found to play a significant advantage over the other methods of available drug delivery systems to deliver the drug across the BBB. Nanoparticles may be because of its size and functionalization characteristics able to penetrate and facilitate the drug delivery through the barrier. There are number of mechanisms and strategies found to be involved in this process, which are based on the type of nanomaterials used and its combination with therapeutic agents, such materials include liposomes, polymeric nanoparticles and non-viral vectors of nano-sizes for CNS gene therapy, etc. Nanotechnology is expected to reduce the need for invasive procedures for delivery of therapeutics to the CNS. Some devices such as implanted catheters and reservoirs however will still be needed to overcome the problems in effective drug delivery to the CNS. Nanomaterials are found to improve the safety and efficacy level of drug delivery devices in brain targeting. Nanoegineered devices are found to be delivering the drugs at cellular levels through nono-fluidic channels. Different drug delivery systems such as liposomes, microspheres, nanoparticles, nonogels and nonobiocapsules have been used to improve the bioavailability of the drug in the brain, but microchips and biodegradable polymeric nanoparticulate careers are found to be more effective therapeutically in treating brain tumor. The physiological approaches also utilized to improve the transcytosis capacity

Functional Geometry Alignment and Localization of Brain Areas.

PubMed

Langs, Georg; Golland, Polina; Tie, Yanmei; Rigolo, Laura; Golby, Alexandra J

2010-01-01

Matching functional brain regions across individuals is a challenging task, largely due to the variability in their location and extent. It is particularly difficult, but highly relevant, for patients with pathologies such as brain tumors, which can cause substantial reorganization of functional systems. In such cases spatial registration based on anatomical data is only of limited value if the goal is to establish correspondences of functional areas among different individuals, or to localize potentially displaced active regions. Rather than rely on spatial alignment, we propose to perform registration in an alternative space whose geometry is governed by the functional interaction patterns in the brain. We first embed each brain into a functional map that reflects connectivity patterns during a fMRI experiment. The resulting functional maps are then registered, and the obtained correspondences are propagated back to the two brains. In application to a language fMRI experiment, our preliminary results suggest that the proposed method yields improved functional correspondences across subjects. This advantage is pronounced for subjects with tumors that affect the language areas and thus cause spatial reorganization of the functional regions.

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

PubMed Central

2013-01-01

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. PMID:23379618

Combinatorial Approaches for the Identification of Brain Drug Delivery Targets

PubMed Central

Stutz, Charles C.; Zhang, Xiaobin; Shusta, Eric V.

2018-01-01

The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral vasculature and the inherent low levels of transcytosis mediated by such systems. In this review, approaches designed to increase the repertoire of transcytosing receptors which can be targeted for the purpose of drug delivery are discussed. In particular, combinatorial protein libraries can be screened on BBB cells in vitro or in vivo to isolate targeting peptides or antibodies that can trigger transcytosis. Once these targeting reagents are discovered, the cognate BBB transcytosis system can be identified using techniques such as expression cloning or immunoprecipitation coupled with mass spectrometry. Continued technological advances in BBB genomics and proteomics, membrane protein manipulation, and in vitro BBB technology promise to further advance the capability to identify and optimize peptides and antibodies capable of mediating drug transport across the BBB. PMID:23789958

Transcranial route of brain targeted delivery of methadone in oil.

PubMed

Pathirana, W; Abhayawardhana, P; Kariyawasam, H; Ratnasooriya, W D

2009-05-01

The unique anatomical arrangement of blood vessels and sinuses in the human skull and the brain, the prevalence of a high density of skin appendages in the scalp, extracranial vessels of the scalp communicating with the brain via emissary veins and most importantly, the way that the scalp is used in Ayurvedic medical system in treating diseases associated with the brain show that a drug could be transcranially delivered and targeted to the brain through the scalp. The present study was to investigate by measuring the antinociceptive effect on rats whether the opioid analgesic methadone could be delivered and targeted to the brain by transcranial delivery route. A non aqueous solution of methadone base in sesame oil was used for the application on the scalp. Animal studies were carried out using six groups of male rats consisting of group 1, the oral control treated with distilled water 1 ml; group 2, the oral positive control treated with methadone hydrochloride solution 316.5 mug/ml; group 3, the negative control treated transcranially with the blank sesame oil 0.2 ml and three test groups 4, 5 and 6 treated with three different dose levels of the transcranial oil formulation of methadone base, 41.6 mug/0.2 ml, 104 mug/0.2 ml and 208 mug/0.2 ml, respectively. The antinociceptive effects were examined by subjecting the rats to the hot plate and tail flick tests. The two higher concentrations of the three transcranial methadone formulations yielded response vs time curves showing nearly equal maximum antinociceptive effects similar to that of the oral positive control. Maximum analgesic effect after transcranial administration was observed between 1st and 2nd h and declined up to 6th hour. The results indicate that the transcranial brain targeted delivery of methadone base in the form of an oil based non aqueous solution results in statistically significant antinociceptive effects under experimental conditions. Therefore, it is possible to deliver central nervous

Gene therapy to target ER stress in brain diseases.

PubMed

Valenzuela, Vicente; Martínez, Gabriela; Duran-Aniotz, Claudia; Hetz, Claudio

2016-10-01

Gene therapy based on the use of Adeno-associated viruses (AAVs) is emerging as a safe and stable strategy to target molecular pathways involved in a variety of brain diseases. Endoplasmic reticulum (ER) stress is proposed as a transversal feature of most animal models and clinical samples from patients affected with neurodegenerative diseases. Manipulation of the unfolded protein response (UPR), a major homeostatic reaction under ER stress conditions, had proved beneficial in diverse models of neurodegeneration. Although increasing number of drugs are available to target ER stress, the use of small molecules to treat chronic brain diseases is challenging because of poor blood brain barrier permeability and undesirable side effects due to the role of the UPR in the physiology of peripheral organs. Gene therapy is currently considered a possible future alternative to circumvent these problems by the delivery of therapeutic agents to selective regions and cell types of the nervous system. Here we discuss current efforts to design gene therapy strategies to alleviate ER stress on a disease context. This article is part of a Special Issue entitled SI:ER stress. Copyright © 2016 Elsevier B.V. All rights reserved.

Biologically Targeted Therapeutics in Pediatric Brain Tumors

PubMed Central

Nageswara Rao, Amulya A.; Scafidi, Joseph; Wells, Elizabeth M.; Packer, Roger J.

2013-01-01

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale. PMID:22490764

Biologically targeted therapeutics in pediatric brain tumors.

PubMed

Nageswara Rao, Amulya A; Scafidi, Joseph; Wells, Elizabeth M; Packer, Roger J

2012-04-01

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale. Copyright © 2012 Elsevier Inc. All rights reserved.

Individual Human Brain Areas Can Be Identified from Their Characteristic Spectral Activation Fingerprints

PubMed Central

Keitel, Anne; Gross, Joachim

2016-01-01

The human brain can be parcellated into diverse anatomical areas. We investigated whether rhythmic brain activity in these areas is characteristic and can be used for automatic classification. To this end, resting-state MEG data of 22 healthy adults was analysed. Power spectra of 1-s long data segments for atlas-defined brain areas were clustered into spectral profiles (“fingerprints”), using k-means and Gaussian mixture (GM) modelling. We demonstrate that individual areas can be identified from these spectral profiles with high accuracy. Our results suggest that each brain area engages in different spectral modes that are characteristic for individual areas. Clustering of brain areas according to similarity of spectral profiles reveals well-known brain networks. Furthermore, we demonstrate task-specific modulations of auditory spectral profiles during auditory processing. These findings have important implications for the classification of regional spectral activity and allow for novel approaches in neuroimaging and neurostimulation in health and disease. PMID:27355236

Individual Human Brain Areas Can Be Identified from Their Characteristic Spectral Activation Fingerprints.

PubMed

Keitel, Anne; Gross, Joachim

2016-06-01

The human brain can be parcellated into diverse anatomical areas. We investigated whether rhythmic brain activity in these areas is characteristic and can be used for automatic classification. To this end, resting-state MEG data of 22 healthy adults was analysed. Power spectra of 1-s long data segments for atlas-defined brain areas were clustered into spectral profiles ("fingerprints"), using k-means and Gaussian mixture (GM) modelling. We demonstrate that individual areas can be identified from these spectral profiles with high accuracy. Our results suggest that each brain area engages in different spectral modes that are characteristic for individual areas. Clustering of brain areas according to similarity of spectral profiles reveals well-known brain networks. Furthermore, we demonstrate task-specific modulations of auditory spectral profiles during auditory processing. These findings have important implications for the classification of regional spectral activity and allow for novel approaches in neuroimaging and neurostimulation in health and disease.

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

Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2013-11-01

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

Targeting the brain: considerations in 332 consecutive patients treated by deep brain stimulation (DBS) for severe neurological diseases.

PubMed

Franzini, Angelo; Cordella, Roberto; Messina, Giuseppe; Marras, Carlo Efisio; Romito, Luigi Michele; Albanese, Alberto; Rizzi, Michele; Nardocci, Nardo; Zorzi, Giovanna; Zekaj, Edvin; Villani, Flavio; Leone, Massimo; Gambini, Orsola; Broggi, Giovanni

2012-12-01

Deep brain stimulation (DBS) extends the treatment of some severe neurological diseases beyond pharmacological and conservative therapy. Our experience extends the field of DBS beyond the treatment of Parkinson disease and dystonia, including several other diseases such as cluster headache and disruptive behavior. Since 1993, at the Istituto Nazionale Neurologico "Carlo Besta" in Milan, 580 deep brain electrodes were implanted in 332 patients. The DBS targets include Stn, GPi, Voa, Vop, Vim, CM-pf, pHyp, cZi, Nacc, IC, PPN, and Brodmann areas 24 and 25. Three hundred patients are still available for follow-up and therapeutic considerations. DBS gave a new therapeutic chance to these patients affected by severe neurological diseases and in some cases controlled life-threatening pathological conditions, which would otherwise result in the death of the patient such as in status dystonicus, status epilepticus and post-stroke hemiballismus. The balance of DBS in severe neurological disease is strongly positive even if further investigations and studies are needed to search for new applications and refine the selection criteria for the actual indications.

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. Copyright © 2013 Elsevier Ltd. All rights reserved.

Intranasal mucoadhesive microemulsions of clonazepam: preliminary studies on brain targeting.

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 clonazepam microemulsions (CME) for rapid drug delivery to the brain to treat acute status epileptic patients and to characterize and evaluate the performance of CME in vitro and in vivo in rats. The CME were prepared by the titration method and were characterized for globule size and size distribution, zeta potential, and drug content. CME was radiolabeled with (99m)Tc (technetium) and biodistribution of drug in the brain was studied in Swiss albino rats after intranasal and intravenous administrations. Brain scintigraphy imaging in rabbits was also performed to ascertain the uptake of the drug into the brain. Pre and postCME formulation treated human nasal mucosa was subjected to transmission electron microscopy to investigate the mechanism of drug uptake across the nasal mucosa. CME were transparent and stable with mean globule size of 15 +/- 10 nm and zeta potential of -30 mV to -40 mV. (99m)Tc-labeled clonazepam solution ((99m)Tc CS)/ clonazepam microemulsion (CME)/clonazepam mucoadhesive microemulsion (CMME) were found to be stable and suitable for in vivo studies. Brain/blood uptake ratios at 0.50 hour (h) following intranasal CMME, CME, clonazepam solution (CS), and intravenous CME administrations were found to be 0.67, 0.50, 0.48, and 0.13, respectively indicating more effective targeting with intranasal administration and best targeting of the brain with intranasal CMME. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of CMME compared to intravenous was found to be twofold higher indicating larger extent of distribution of the drug in brain. Rabbit brain scintigraphy also showed higher intranasal uptake of the drug into the brain. Transmission electron microscopy revealed significant accretion of CMME within interstitial spaces and paracellular mode of transport due to stretching of the tight junctions present in the nasal mucosa. This investigation demonstrates a more

The coil orientation dependency of the electric field induced by TMS for M1 and other brain areas.

PubMed

Janssen, Arno M; Oostendorp, Thom F; Stegeman, Dick F

2015-05-17

The effectiveness of transcranial magnetic stimulation (TMS) depends highly on the coil orientation relative to the subject's head. This implies that the direction of the induced electric field has a large effect on the efficiency of TMS. To improve future protocols, knowledge about the relationship between the coil orientation and the direction of the induced electric field on the one hand, and the head and brain anatomy on the other hand, seems crucial. Therefore, the induced electric field in the cortex as a function of the coil orientation has been examined in this study. The effect of changing the coil orientation on the induced electric field was evaluated for fourteen cortical targets. We used a finite element model to calculate the induced electric fields for thirty-six coil orientations (10 degrees resolution) per target location. The effects on the electric field due to coil rotation, in combination with target site anatomy, have been quantified. The results confirm that the electric field perpendicular to the anterior sulcal wall of the central sulcus is highly susceptible to coil orientation changes and has to be maximized for an optimal stimulation effect of the motor cortex. In order to obtain maximum stimulation effect in areas other than the motor cortex, the electric field perpendicular to the cortical surface in those areas has to be maximized as well. Small orientation changes (10 degrees) do not alter the induced electric field drastically. The results suggest that for all cortical targets, maximizing the strength of the electric field perpendicular to the targeted cortical surface area (and inward directed) optimizes the effect of TMS. Orienting the TMS coil based on anatomical information (anatomical magnetic resonance imaging data) about the targeted brain area can improve future results. The standard coil orientations, used in cognitive and clinical neuroscience, induce (near) optimal electric fields in the subject-specific head model in

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. © The Author(s) 2015.

Neuroprotection in Hypoxic-Ischemic Brain Injury Targeting Glial Cells.

PubMed

Mucci, Sofia; Herrera, Maria Ines; Barreto, George E; Kolliker-Frers, Rodolfo; Capani, Francisco

2017-01-01

Brain injury constitutes a disabling health condition of several etiologies. One of the major causes of brain injury is hypoxia-ischemia. Until recently, pharmacological treatments were solely focused on neurons. In the last decades, glial cells started to be considered as alternative targets for neuroprotection. Novel treatments for hypoxia-ischemia intend to modulate reactive forms of glial cells, and/or potentiate their recovery response. In this review, we summarize these neuroprotective strategies in hypoxia-ischemia and discuss their mechanisms of action. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Delayed brain radiation necrosis: pathological review and new molecular targets for treatment.

PubMed

Furuse, Motomasa; Nonoguchi, Naosuke; Kawabata, Shinji; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko

2015-12-01

Delayed radiation necrosis is a well-known adverse event following radiotherapy for brain diseases and has been studied since the 1930s. The primary pathogenesis is thought to be the direct damage to endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination. This primary pathology leads to tissue inflammation and ischemia, inducing various tissue protective responses including angiogenesis. Macrophages and lymphocytes then infiltrate the surrounding areas of necrosis, releasing inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α. Microglia also express these inflammatory cytokines. Reactive astrocytes play an important role in angiogenesis, expressing vascular endothelial growth factor (VEGF). Some chemokine networks, like the CXCL12/CXCR4 axis, are upregulated by tissue inflammation. Hypoxia may mediate the cell-cell interactions among reactive astrocytes, macrophages, and microglial cells around the necrotic core. Recently, bevacizumab, an anti-VEGF antibody, has demonstrated promising results as an alternative treatment for radiation necrosis. The importance of VEGF in the pathophysiology of brain radiation necrosis is being recognized. The discovery of new molecular targets could facilitate novel treatments for radiation necrosis. This literature review will focus on recent work characterizing delayed radiation necrosis in the brain.

Trans-cranial opening of the blood-brain barrier in targeted regions using a stereotaxic brain atlas and focused ultrasound energy.

PubMed

Bing, Chenchen; Ladouceur-Wodzak, Michelle; Wanner, Clinton R; Shelton, John M; Richardson, James A; Chopra, Rajiv

2014-01-01

The blood-brain barrier (BBB) protects the brain by preventing the entry of large molecules; this poses a major obstacle for the delivery of drugs to the brain. A novel technique using focused ultrasound (FUS) energy combined with microbubble contrast agents has been widely used for non-invasive trans-cranial BBB opening. Traditionally, FUS research is conducted with magnetic resonance imaging (MRI) guidance, which is expensive and poses physical limitations due to the magnetic field. A system that could allow researchers to test brain therapies without MR intervention could facilitate and accelerate translational research. In this study, we present a novel FUS system that uses a custom-built FUS generator mounted on a motorized stereotaxic apparatus with embedded brain atlas to locally open the BBB in rodents. The system was initially characterized using a tissue-mimicking phantom. Rodent studies were also performed to evaluate whether non-invasive, localized BBB opening could be achieved using brain atlas-based targeting. Brains were exposed to pulsed focused ultrasound energy at 1.06 MHz in rats and 3.23 MHz in mice, with the focal pressure estimated to be 0.5-0.6 MPa through the skull. BBB opening was confirmed in gross tissue sections by the presence of Evans blue leakage in the exposed region of the brain and by histological assessment. The targeting accuracy of the stereotaxic system was better than 0.5 mm in the tissue-mimicking phantom. Reproducible localized BBB opening was verified with Evans blue dye leakage in 32/33 rats and had a targeting accuracy of ±0.3 mm. The use of higher frequency exposures in mice enabled a similar precision of localized BBB opening as was observed with the low frequency in the rat model. With this dedicated small-animal motorized stereotaxic-FUS system, we achieved accurate targeting of focused ultrasound exposures in the brain for non-invasive opening of the BBB. This system can be used as an alternative to MR

Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

DTIC Science & Technology

2014-10-01

remained negative for exposed PS. 15. SUBJECT TERMS Nothing Listed 16. SECURITY CLASSIFICATION OF: unclassified 17. LIMITATION OF ABSTRACT 18...cells of brain metastases. • PS-targeting antibody, PGN635F(ab’)2 has been successfully conjugated with radioisotope , enabling in vivo PET imaging

Optical Imaging of Targeted β-Galactosidase in Brain Tumors to Detect EGFR Levels

PubMed Central

Broome, Ann-Marie; Ramamurthy, Gopal; Lavik, Kari; Liggett, Alexander; Kinstlinger, Ian; Basilion, James

2015-01-01

A current limitation in molecular imaging is that it often requires genetic manipulation of cancer cells for noninvasive imaging. Other methods to detect tumor cells in vivo using exogenously delivered and functionally active reporters, such as β-gal, are required. We report the development of a platform system for linking β-gal to any number of different ligands or antibodies for in vivo targeting to tissue or cells, without the requirement for genetic engineering of the target cells prior to imaging. Our studies demonstrate significant uptake in vitro and in vivo of an EGFR-targeted β-gal complex. We were then able to image orthotopic brain tumor accumulation and localization of the targeted enzyme when a fluorophore was added to the complex, as well as validate the internalization of the intravenously administered β-gal reporter complex ex vivo. After fluorescence imaging localized the β-gal complexes to the brain tumor, we topically applied a bioluminescent β-gal substrate to serial sections of the brain to evaluate the delivery and integrity of the enzyme. Finally, robust bioluminescence of the EGFR-targeted β-gal complex was captured within the tumor during noninvasive in vivo imaging. PMID:25775241

Optical imaging of targeted β-galactosidase in brain tumors to detect EGFR levels.

PubMed

Broome, Ann-Marie; Ramamurthy, Gopal; Lavik, Kari; Liggett, Alexander; Kinstlinger, Ian; Basilion, James

2015-04-15

A current limitation in molecular imaging is that it often requires genetic manipulation of cancer cells for noninvasive imaging. Other methods to detect tumor cells in vivo using exogenously delivered and functionally active reporters, such as β-gal, are required. We report the development of a platform system for linking β-gal to any number of different ligands or antibodies for in vivo targeting to tissue or cells, without the requirement for genetic engineering of the target cells prior to imaging. Our studies demonstrate significant uptake in vitro and in vivo of an EGFR-targeted β-gal complex. We were then able to image orthotopic brain tumor accumulation and localization of the targeted enzyme when a fluorophore was added to the complex, as well as validate the internalization of the intravenously administered β-gal reporter complex ex vivo. After fluorescence imaging localized the β-gal complexes to the brain tumor, we topically applied a bioluminescent β-gal substrate to serial sections of the brain to evaluate the delivery and integrity of the enzyme. Finally, robust bioluminescence of the EGFR-targeted β-gal complex was captured within the tumor during noninvasive in vivo imaging.

Xingnaojing mPEG2000-PLA modified microemulsion for transnasal delivery: pharmacokinetic and brain-targeting evaluation.

PubMed

Wen, Ran; Zhang, Qing; Xu, Pan; Bai, Jie; Li, Pengyue; Du, Shouying; Lu, Yang

2016-01-01

Xingnaojing microemulsion (XNJ-M) administered intranasally is used for stroke treatment. In order to decrease the XNJ-M-induced mucosal irritation, XNJ-M modified by mPEG2000-PLA (XNJ-MM) were prepared in a previous work. The present work aimed to assess the impact of mPEG2000-PLA on pharmacokinetic features and brain-targeting ability of XNJ-M. The bioavailability and brain-target effects of borneol and geniposide in XNJ-M and XNJ-MM were compared in mice after intravenous (i.v.) and intranasal (i.n.) administrations. Gas chromatography, high-performance liquid chromatography, and ultra-performance liquid chromatography/tandem mass spectrometry methods were developed for the quantification of borneol and geniposide. Blood and brain samples were collected from mice at different time points after i.v. and i.n. treatments with borneol at 8.0 mg/kg, geniposide at 4.12 mg/kg. In addition, near-infrared fluorescence dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide was loaded into microemulsions to evaluate the brain-targeting ability of XNJ-M and XNJ-MM by near-infrared fluorescence imaging in vivo and ex vivo. For XNJ-M and XNJ-MM, the relative brain targeted coefficients (Re) were 134.59% and 198.09% (borneol), 89.70% and 188.33% (geniposide), respectively. Besides, significant near-infrared fluorescent signal was detected in the brain after i.n. administration of microemulsions, compared with that of groups for i.v. administration. These findings indicated that mPEG2000-PLA modified microemulsion improved drug entry into blood and brain compared with normal microemulsion: the introduction of mPEG2000-PLA in microemulsion resulted in brain-targeting enhancement of both fat-soluble and water-soluble drugs. These findings provide a basis for the significance of mPEG2000-PLA addition in microemulsion, defining its effects on the drugs in microemulsion.

Management of melanoma brain metastases in the era of targeted therapy.

PubMed

Shapiro, Daniela Gonsalves; Samlowski, Wolfram E

2011-01-01

Disseminated metastatic disease, including brain metastases, is commonly encountered in malignant melanoma. The classical treatment approach for melanoma brain metastases has been neurosurgical resection followed by whole brain radiotherapy. Traditionally, if lesions were either too numerous or surgical intervention would cause substantial neurologic deficits, patients were either treated with whole brain radiotherapy or referred to hospice and supportive care. Chemotherapy has not proven effective in treating brain metastases. Improvements in surgery, radiosurgery, and new drug discoveries have provided a wider range of treatment options. Additionally, recently discovered mutations in the melanoma genome have led to the development of "targeted therapy." These vastly improved options are resulting in novel treatment paradigms for approaching melanoma brain metastases in patients with and without systemic metastatic disease. It is therefore likely that improved survival can currently be achieved in at least a subset of melanoma patients with brain metastases.

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

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. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

TDO as a therapeutic target in brain diseases.

PubMed

Yu, Cheng-Peng; Pan, Ze-Zheng; Luo, Da-Ya

2016-08-01

Tryptophan-2, 3-dioxygenase (TDO) is a heme-containing protein catalyzing the first reaction in the kynurenine pathway, which incorporates oxygen into the indole moiety of tryptophan and catalyzes it into kynurenine (KYN). The activation of TDO results in the depletion of tryptophan and the accumulation of kynurenine and its metabolites. These metabolites can affect the function of neurons and inhibit the proliferation of T cells. Increasing evidence demonstrates that TDO is a potential therapeutic target in the treatment of brain diseases as well as in the antitumor and transplant fields. Despite its growing popularity, there are few reviews only focusing on TDO. Hence, we herein review TDO by providing a comprehensive overview of TDO, including its biological functions as well as the evolution, structure and catalytic process of TDO. Additionally, this review will focus on the role of TDO in the pathology of three groups of brain diseases: Schizophrenia, Alzheimer's disease (AD) and Glioma. Finally, we will also provide an opinion regarding the future developmental directions of TDO in brain diseases, especially whether TDO has a potential role in other brain diseases as well as the development and applications of TDO inhibitors as treatments.

Lactate transport and signaling in the brain: potential therapeutic targets and roles in body–brain interaction

PubMed Central

Bergersen, Linda Hildegard

2015-01-01

Lactate acts as a ‘buffer' between glycolysis and oxidative metabolism. In addition to being exchanged as a fuel by the monocarboxylate transporters (MCTs) between cells and tissues with different glycolytic and oxidative rates, lactate may be a ‘volume transmitter' of brain signals. According to some, lactate is a preferred fuel for brain metabolism. Immediately after brain activation, the rate of glycolysis exceeds oxidation, leading to net production of lactate. At physical rest, there is a net efflux of lactate from the brain into the blood stream. But when blood lactate levels rise, such as in physical exercise, there is net influx of lactate from blood to brain, where the lactate is used for energy production and myelin formation. Lactate binds to the lactate receptor GPR81 aka hydroxycarboxylic acid receptor (HCAR1) on brain cells and cerebral blood vessels, and regulates the levels of cAMP. The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain constitute the focus of this review. They are possible targets for new therapeutic drugs and interventions. The author proposes that lactate actions in the brain through MCTs and the lactate receptor underlie part of the favorable effects on the brain resulting from physical exercise. PMID:25425080

Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction.

PubMed

Bergersen, Linda Hildegard

2015-02-01

Lactate acts as a 'buffer' between glycolysis and oxidative metabolism. In addition to being exchanged as a fuel by the monocarboxylate transporters (MCTs) between cells and tissues with different glycolytic and oxidative rates, lactate may be a 'volume transmitter' of brain signals. According to some, lactate is a preferred fuel for brain metabolism. Immediately after brain activation, the rate of glycolysis exceeds oxidation, leading to net production of lactate. At physical rest, there is a net efflux of lactate from the brain into the blood stream. But when blood lactate levels rise, such as in physical exercise, there is net influx of lactate from blood to brain, where the lactate is used for energy production and myelin formation. Lactate binds to the lactate receptor GPR81 aka hydroxycarboxylic acid receptor (HCAR1) on brain cells and cerebral blood vessels, and regulates the levels of cAMP. The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain constitute the focus of this review. They are possible targets for new therapeutic drugs and interventions. The author proposes that lactate actions in the brain through MCTs and the lactate receptor underlie part of the favorable effects on the brain resulting from physical exercise.

Intravenous siRNA of brain cancer with receptor targeting and avidin-biotin technology.

PubMed

Xia, Chun-Fang; Zhang, Yufeng; Zhang, Yun; Boado, Ruben J; Pardridge, William M

2007-12-01

The effective delivery of short interfering RNA (siRNA) to brain following intravenous administration requires the development of a delivery system for transport of the siRNA across the brain capillary endothelial wall, which forms the blood-brain barrier in vivo. siRNA was delivered to brain in vivo with the combined use of a receptor-specific monoclonal antibody delivery system, and avidin-biotin technology. The siRNA was mono-biotinylated on either terminus of the sense strand, in parallel with the production of a conjugate of the targeting MAb and streptavidin. Rat glial cells (C6 or RG-2) were permanently transfected with the luciferase gene, and implanted in the brain of adult rats. Following the formation of intra-cranial tumors, the rats were treated with a single intravenous injection of 270 microg/kg of biotinylated siRNA attached to a transferrin receptor antibody via a biotin-streptavidin linker. The intravenous administration of the siRNA caused a 69-81% decrease in luciferase gene expression in the intracranial brain cancer in vivo. Brain delivery of siRNA following intravenous administration is possible with siRNAs that are targeted to brain with the combined use of receptor specific antibody delivery systems and avidin-biotin technology.

The Co-Metabolism within the Gut-Brain Metabolic Interaction: Potential Targets for Drug Treatment and Design.

PubMed

Obrenovich, Mark; Flückiger, Rudolf; Sykes, Lorraine; Donskey, Curtis

2016-01-01

We know that within the complex mammalian gut is any number of metabolic biomes. The gut has been sometimes called the "second brain" within the "gut-brain axis". A more informative term would be the gut-brain metabolic interactome, which is coined here to underscore the relationship between the digestive system and cognitive function or dysfunction as the case may be. Co-metabolism between the host and the intestinal microbiota is essential for life's processes. How diet, lifestyle, antibiotics and other factors shape the gut microbiome constitutes a rapidly growing area of research. Conversely, the gut microbiome also affects mammalian systems. Metabolites of the gut-brain axis are potential targets for treatment and drug design since the interaction or biochemical interplay results in net metabolite production or end-products with either positive or negative effects on human health. This review explores the gut-brain metabolic interactome, with particular emphasis on drug design and treatment strategies and how commensal bacteria or their disruption lead to dysbiosis and the effect this has on neurochemistry. Increasing data indicate that the intestinal microbiome can affect neurobiology, from mental and even behavioral health to memory, depression, mood, anxiety, obesity, cravings and even the creation and maintenance of the blood brain barrier.

Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma

PubMed Central

Ju, Rui-Jun; Zeng, Fan; Liu, Lei; Mu, Li-Min; Xie, Hong-Jun; Zhao, Yao; Yan, Yan; Wu, Jia-Shuan; Hu, Ying-Jie; Lu, Wan-Liang

2016-01-01

The efficacy of chemotherapy for brain glioma is restricted by the blood–brain barrier (BBB), and surgery or radiotherapy cannot eliminate the glioma cells because of their unique location. Residual brain glioma cells can form vasculogenic mimicry (VM) channels that can cause a recurrence of brain glioma. In the present study, targeting liposomes incorporating epirubicin and celecoxib were prepared and used for the treatment of brain glioma, along with the destruction of their VM channels. Evaluations were performed on the human brain glioma U87MG cells in vitro and on intracranial brain glioma-bearing nude mice. Targeting epirubicin plus celecoxib liposomes in the circulatory blood system were able to be transported across the BBB, and accumulated in the brain glioma region. Then, the liposomes were internalized by brain glioma cells and killed glioma cells by direct cytotoxic injury and the induction of apoptosis. The induction of apoptosis was related to the activation of caspase-8- and -3-signaling pathways, the activation of the proapoptotic protein Bax, and the suppression of the antiapoptotic protein Mcl-1. The destruction of brain glioma VM channels was related to the downregulation of VM channel-forming indictors, which consisted of MMP-2, MMP-9, FAK, VE-Cad, and VEGF. The results demonstrated that the targeting epirubicin plus celecoxib liposomes were able to effectively destroy the glioma VM channels and exhibited significant efficacy in the treatment of intracranial glioma-bearing nude mice. Therefore, targeting epirubicin plus celecoxib liposomes could be a potential nanostructured formulation to treat gliomas and destroy their VM channels. PMID:27042063

Visual encoding and fixation target selection in free viewing: presaccadic brain potentials

PubMed Central

Nikolaev, Andrey R.; Jurica, Peter; Nakatani, Chie; Plomp, Gijs; van Leeuwen, Cees

2013-01-01

In scrutinizing a scene, the eyes alternate between fixations and saccades. During a fixation, two component processes can be distinguished: visual encoding and selection of the next fixation target. We aimed to distinguish the neural correlates of these processes in the electrical brain activity prior to a saccade onset. Participants viewed color photographs of natural scenes, in preparation for a change detection task. Then, for each participant and each scene we computed an image heat map, with temperature representing the duration and density of fixations. The temperature difference between the start and end points of saccades was taken as a measure of the expected task-relevance of the information concentrated in specific regions of a scene. Visual encoding was evaluated according to whether subsequent change was correctly detected. Saccades with larger temperature difference were more likely to be followed by correct detection than ones with smaller temperature differences. The amplitude of presaccadic activity over anterior brain areas was larger for correct detection than for detection failure. This difference was observed for short “scrutinizing” but not for long “explorative” saccades, suggesting that presaccadic activity reflects top-down saccade guidance. Thus, successful encoding requires local scanning of scene regions which are expected to be task-relevant. Next, we evaluated fixation target selection. Saccades “moving up” in temperature were preceded by presaccadic activity of higher amplitude than those “moving down”. This finding suggests that presaccadic activity reflects attention deployed to the following fixation location. Our findings illustrate how presaccadic activity can elucidate concurrent brain processes related to the immediate goal of planning the next saccade and the larger-scale goal of constructing a robust representation of the visual scene. PMID:23818877

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

2017-04-01

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Targeting modulates audiences’ brain and behavioral responses to safe sex video ads

PubMed Central

Lowen, Steven B; Shi, Zhenhao; Bissey, Bryn; Metzger, David S.; Langleben, Daniel D.

2016-01-01

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. PMID:27217112

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.

Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms.

PubMed

Gleitz, Hélène Fe; Liao, Ai Yin; Cook, James R; Rowlston, Samuel F; Forte, Gabriella Ma; D'Souza, Zelpha; O'Leary, Claire; Holley, Rebecca J; Bigger, Brian W

2018-06-08

The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross-correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE-dependent receptors and mannose-6-phosphate receptors. Brain-targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

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.

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

PubMed Central

Jiang, Xiaoyan; Zhang, Lili; Pu, Hongjian; Hu, Xiaoming; Zhang, Wenting; Cai, Wei; Gao, Yanqin; Leak, Rehana K.; Keep, Richard F.; Bennett, Michael V. L.; Chen, Jun

2017-01-01

The damage borne by the endothelial cells (ECs) forming the blood–brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs—namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30–60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs—but not within neurons—ameliorated BBB impairment 1–24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown. PMID:28137866

Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases.

PubMed

Sun, Bao-Liang; Wang, Li-Hua; Yang, Tuo; Sun, Jing-Yi; Mao, Lei-Lei; Yang, Ming-Feng; Yuan, Hui; Colvin, Robert A; Yang, Xiao-Yi

2017-09-10

The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange. Copyright © 2017. Published by Elsevier Ltd.

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…

Frameless robotically targeted stereotactic brain biopsy: feasibility, diagnostic yield, and safety.

PubMed

Bekelis, Kimon; Radwan, Tarek A; Desai, Atman; Roberts, David W

2012-05-01

Frameless stereotactic brain biopsy has become an established procedure in many neurosurgical centers worldwide. Robotic modifications of image-guided frameless stereotaxy hold promise for making these procedures safer, more effective, and more efficient. The authors hypothesized that robotic brain biopsy is a safe, accurate procedure, with a high diagnostic yield and a safety profile comparable to other stereotactic biopsy methods. This retrospective study included 41 patients undergoing frameless stereotactic brain biopsy of lesions (mean size 2.9 cm) for diagnostic purposes. All patients underwent image-guided, robotic biopsy in which the SurgiScope system was used in conjunction with scalp fiducial markers and a preoperatively selected target and trajectory. Forty-five procedures, with 50 supratentorial targets selected, were performed. The mean operative time was 44.6 minutes for the robotic biopsy procedures. This decreased over the second half of the study by 37%, from 54.7 to 34.5 minutes (p < 0.025). The diagnostic yield was 97.8% per procedure, with a second procedure being diagnostic in the single nondiagnostic case. Complications included one transient worsening of a preexisting deficit (2%) and another deficit that was permanent (2%). There were no infections. Robotic biopsy involving a preselected target and trajectory is safe, accurate, efficient, and comparable to other procedures employing either frame-based stereotaxy or frameless, nonrobotic stereotaxy. It permits biopsy in all patients, including those with small target lesions. Robotic biopsy planning facilitates careful preoperative study and optimization of needle trajectory to avoid sulcal vessels, bridging veins, and ventricular penetration.

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.

Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

PubMed

Boche, Mithila; Pokharkar, Varsha

2017-04-01

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.

siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery.

PubMed

Gomes, Maria João; Martins, Susana; Sarmento, Bruno

2015-05-01

As the population ages, brain pathologies such as neurodegenerative diseases and brain cancer increase their incidence, being the need to find successful treatments of upmost importance. Drug delivery to the central nervous system (CNS) is required in order to reach diseases causes and treat them. However, biological barriers, mainly blood-brain barrier (BBB), are the key obstacles that prevent the effectiveness of possible treatments due to their ability to strongly limit the perfusion of compounds into the brain. Over the past decades, new approaches towards overcoming BBB and its efflux transporters had been proposed. One of these approaches here reviewed is through small interfering RNA (siRNA), which is capable to specifically target one gene and silence it in a post-transcriptional way. There are different possible functional proteins at the BBB, as the ones responsible for transport or just for its tightness, which could be a siRNA target. As important as the effective silence is the way to delivery siRNA to its anatomical site of action. This is where nanotechnology-based systems may help, by protecting siRNA circulation and providing cell/tissue-targeting and intracellular siRNA delivery. After an initial overview on incidence of brain diseases and basic features of the CNS, BBB and its efflux pumps, this review focuses on recent strategies to reach brain based on siRNA, and how to specifically target these approaches in order to treat brain diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Age-related differences in the brain areas outside the classical language areas among adults using category decision task.

PubMed

Cho, Yong Won; Song, Hui-Jin; Lee, Jae Jun; Lee, Joo Hwa; Lee, Hui Joong; Yi, Sang Doe; Chang, Hyuk Won; Berl, Madison M; Gaillard, William D; Chang, Yongmin

2012-03-01

Older adults perform much like younger adults on language. This similar level of performance, however, may come about through different underlying brain processes. In the present study, we evaluated age-related differences in the brain areas outside the typical language areas among adults using a category decision task. Our results showed that similar activation patterns were found in classical language processing areas across the three age groups although regional lateralization indices in Broca's and Wernicke's areas decreased with age. The greatest differences, however, among the three groups were found primarily in the brain areas not associated with core language functioning including the hippocampus, middle frontal gyrus, ventromedial frontal cortex, medial superior parietal cortex and posterior cingulate cortex. Therefore, the non-classical language areas may exhibit an age-related difference between three age groups while the subjects show a similar activation pattern in the core, primary language processing during a semantic decision task. Copyright © 2012 Elsevier Inc. All rights reserved.

Age-Related Differences in the Brain Areas outside the Classical Language Areas among Adults Using Category Decision Task

ERIC Educational Resources Information Center

Cho, Yong Won; Song, Hui-Jin; Lee, Jae Jun; Lee, Joo Hwa; Lee, Hui Joong; Yi, Sang Doe; Chang, Hyuk Won; Berl, Madison M.; Gaillard, William D.; Chang, Yongmin

2012-01-01

Older adults perform much like younger adults on language. This similar level of performance, however, may come about through different underlying brain processes. In the present study, we evaluated age-related differences in the brain areas outside the typical language areas among adults using a category decision task. Our results showed that…

Multiwaveguide implantable probe for light delivery to sets of distributed brain targets.

PubMed

Zorzos, Anthony N; Boyden, Edward S; Fonstad, Clifton G

2010-12-15

Optical fibers are commonly inserted into living tissues such as the brain in order to deliver light to deep targets for neuroscientific and neuroengineering applications such as optogenetics, in which light is used to activate or silence neurons expressing specific photosensitive proteins. However, an optical fiber is limited to delivering light to a single target within the three-dimensional structure of the brain. We here demonstrate a multiwaveguide probe capable of independently delivering light to multiple targets along the probe axis, thus enabling versatile optical control of sets of distributed brain targets. The 1.45-cm-long probe is microfabricated in the form of a 360-μm-wide array of 12 parallel silicon oxynitride (SiON) multimode waveguides clad with SiO(2) and coated with aluminum; probes of custom dimensions are easily created as well. The waveguide array accepts light from a set of sources at the input end and guides the light down each waveguide to an aluminum corner mirror that efficiently deflects light away from the probe axis. Light losses at each stage are small (input coupling loss, 0.4 ± 0.3 dB; bend loss, negligible; propagation loss, 3.1 ± 1 dB/cm using the outscattering method and 3.2 ± 0.4 dB/cm using the cutback method; corner mirror loss, 1.5 ± 0.4 dB); a waveguide coupled, for example, to a 5 mW source will deliver over 1.5 mW to a target at a depth of 1 cm.

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 (β 2 adrenoceptor, Dopamine D 3 , 5HT 1B , 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), β 2 adrenoceptor (3NYA) and Dopamine D 3 (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. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeted DNA sequencing of non-small cell lung cancer identifies mutations associated with brain metastases.

PubMed

Wilson, George D; Johnson, Matthew D; Ahmed, Samreen; Cardenas, Paola Yumpo; Grills, Inga S; Thibodeau, Bryan J

2018-05-25

This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain. NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing. In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions. While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target.

Targeted DNA sequencing of non-small cell lung cancer identifies mutations associated with brain metastases

PubMed Central

Wilson, George D.; Johnson, Matthew D.; Ahmed, Samreen; Cardenas, Paola Yumpo; Grills, Inga S.; Thibodeau, Bryan J.

2018-01-01

Introduction This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain. Methods NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing. Results In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions. Conclusion While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target. PMID:29899834

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. Copyright © 2014 Elsevier B.V. All rights reserved.

Deep Brain Stimulation for Essential Tremor: Aligning Thalamic and Posterior Subthalamic Targets in 1 Surgical Trajectory.

PubMed

Bot, Maarten; van Rootselaar, Fleur; Contarino, Maria Fiorella; Odekerken, Vincent; Dijk, Joke; de Bie, Rob; Schuurman, Richard; van den Munckhof, Pepijn

2017-12-21

Ventral intermediate nucleus (VIM) deep brain stimulation (DBS) and posterior subthalamic area (PSA) DBS suppress tremor in essential tremor (ET) patients, but it is not clear which target is optimal. Aligning both targets in 1 surgical trajectory would facilitate exploring stimulation of either target in a single patient. To evaluate aligning VIM and PSA in 1 surgical trajectory for DBS in ET. Technical aspects of trajectories, intraoperative stimulation findings, final electrode placement, target used for chronic stimulation, and adverse and beneficial effects were evaluated. In 17 patients representing 33 trajectories, we successfully aligned VIM and PSA targets in 26 trajectories. Trajectory distance between targets averaged 7.2 (range 6-10) mm. In all but 4 aligned trajectories, optimal intraoperative tremor suppression was obtained in the PSA. During follow-up, active electrode contacts were located in PSA in the majority of cases. Overall, successful tremor control was achieved in 69% of patients. Stimulation-induced dysarthria or gait ataxia occurred in, respectively, 56% and 44% of patients. Neither difference in tremor suppression or side effects was noted between aligned and nonaligned leads nor between the different locations of chronic stimulation. Alignment of VIM and PSA for DBS in ET is feasible and enables intraoperative exploration of both targets in 1 trajectory. This facilitates positioning of electrode contacts in both areas, where multiple effective points of stimulation can be found. In the majority of aligned leads, optimal intraoperative and chronic stimulation were located in the PSA. Copyright © 2017 by the Congress of Neurological Surgeons

Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases

PubMed Central

Johnson, Adam G.; Ruiz, Jimmy; Hughes, Ryan; Page, Brandi R.; Isom, Scott; Lucas, John T.; McTyre, Emory R.; Houseknecht, Kristin W.; Ayala-Peacock, Diandra N.; Bourland, Daniel J.; Hinson, William H.; Laxton, Adrian W.; Tatter, Stephen B.; Debinski, Waldemar; Watabe, Kounosuke; Chan, Michael D.

2015-01-01

Background To determine the clinical benefits of systemic targeted agents across multiple histologies after stereotactic radiosurgery (SRS) for brain metastases. Methods Between 2000 and 2013, 737 patients underwent upfront SRS for brain metastases. Patients were stratified by whether or not they received targeted agents with SRS. 167 (23%) received targeted agents compared to 570 (77%) that received other available treatment options. Time to event data were summarized using Kaplan-Meier plots, and the log rank test was used to determine statistical differences between groups. Results Patients who received SRS with targeted agents vs those that did not had improved overall survival (65% vs. 30% at 12 months, p < 0.0001), improved freedom from local failure (94% vs 90% at 12 months, p = 0.06), improved distant failure-free survival (32% vs. 18% at 12 months, p = 0.0001) and improved freedom from whole brain radiation (88% vs. 77% at 12 months, p = 0.03). Improvement in freedom from local failure was driven by improvements seen in breast cancer (100% vs 92% at 12 months, p < 0.01), and renal cell cancer (100% vs 88%, p = 0.04). Multivariate analysis revealed that use of targeted agents improved all cause mortality (HR = 0.6, p < 0.0001). Conclusions Targeted agent use with SRS appears to improve survival and intracranial outcomes. PMID:26087184

The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk.

PubMed

Silachev, Denis N; Isaev, Nikolay K; Pevzner, Irina B; Zorova, Ljubava D; Stelmashook, Elena V; Novikova, Svetlana V; Plotnikov, Egor Y; Skulachev, Vladimir P; Zorov, Dmitry B

2012-01-01

Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced

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

PubMed Central

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

2014-01-01

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 nanovesicles 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. PMID:25051370

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

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

PubMed

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

2014-11-17

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.

Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0389 TITLE: Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury...2015 4. TITLE AND SUBTITLE Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury 5a. CONTRACT NUMBER 5b...disabling behavioral and cognitive abnormalities noted in significant number of combat veterans. These clinical phenotypes suggest impairment in

Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0388 TITLE: Demyelination as a Target for Cell-Based Therapy of Chronic Blast- Induced Traumatic Brain Injury...SUBTITLE Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...disabling behavioral and cognitive abnormalities noted in significant number of combat veterans. These clinical phenotypes suggest impairment in

[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies].

PubMed

Bachelot, Thomas; Le Rhun, Emilie; Labidi-Gally, Intidar; Heudel, Pierre; Gilabert, Marine; Bonneterre, Jacques; Pierga, Jean-Yves; Gonçalves, Anthony

2013-01-01

Prevalence of brain metastases is increasing in breast cancer. Brain metastases represent a poor-prognosis disease for which local treatments continue to play a major role. In spite of the presence of a physiological blood-brain barrier limiting their activity, some systemic treatments may display a significant antitumor activity at the central nervous system level. In HER2-positive metastatic breast cancer with brain metastases not previously treated with whole brain radiotherapy, capecitabine and lapatinib combination obtains a volumetric reponse in two thirds of patients (LANDSCAPE study). If confirmed, these results could modify in selected patients the layout of therapeutic strategies. Promoting novel targeted approaches and innovative therapeutic combinations is a critical need to improve survival of breast cancer patients with brain metastases.

Active Targeted Macrophage-mediated Delivery of Catalase to Affected Brain Regions in Models of Parkinson's Disease.

PubMed

Zhao, Yuling; Haney, Matthew J; Mahajan, Vivek; Reiner, Benjamin C; Dunaevsky, Anna; Mosley, R Lee; Kabanov, Alexander V; Gendelman, Howard E; Batrakova, Elena V

2011-09-10

We previously demonstrated that monocyte-macrophage based drug delivery can be applied to a spectrum of infectious, neoplastic, and degenerative disorders. In particular, bone marrow-derived macrophages (BMM) loaded with nano formulated catalase, "nanozyme", were shown to attenuate neuro inflammation and nigrostriatal degeneration in rodent models of Parkinson's disease (PD). Nonetheless, the pharmacokinetics and biodistribution of BMM-incorporated nanozyme has not been explored. To this end, we now demonstrate that BMM, serving as a "depot" for nanozyme, increased area under the curve(AUC), half-life, and mean residence time in blood circulation of the protein when compared to the nanozyme administered alone. Accordingly, bioavailability of the nanozyme for the brain, spleen, kidney, and liver was substantially increased. Importantly, nanozyme-loaded BMM targeted diseased sites and improved transport across the blood brain barrier. This was seen specifically in affected brain subregions in models of PD. Engaging natural immune cells such as monocyte-macrophages as drug carriers provides a new perspective for therapeutic delivery for PD and also likely a range of other inflammatory and degenerative diseases.

Enhancement of brain-targeting delivery of danshensu in rat through conjugation with pyrazine moiety to form danshensu-pyrazine ester.

PubMed

Hui, Ailing; Yin, Huayang; Zhang, Zheng; Zhou, An; Chen, Jingchao; Yang, Li; Wu, Zeyu; Zhang, Wencheng

2018-06-01

Tetramethylpyrazine was introduced to the structure of danshensu (DSS) as P-glycoprotein (P-gp)-inhibiting carrier, designing some novel brain-targeting DSS-pyrazine derivatives via prodrug delivery strategy. Following the virtual screening, three DSS-pyrazine esters (DT1, DT2, DT3) were selected because of their better prediction parameters related to brain-targeting. Among them, DT3 was thought to be a promising candidate due to its appropriate bioreversible property in vitro release assay. Further investigation with regard to DT3's brain-targeting effects in vivo was also reported in this study. High-performance liquid chromatography-diode array detection (HPLC-DAD) method was established for the quantitative determination of DT3 and DSS in rat plasma, brain homogenate after intravenous injection. In vivo metabolism of DT3 indicated that it was first converted into DT1, DT2, then the generation of DSS, which could be the result of carboxylesterase activity in rat blood and brain tissue. Moreover, the brain pharmacokinetics of DT3 was significantly altered with 2.16 times increase in half-life compared with that of DSS, and its drug targeting index (DTI) was up to 16.95. Above these data demonstrated that DT3 had better tendency of brain-targeting delivery, which would be positive for the treatment of brain-related disorders.

Neurocognitive Brain Response to Transient Impairment of Wernicke's Area

PubMed Central

Mason, Robert A.; Prat, Chantel S.; Just, Marcel Adam

2014-01-01

This study examined how the brain system adapts and reconfigures its information processing capabilities to maintain cognitive performance after a key cortical center [left posterior superior temporal gyrus (LSTGp)] is temporarily impaired during the performance of a language comprehension task. By applying repetitive transcranial magnetic stimulation (rTMS) to LSTGp and concurrently assessing the brain response with functional magnetic resonance imaging, we found that adaptation consisted of 1) increased synchronization between compensating regions coupled with a decrease in synchronization within the primary language network and 2) a decrease in activation at the rTMS site as well as in distal regions, followed by their recovery. The compensatory synchronization included 3 centers: The contralateral homolog (RSTGp) of the area receiving rTMS, areas adjacent to the rTMS site, and a region involved in discourse monitoring (medial frontal gyrus). This approach reveals some principles of network-level adaptation to trauma with potential application to traumatic brain injury, stroke, and seizure. PMID:23322403

Neurocognitive brain response to transient impairment of Wernicke's area.

PubMed

Mason, Robert A; Prat, Chantel S; Just, Marcel Adam

2014-06-01

This study examined how the brain system adapts and reconfigures its information processing capabilities to maintain cognitive performance after a key cortical center [left posterior superior temporal gyrus (LSTGp)] is temporarily impaired during the performance of a language comprehension task. By applying repetitive transcranial magnetic stimulation (rTMS) to LSTGp and concurrently assessing the brain response with functional magnetic resonance imaging, we found that adaptation consisted of 1) increased synchronization between compensating regions coupled with a decrease in synchronization within the primary language network and 2) a decrease in activation at the rTMS site as well as in distal regions, followed by their recovery. The compensatory synchronization included 3 centers: The contralateral homolog (RSTGp) of the area receiving rTMS, areas adjacent to the rTMS site, and a region involved in discourse monitoring (medial frontal gyrus). This approach reveals some principles of network-level adaptation to trauma with potential application to traumatic brain injury, stroke, and seizure.

Brain areas impaired in oral and verbal apraxic patients

PubMed Central

Yadegari, Fariba; Azimian, Mojtaba; Rahgozar, Mahdi; Shekarchi, Babak

2014-01-01

Background: As both oral and verbal apraxia are related to vocal orofacial musculature, this study aimed at identifying brain regions impaired in cases with oral and verbal apraxia. Methods: In this non-experimental study, 46 left brain damaged subjects (17 females) aged 23–84 years, were examined by oral and verbal apraxia tasks. Impaired and spared Broca’s area, insula, and middle frontal gyrus in the left hemisphere were checked from magnetic resonance imaging and computed tomography scans utilizing Talairach Atlas. Data were analyzed using chi-square test. Results: Insula was significantly impaired in both forms of oral and verbal apraxia and different severities and prominent forms of both apraxias (P < 0.05). Broca’s area was slightly less involved than insula in two forms of apraxia. Conclusion: As the damage of insula was more prominent in both forms of apraxias, it seems that oral and verbal apraxia may have commonalities regarding their underlying brain lesions. PMID:25295150

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

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

The Brain-Targeted Teaching Model for 21st-Century Schools

ERIC Educational Resources Information Center

Hardiman, Mariale

2012-01-01

"The Brain-Targeted Teaching Model for 21st-Century Schools" serves as a bridge between research and practice by providing a cohesive, proven, and usable model of effective instruction. Compatible with other professional development programs, this model shows how to apply relevant research from educational and cognitive neuroscience to classroom…

Identification of the Transcriptional Targets of FOXP2, a Gene Linked to Speech and Language, in Developing Human Brain

PubMed Central

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

2007-01-01

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. PMID:17999357

Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain.

PubMed

Somani, Sukrut; Blatchford, David R; Millington, Owain; Stevenson, M Lynn; Dufès, Christine

2014-08-28

The possibility of using genes as medicines to treat brain diseases is currently limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier, thus resulting in a failure to reach the brain after intravenous administration. On the basis that iron can effectively reach the brain by using transferrin receptors for crossing the blood-brain barrier, we propose to investigate if a transferrin-bearing generation 3-polypropylenimine dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration. In vitro, the conjugation of transferrin to the polypropylenimine dendrimer increased the DNA uptake by bEnd.3 murine brain endothelioma cells overexpressing transferrin receptors, by about 1.4-fold and 2.3-fold compared to that observed with the non-targeted dendriplex and naked DNA. This DNA uptake appeared to be optimal following 2h incubation with the treatment. In vivo, the intravenous injection of transferrin-bearing dendriplex more than doubled the gene expression in the brain compared to the unmodified dendriplex, while decreasing the non-specific gene expression in the lung. Gene expression was at least 3-fold higher in the brain than in any tested peripheral organs and was at its highest 24h following the injection of the treatments. These results suggest that transferrin-bearing polypropylenimine dendrimer is a highly promising gene delivery system to the brain. Copyright © 2014 Elsevier B.V. All rights reserved.

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

PubMed Central

Sakic, Boris; Kirkham, David L.; Ballok, David A.; Mwanjewe, James; Fearon, Ian M.; Macri, Joseph; Yu, Guanhua; Sidor, Michelle M.; Denburg, Judah A.; Szechtman, Henry; Lau, Jonathan; Ball, Alexander K.; Doering, Laurie C.

2006-01-01

Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented. PMID:16198428

Metabolic connectomics targeting brain pathology in dementia with Lewy bodies

PubMed Central

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

2016-01-01

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. PMID:27306756

Preservation of mitochondrial functional integrity in mitochondria isolated from small cryopreserved mouse brain areas.

PubMed

Valenti, Daniela; de Bari, Lidia; De Filippis, Bianca; Ricceri, Laura; Vacca, Rosa Anna

2014-01-01

Studies of mitochondrial bioenergetics in brain pathophysiology are often precluded by the need to isolate mitochondria immediately after tissue dissection from a large number of brain biopsies for comparative studies. Here we present a procedure of cryopreservation of small brain areas from which mitochondrial enriched fractions (crude mitochondria) with high oxidative phosphorylation efficiency can be isolated. Small mouse brain areas were frozen and stored in a solution containing glycerol as cryoprotectant. Crude mitochondria were isolated by differential centrifugation from both cryopreserved and freshly explanted brain samples and were compared with respect to their ability to generate membrane potential and produce ATP. Intactness of outer and inner mitochondrial membranes was verified by polarographic ascorbate and cytochrome c tests and spectrophotometric assay of citrate synthase activity. Preservation of structural integrity and oxidative phosphorylation efficiency was successfully obtained in crude mitochondria isolated from different areas of cryopreserved mouse brain samples. Long-term cryopreservation of small brain areas from which intact and phosphorylating mitochondria can be isolated for the study of mitochondrial bioenergetics will significantly expand the study of mitochondrial defects in neurological pathologies, allowing large comparative studies and favoring interlaboratory and interdisciplinary analyses. Copyright © 2013 Elsevier Inc. All rights reserved.

Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting.

PubMed

Feng, Qishuai; Shen, Yajing; Fu, Yingjie; Muroski, Megan E; Zhang, Peng; Wang, Qiaoyue; Xu, Chang; Lesniak, Maciej S; Li, Gang; Cheng, Yu

2017-01-01

Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH-responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment.

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

PubMed

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

2016-01-01

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

In Silico Prediction and Validation of Gfap as an miR-3099 Target in Mouse Brain.

PubMed

Abidin, Shahidee Zainal; Leong, Jia-Wen; Mahmoudi, Marzieh; Nordin, Norshariza; Abdullah, Syahril; Cheah, Pike-See; Ling, King-Hwa

2017-08-01

MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms (miRDB, miRanda, TargetScan, and DIANA-micro-T-CDS) with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms (324 genes) were subjected to DAVID bioinformatics analysis to understand their overall functional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization (ISH) expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes (Dnmt3a, Gabpa, Gfap, Itga4, Lxn, Smad7, and Tbx18) having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset.

Relationship between ventricular characteristics on brain computed tomography and 6-month neurologic outcome in cardiac arrest survivors who underwent targeted temperature management.

PubMed

Lee, Dong Hun; Lee, Byung Kook; Jeung, Kyung Woon; Jung, Yong Hun; Cho, Yong Soo; Cho, In Soo; Youn, Chun Song; Kim, Jin Woong; Park, Jung Soo; Min, Yong Il

2018-06-11

Brain swelling after cardiac arrest may affect the ventricles. We aimed to investigate the prognostic performance of ventricular characteristics on brain computed tomography (CT) in cardiac arrest survivors who underwent targeted temperature management (TTM). This retrospective cohort study included adult comatose cardiac arrest survivors who underwent brain CT scan within 24 h after resuscitation and underwent TTM from 2014 to 2016. The ventricular areas (lateral, third, and fourth ventricle), distances between the anterior horns of the lateral ventricle (LV) and the posterior horns of the LV, and maximal internal diameter of the skull were measured. Grey-to-white matter ratio (GWR), Evans' index, and relative LV area were calculated. The primary outcome was a 6-month neurologic outcome. Of 258 patients, 176 (68.2%) had an unfavourable neurologic outcome. GWR, LV area, third ventricle area, distance between the anterior horns of the LV, distance between the posterior horns of the LV, Evans' index, and relative LV area were different between neurologic outcome groups. Evans' index (0.683; 95% confidence interval [CI], 0.623-0.739) and relative LV area (0.670; 95% CI, 0.609-0.727) had higher value of area under the curve than the other ventricular characteristics and showed prognostic performance comparable with GWR (0.600; 95% CI, 0.538-0.661). All ventricular characteristics and GWR were not independently associated with neurologic outcome after adjusting for covariates. Ventricular characteristics on brain CT were associated with 6 months neurologic outcome in cardiac arrest survivors. Ventricular characteristics were objective measures that had comparable prognostic performance with GWR. Copyright © 2018 Elsevier B.V. All rights reserved.

Activity-Based Protein Profiling of Organophosphorus and Thiocarbamate Pesticides Reveals Multiple Serine Hydrolase Targets in Mouse Brain

PubMed Central

NOMURA, DANIEL K.; CASIDA, JOHN E.

2010-01-01

Organophosphorus (OP) and thiocarbamate (TC) agrochemicals are used worldwide as insecticides, herbicides, and fungicides, but their safety assessment in terms of potential off-targets remains incomplete. In this study, we used a chemoproteomic platform, termed activity-based protein profiling, to broadly define serine hydrolase targets in mouse brain of a panel of 29 OP and TC pesticides. Among the secondary targets identified, enzymes involved in degradation of endocannabinoid signaling lipids, monoacylglycerol lipase and fatty acid amide hydrolase, were inhibited by several OP and TC pesticides. Blockade of these two enzymes led to elevations in brain endocannabinoid levels and dysregulated brain arachidonate metabolism. Other secondary targets include enzymes thought to also play important roles in the nervous system and unannotated proteins. This study reveals a multitude of secondary targets for OP and TC pesticides and underscores the utility of chemoproteomic platforms in gaining insights into biochemical pathways that are perturbed by these toxicants. PMID:21341672

Targeting of the Subthalamic Nucleus for Deep Brain Stimulation: A Survey Among Parkinson Disease Specialists.

PubMed

Hamel, Wolfgang; Köppen, Johannes A; Alesch, François; Antonini, Angelo; Barcia, Juan A; Bergman, Hagai; Chabardes, Stephan; Contarino, Maria Fiorella; Cornu, Philippe; Demmel, Walter; Deuschl, Günther; Fasano, Alfonso; Kühn, Andrea A; Limousin, Patricia; McIntyre, Cameron C; Mehdorn, H Maximilian; Pilleri, Manuela; Pollak, Pierre; Rodríguez-Oroz, Maria C; Rumià, Jordi; Samuel, Michael; Timmermann, Lars; Valldeoriola, Francesc; Vesper, Jan; Visser-Vandewalle, Veerle; Volkmann, Jens; Lozano, Andres M

2017-03-01

Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target. To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN. The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule. This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Novel targets and stimulation paradigms for deep brain stimulation.

PubMed

De Jesus, Sol; Almeida, Leonardo; Peng-Chen, Zhongxing; Okun, Michael S; Hess, Christopher W

2015-01-01

Deep brain stimulation (DBS) is an accepted therapy for appropriately selected patients with movement disorders and psychiatric disease. The recent advances in lead technology and the advent of novel stimulation parameters have spurred a number of improvements that will likely be implemented in the clinical setting. Although the mechanisms and biology of DBS remain poorly understood, the progress in our understanding of network level dysfunction has driven the introduction of a variety of new targets and approaches to the treatment of human disease. Here we summarize the recent advances in novel stimulation patterns and customized field shaping. We also review new targets, novel applications of DBS and the immediate and long-term horizon for this therapy.

Targeting the ecology within: The role of the gut-brain axis and human microbiota in drug addiction.

PubMed

Skosnik, Patrick D; Cortes-Briones, Jose A

2016-08-01

Despite major advances in our understanding of the brain using traditional neuroscience, reliable and efficacious treatments for drug addiction have remained elusive. Hence, the time has come to utilize novel approaches, particularly those drawing upon contemporary advances in fields outside of established neuroscience and psychiatry. Put another way, the time has come for a paradigm shift in the addiction sciences. Apropos, a revolution in the area of human health is underway, which is occurring at the nexus between enteric microbiology and neuroscience. It has become increasingly clear that the human microbiota (the vast ecology of bacteria residing within the human organism), plays an important role in health and disease. This is not surprising, as it has been estimated that bacteria living in the human body (approximately 1kg of mass, roughly equivalent to that of the human brain) outnumber human cells 10 to 1. While advances in the understanding of the role of microbiota in other areas of human health have yielded intriguing results (e.g., Clostridium difficile, irritable bowel syndrome, autism, etc.), to date, no systematic programs of research have examined the role of microbiota in drug addiction. The current hypothesis, therefore, is that gut dysbiosis plays a key role in addictive disorders. In the context of this hypothesis, this paper provides a rationale for future research to target the "gut-brain axis" in addiction. A brief background of the gut-brain axis is provided, along with a series of hypothesis-driven ideas outlining potential treatments for addiction via manipulations of the "ecology within." Copyright © 2016 Elsevier Ltd. All rights reserved.

Selectivity to Translational Egomotion in Human Brain Motion Areas

PubMed Central

Pitzalis, Sabrina; Sdoia, Stefano; Bultrini, Alessandro; Committeri, Giorgia; Di Russo, Francesco; Fattori, Patrizia; Galletti, Claudio; Galati, Gaspare

2013-01-01

The optic flow generated when a person moves through the environment can be locally decomposed into several basic components, including radial, circular, translational and spiral motion. Since their analysis plays an important part in the visual perception and control of locomotion and posture it is likely that some brain regions in the primate dorsal visual pathway are specialized to distinguish among them. The aim of this study is to explore the sensitivity to different types of egomotion-compatible visual stimulations in the human motion-sensitive regions of the brain. Event-related fMRI experiments, 3D motion and wide-field stimulation, functional localizers and brain mapping methods were used to study the sensitivity of six distinct motion areas (V6, MT, MST+, V3A, CSv and an Intra-Parietal Sulcus motion [IPSmot] region) to different types of optic flow stimuli. Results show that only areas V6, MST+ and IPSmot are specialized in distinguishing among the various types of flow patterns, with a high response for the translational flow which was maximum in V6 and IPSmot and less marked in MST+. Given that during egomotion the translational optic flow conveys differential information about the near and far external objects, areas V6 and IPSmot likely process visual egomotion signals to extract information about the relative distance of objects with respect to the observer. Since area V6 is also involved in distinguishing object-motion from self-motion, it could provide information about location in space of moving and static objects during self-motion, particularly in a dynamically unstable environment. PMID:23577096

Loud Noise Exposure Produces DNA, Neurotransmitter and Morphological Damage within Specific Brain Areas.

PubMed

Frenzilli, Giada; Ryskalin, Larisa; Ferrucci, Michela; Cantafora, Emanuela; Chelazzi, Silvia; Giorgi, Filippo S; Lenzi, Paola; Scarcelli, Vittoria; Frati, Alessandro; Biagioni, Francesca; Gambardella, Stefano; Falleni, Alessandra; Fornai, Francesco

2017-01-01

Exposure to loud noise is a major environmental threat to public health. Loud noise exposure, apart from affecting the inner ear, is deleterious for cardiovascular, endocrine and nervous systems and it is associated with neuropsychiatric disorders. In this study we investigated DNA, neurotransmitters and immune-histochemical alterations induced by exposure to loud noise in three major brain areas (cerebellum, hippocampus, striatum) of Wistar rats. Rats were exposed to loud noise (100 dBA) for 12 h. The effects of noise on DNA integrity in all three brain areas were evaluated by using Comet assay. In parallel studies, brain monoamine levels and morphology of nigrostriatal pathways, hippocampus and cerebellum were analyzed at different time intervals (24 h and 7 days) after noise exposure. Loud noise produced a sudden increase in DNA damage in all the brain areas under investigation. Monoamine levels detected at 7 days following exposure were differently affected depending on the specific brain area. Namely, striatal but not hippocampal dopamine (DA) significantly decreased, whereas hippocampal and cerebellar noradrenaline (NA) was significantly reduced. This is in line with pathological findings within striatum and hippocampus consisting of a decrease in striatal tyrosine hydroxylase (TH) combined with increased Bax and glial fibrillary acidic protein (GFAP). Loud noise exposure lasting 12 h causes immediate DNA, and long-lasting neurotransmitter and immune-histochemical alterations within specific brain areas of the rat. These alterations may suggest an anatomical and functional link to explain the neurobiology of diseases which prevail in human subjects exposed to environmental noise.

Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting

PubMed Central

Feng, Qishuai; Shen, Yajing; Fu, Yingjie; Muroski, Megan E.; Zhang, Peng; Wang, Qiaoyue; Xu, Chang; Lesniak, Maciej S.; Li, Gang; Cheng, Yu

2017-01-01

Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH-responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment. PMID:28638474

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

PubMed

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

2016-03-10

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 24h 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. Copyright © 2016 The Authors. Published

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.

Interictal Epileptiform Discharges Impair Word Recall in Multiple Brain Areas

PubMed Central

Horak, Peter C.; Meisenhelter, Stephen; Song, Yinchen; Testorf, Markus E.; Kahana, Michael J.; Viles, Weston D.; Bujarski, Krzysztof A.; Connolly, Andrew C.; Robbins, Ashlee A.; Sperling, Michael R.; Sharan, Ashwini D.; Worrell, Gregory A.; Miller, Laura R.; Gross, Robert E.; Davis, Kathryn A.; Roberts, David W.; Lega, Bradley; Sheth, Sameer A.; Zaghloul, Kareem A.; Stein, Joel M.; Das, Sandhitsu R.; Rizzuto, Daniel S.; Jobst, Barbara C.

2016-01-01

Summary Objectives Interictal epileptiform discharges (IEDs) have been linked to memory impairment, but the spatial and temporal dynamics of this relationship remain elusive. In the present study, we aim to systematically characterize the brain areas and times at which IEDs affect memory. Methods Eighty epilepsy patients participated in a delayed free recall task while undergoing intracranial EEG monitoring. We analyzed the locations and timing of IEDs relative to the behavioral data in order to measure their effects on memory. Results Overall IED rates did not correlate with task performance across subjects (r = 0.03, p = 0.8). However, at a finer temporal scale, within-subject memory was negatively affected by IEDs during the encoding and recall periods of the task but not during the rest and distractor periods (p < 0.01, p < 0.001, p = 0.3, and p = 0.8 respectively). The effects of IEDs during encoding and recall were stronger in the left hemisphere than in the right (p < 0.05). Out of six brain areas analyzed, IEDs in the inferior temporal, medial temporal, and parietal areas significantly affected memory (false discovery rate < 0.05). Significance These findings reveal a network of brain areas sensitive to IEDs with key nodes in temporal as well as parietal lobes. They also demonstrate the time-dependent effects of IEDs in this network on memory. PMID:27935031

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

PubMed Central

Honório Junior, José Eduardo Ribeiro; Vasconcelos, Germana Silva; Rodrigues, Francisca Taciana Sousa; Sena Filho, José Guedes; Barbosa-Filho, José Maria; Aguiar, Carlos Clayton Torres; Leal, Luzia Kalyne Almeida Moreira; Soares, Pedro Marcos Gomes; Woods, David John; Fonteles, Marta Maria de França; Vasconcelos, Silvânia Maria Mendes

2012-01-01

This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25–30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound. PMID:23251721

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.

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.

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

PubMed Central

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

2013-01-01

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 Aβ1–40 and Aβ1–42 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.—Ho, L., Ferruzzi, M. G

Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model.

PubMed

Sharma, Anjali; Porterfield, Joshua E; Smith, Elizabeth; Sharma, Rishi; Kannan, Sujatha; Kannan, Rangaramanujam M

2018-06-05

Neurotherapeutics for the treatment of central nervous system (CNS) disorders must overcome challenges relating to the blood-brain barrier (BBB), brain tissue penetration, and the targeting of specific cells. Neuroinflammation mediated by activated microglia is a major hallmark of several neurological disorders, making these cells a desirable therapeutic target. Building on the promise of hydroxyl-terminated generation four polyamidoamine (PAMAM) dendrimers (D4-OH) for penetrating the injured BBB and targeting activated glia, we explored if conjugation of targeting ligands would enhance and modify brain and organ uptake. Since mannose receptors [cluster of differentiation (CD) 206] are typically over-expressed on injured microglia, we conjugated mannose to the surface of multifunctional D4-OH using highly efficient, atom-economical, and orthogonal Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry and evaluated the effect of mannose conjugation on the specific cell uptake of targeted and non-targeted dendrimers both in vitro and in vivo. In vitro results indicate that the conjugation of mannose as a targeting ligand significantly changes the mechanism of dendrimer internalization, giving mannosylated dendrimer a preference for mannose receptor-mediated endocytosis as opposed to non-specific fluid phase endocytosis. We further investigated the brain uptake and biodistribution of targeted and non-targeted fluorescently labeled dendrimers in a maternal intrauterine inflammation-induced cerebral palsy (CP) rabbit model using quantification methods based on fluorescence spectroscopy and confocal microscopy. We found that the conjugation of mannose modified the distribution of D4-OH throughout the body in this neonatal rabbit CP model without lowering the amount of dendrimer delivered to injured glia in the brain, even though significantly higher glial uptake was not observed in this model. Mannose conjugation to the dendrimer modifies the dendrimer

The CLAIR model: Extension of Brodmann areas based on brain oscillations and connectivity.

PubMed

Başar, Erol; Düzgün, Aysel

2016-05-01

Since the beginning of the last century, the localization of brain function has been represented by Brodmann areas, maps of the anatomic organization of the brain. They are used to broadly represent cortical structures with their given sensory-cognitive functions. In recent decades, the analysis of brain oscillations has become important in the correlation of brain functions. Moreover, spectral connectivity can provide further information on the dynamic connectivity between various structures. In addition, brain responses are dynamic in nature and structural localization is almost impossible, according to Luria (1966). Therefore, brain functions are very difficult to localize; hence, a combined analysis of oscillation and event-related coherences is required. In this study, a model termed as "CLAIR" is described to enrich and possibly replace the concept of the Brodmann areas. A CLAIR model with optimum function may take several years to develop, but this study sets out to lay its foundation. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Synergistic tumor microenvironment targeting and blood-brain barrier penetration via a pH-responsive dual-ligand strategy for enhanced breast cancer and brain metastasis therapy.

PubMed

Li, Man; Shi, Kairong; Tang, Xian; Wei, Jiaojie; Cun, Xingli; Long, Yang; Zhang, Zhirong; He, Qin

2018-05-22

Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment. Copyright © 2018. Published by Elsevier Inc.

A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain.

PubMed

Haroon, Mohamed Mohamed; Dar, Ghulam Hassan; Jeyalakshmi, Durga; Venkatraman, Uthra; Saba, Kamal; Rangaraj, Nandini; Patel, Anant Bahadur; Gopal, Vijaya

2016-04-28

RNA interference represents a novel therapeutic approach to modulate several neurodegenerative disease-related genes. However, exogenous delivery of siRNA restricts their transport into different tissues and specifically into the brain mainly due to its large size and the presence of the blood-brain barrier (BBB). To overcome these challenges, we developed here a strategy wherein a peptide known to target specific gangliosides was fused to a double-stranded RNA binding protein to deliver siRNA to the brain parenchyma. The designed fusion protein designated as TARBP-BTP consists of a double-stranded RNA-binding domain (dsRBD) of human Trans Activation response element (TAR) RNA Binding Protein (TARBP2) fused to a brain targeting peptide that binds to monosialoganglioside GM1. Conformation-specific binding of TARBP2 domain to siRNA led to the formation of homogenous serum-stable complex with targeting potential. Further, uptake of the complex in Neuro-2a, IMR32 and HepG2 cells analyzed by confocal microscopy and fluorescence activated cell sorting, revealed selective requirement of GM1 for entry. Remarkably, systemic delivery of the fluorescently labeled complex (TARBP-BTP:siRNA) in ΑβPP-PS1 mouse model of Alzheimer's disease (AD) led to distinctive localization in the cerebral hemisphere. Further, the delivery of siRNA mediated by TARBP-BTP led to significant knockdown of BACE1 in the brain, in both ΑβPP-PS1 mice and wild type C57BL/6. The study establishes the growing importance of fusion proteins in delivering therapeutic siRNA to brain tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

PubMed

Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying; Olumolade, Oluyemi O; Dayton, Paul A; Konofagou, Elisa E

2013-12-28

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. © 2013.

Organochlorine Pesticides in Gonad, Brain, and Blood of Mice in Two Agricultural Areas of Sinaloa.

PubMed

Perez-Gonzalez, Ernestina; Osuna-Martinez, Ulises-Giovanni; Herrera-Moreno, Maria-Nancy; Rodriguez-Meza, Guadalupe-Durga; Gonzalez-Ocampo, Hector-A; Bucio-Pacheco, Marcos

2017-04-01

The adverse effect of pesticides on non-target wildlife and human health is a primary concern in the world, but in Mexico, we do not know which wildlife species are at the greatest risk. The aim of this study was to determine organochlorine pesticides in mice of two agricultural fields in Sinaloa, Culiacan and Guasave. Procedures of extraction, analysis, and quantification were followed according to the modified EPA 8081b method. In three mouse tissues (gonad, brain, and blood), γBHC and decachlorobiphenyl with a frequency higher than 50% and endosulfan sulfate with 43% were observed. The wildlife fauna living in agricultural areas are at great risk due to: (1) diversity of the chemicals used for pest control, like mice, and (2) variety of organochlorine pesticides in direct or indirect contact with non-target organisms, affecting the health of animals and humans (toxic effects and accumulation).

Macrophages with cellular backpacks for targeted drug delivery to the brain.

PubMed

Klyachko, Natalia L; Polak, Roberta; Haney, Matthew J; Zhao, Yuling; Gomes Neto, Reginaldo J; Hill, Michael C; Kabanov, Alexander V; Cohen, Robert E; Rubner, Michael F; Batrakova, Elena V

2017-09-01

Most potent therapeutics are unable to cross the blood-brain barrier following systemic administration, which necessitates the development of unconventional, clinically applicable drug delivery systems. With the given challenges, biologically active vehicles are crucial to accomplishing this task. We now report a new method for drug delivery that utilizes living cells as vehicles for drug carriage across the blood brain barrier. Cellular backpacks, 7-10 μm diameter polymer patches of a few hundred nanometers in thickness, are a potentially interesting approach, because they can act as drug depots that travel with the cell-carrier, without being phagocytized. Backpacks loaded with a potent antioxidant, catalase, were attached to autologous macrophages and systemically administered into mice with brain inflammation. Using inflammatory response cells enabled targeted drug transport to the inflamed brain. Furthermore, catalase-loaded backpacks demonstrated potent therapeutic effects deactivating free radicals released by activated microglia in vitro. This approach for drug carriage and release can accelerate the development of new drug formulations for all the neurodegenerative disorders. Copyright © 2017. Published by Elsevier Ltd.

Addressing the selective role of distinct prefrontal areas in response suppression: A study with brain tumor patients.

PubMed

Arbula, Sandra; Pacella, Valentina; De Pellegrin, Serena; Rossetto, Marta; Denaro, Luca; D'Avella, Domenico; Della Puppa, Alessandro; Vallesi, Antonino

2017-06-01

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies. Copyright © 2017 The Authors

Activation of neurons in cardiovascular areas of cat brain stem affects spinal reflexes.

PubMed

Wu, W C; Wang, S D; Liu, J C; Horng, H T; Wayner, M J; Ma, J C; Chai, C Y

1994-01-01

In 65 cats anesthetized with chloralose (40 mg/kg) and urethane (400 mg/kg), the effects of electrical stimulation and microinjection of sodium glutamate (0.25 M, 100-200 nl) in the pressor areas in the rostral brain stem on the evoked L5 ventral root response (EVRR) due to intermittent stimulation of sciatic afferents were compared to stimulating the dorsomedial (DM) and ventrolateral (VLM) medulla. In general, stimulating these rostral brain stem pressor areas including the diencephalon (DIC) and rostral pons (RP) produced increases in systemic arterial pressure (SAP). In most of the cases (85%) there were associated changes in the EVRR, predominantly a decrease in EVRR (72%). Stimulation of the midbrain (MB, principally in the periaqueductal grey) produced decreases in SAP and EVRR. Decreases in EVRR was observed in 91% of the DM and VLM stimulations in which an increase in SAP was produced. This EVRR inhibition was essentially unaltered after acute midcollicular decerebration. Increases in EVRR were also observed and occurred more often in the rostral brain stem than in the medulla. Since changes of both EVRR and SAP could be reproduced by microinjection of Glu into the cardiovascular-reactive areas of the brain stem, this suggests that neuronal perikarya in these areas are responsible for both actions. On some occasions, Glu induced changes in EVRR but not in SAP. This effect occurred more frequently in the rostral brain stem than in the medulla. The present data suggest that separate neuron population exist in the brain stem for the integration of SAP and spinal reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Revisiting nanoparticle technology for blood-brain barrier transport: Unfolding at the endothelial gate improves the fate of transferrin receptor-targeted liposomes.

PubMed

Johnsen, Kasper Bendix; Moos, Torben

2016-01-28

An unmet need exists for therapeutic compounds to traverse the brain capillary endothelial cells that denote the blood-brain barrier (BBB) to deliver effective treatment to the diseased brain. The use of nanoparticle technology for targeted delivery to the brain implies that targeted liposomes encapsulating a drug of interest will undergo receptor-mediated uptake and transport through the BBB with a subsequent unfolding of the liposomal content inside the brain, hence revealing drug release to adjacent drug-demanding neurons. As transferrin receptors (TfRs) are present on brain capillary endothelial, but not on endothelial cells elsewhere in the body, the use of TfR-targeted liposomes - colloidal particulates with a phospholipid bilayer membrane - remains the most relevant strategy to obtain efficient drug delivery to the brain. However, many studies have failed to provide sufficient quantitative data to proof passage of the BBB and significant appearance of drugs inside the brain parenchyma. Here, we critically evaluate the current evidence on the use of TfR-targeted liposomes for brain drug delivery based on a thorough investigation of all available studies within this research field. We focus on issues with respect to experimental design and data analysis that may provide an explanation to conflicting reports, and we discuss possible explanations for the current lack of sufficient transcytosis across the BBB for implementation in the design of TfR-targeted liposomes. We finally provide a list of suggestions for strategies to obtain substantial uptake and transport of drug carriers at the BBB with a concomitant transport of therapeutics into the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Non-invasive intranasal delivery of quetiapine fumarate loaded microemulsion for brain targeting: Formulation, physicochemical and pharmacokinetic consideration.

PubMed

Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

2016-08-25

Systemic drug delivery in schizophrenia is a major challenge due to presence of obstacles like, blood-brain barrier and P-glycoprotein, which prohibit entry of drugs into the brain. Quetiapine fumarate (QF), a substrate to P-glycoprotein under goes extensive first pass metabolism leading to limited absorption thus necessitating frequent oral administration. The aim of this study was to develop QF based microemulsion (ME) with and without chitosan (CH) to investigate its potential use in improving the bioavailability and brain targeting efficiency following non-invasive intranasal administration. QF loaded ME and mucoadhesive ME (MME) showed globule size, pH and viscosity in the range of 29-47nm, 5.5-6.5 and 17-40cP respectively. CH-ME with spherical globules having mean size of 35.31±1.71nm, pH value of 5.61±0.16 showed highest ex-vivo nasal diffusion (78.26±3.29%) in 8h with no sign of structural damage upon histopathological examination. Circular plume with an ovality ratio closer to 1.3 for CH-ME depicted ideal spray pattern. Significantly higher brain/blood ratio of CH-ME in comparison to QF-ME and drug solution following intranasal administration revealed prolonged retention of QF at site of action suggesting superiority of CH as permeability enhancer. Following intranasal administration, 2.7 and 3.8 folds higher nasal bioavailability in brain with CH-ME compared to QF-ME and drug solution respectively is indicative of preferential nose to brain transport (80.51±6.46%) bypassing blood-brain barrier. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Interactive target tracking for persistent wide-area surveillance

NASA Astrophysics Data System (ADS)

Ersoy, Ilker; Palaniappan, Kannappan; Seetharaman, Guna S.; Rao, Raghuveer M.

2012-06-01

Persistent aerial surveillance is an emerging technology that can provide continuous, wide-area coverage from an aircraft-based multiple-camera system. Tracking targets in these data sets is challenging for vision algorithms due to large data (several terabytes), very low frame rate, changing viewpoint, strong parallax and other imperfections due to registration and projection. Providing an interactive system for automated target tracking also has additional challenges that require online algorithms that are seamlessly integrated with interactive visualization tools to assist the user. We developed an algorithm that overcomes these challenges and demonstrated it on data obtained from a wide-area imaging platform.

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. Copyright © 2016 Elsevier B.V. All rights reserved.

Developing a de novo targeted knock-in method based on in utero electroporation into the mammalian brain.

PubMed

Tsunekawa, Yuji; Terhune, Raymond Kunikane; Fujita, Ikumi; Shitamukai, Atsunori; Suetsugu, Taeko; Matsuzaki, Fumio

2016-09-01

Genome-editing technology has revolutionized the field of biology. Here, we report a novel de novo gene-targeting method mediated by in utero electroporation into the developing mammalian brain. Electroporation of donor DNA with the CRISPR/Cas9 system vectors successfully leads to knock-in of the donor sequence, such as EGFP, to the target site via the homology-directed repair mechanism. We developed a targeting vector system optimized to prevent anomalous leaky expression of the donor gene from the plasmid, which otherwise often occurs depending on the donor sequence. The knock-in efficiency of the electroporated progenitors reached up to 40% in the early stage and 20% in the late stage of the developing mouse brain. Furthermore, we inserted different fluorescent markers into the target gene in each homologous chromosome, successfully distinguishing homozygous knock-in cells by color. We also applied this de novo gene targeting to the ferret model for the study of complex mammalian brains. Our results demonstrate that this technique is widely applicable for monitoring gene expression, visualizing protein localization, lineage analysis and gene knockout, all at the single-cell level, in developmental tissues. © 2016. Published by The Company of Biologists Ltd.

Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface

PubMed Central

Lee, Wonhye; Kim, Suji; Kim, Byeongnam; Lee, Chungki; Chung, Yong An; Kim, Laehyun; Yoo, Seung-Schik

2017-01-01

We present non-invasive means that detect unilateral hand motor brain activity from one individual and subsequently stimulate the somatosensory area of another individual, thus, enabling the remote hemispheric link between each brain hemisphere in humans. Healthy participants were paired as a sender and a receiver. A sender performed a motor imagery task of either right or left hand, and associated changes in the electroencephalogram (EEG) mu rhythm (8–10 Hz) originating from either hemisphere were programmed to move a computer cursor to a target that appeared in either left or right of the computer screen. When the cursor reaches its target, the outcome was transmitted to another computer over the internet, and actuated the focused ultrasound (FUS) devices that selectively and non-invasively stimulated either the right or left hand somatosensory area of the receiver. Small FUS transducers effectively allowed for the independent administration of stimulatory ultrasonic waves to somatosensory areas. The stimulation elicited unilateral tactile sensation of the hand from the receiver, thus establishing the hemispheric brain-to-brain interface (BBI). Although there was a degree of variability in task accuracy, six pairs of volunteers performed the BBI task in high accuracy, transferring approximately eight commands per minute. Linkage between the hemispheric brain activities among individuals suggests the possibility for expansion of the information bandwidth in the context of BBI. PMID:28598972

Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.

PubMed

Yu, Lei; Petyuk, Vladislav A; Gaiteri, Chris; Mostafavi, Sara; Young-Pearse, Tracy; Shah, Raj C; Buchman, Aron S; Schneider, Julie A; Piehowski, Paul D; Sontag, Ryan L; Fillmore, Thomas L; Shi, Tujin; Smith, Richard D; De Jager, Philip L; Bennett, David A

2018-06-16

Previous gene expression analysis identified a network of co-expressed genes that is associated with β-amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets. Data came from 834 community-based older persons who were followed annually, died and underwent brain autopsy. Uniform structured postmortem evaluations assessed the burden of β-amyloid and other common age-related neuropathologies. Selected reaction monitoring quantified cortical protein abundance of 12 genes prioritized from a molecular network of aging human brain that is implicated in Alzheimer's dementia. Regression and linear mixed models examined the protein associations with β-amyloid load and other neuropathologic indices as well as cognitive decline over multiple years prior to death. The average age at death was 88.6 years. 349 participants (41.9%) had Alzheimer's dementia at death. A higher level of PLXNB1 abundance was associated with more β-amyloid load (p=1.0 × 10 -7 ) and higher PHFtau tangle density (p=2.3 × 10 -7 ), and the association of PLXNB1 with cognitive decline is mediated by these known Alzheimer's disease pathologies. On the other hand, higher IGFBP5, HSPB2, AK4 and lower ITPK1 levels were associated with faster cognitive decline and, unlike PLXNB1, these associations were not fully explained by common neuropathologic indices, suggesting novel mechanisms leading to cognitive decline. Using targeted proteomics, this work identified cortical proteins involved in Alzheimer's dementia and begins to dissect two different molecular pathways: one affecting β-amyloid deposition and another affecting resilience without a known pathologic footprint. This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

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

Brain networks modulated by subthalamic nucleus deep brain stimulation.

PubMed

Accolla, Ettore A; Herrojo Ruiz, Maria; Horn, Andreas; Schneider, Gerd-Helge; Schmitz-Hübsch, Tanja; Draganski, Bogdan; Kühn, Andrea A

2016-09-01

Deep brain stimulation of the subthalamic nucleus is an established treatment for the motor symptoms of Parkinson's disease. Given the frequent occurrence of stimulation-induced affective and cognitive adverse effects, a better understanding about the role of the subthalamic nucleus in non-motor functions is needed. The main goal of this study is to characterize anatomical circuits modulated by subthalamic deep brain stimulation, and infer about the inner organization of the nucleus in terms of motor and non-motor areas. Given its small size and anatomical intersubject variability, functional organization of the subthalamic nucleus is difficult to investigate in vivo with current methods. Here, we used local field potential recordings obtained from 10 patients with Parkinson's disease to identify a subthalamic area with an analogous electrophysiological signature, namely a predominant beta oscillatory activity. The spatial accuracy was improved by identifying a single contact per macroelectrode for its vicinity to the electrophysiological source of the beta oscillation. We then conducted whole brain probabilistic tractography seeding from the previously identified contacts, and further described connectivity modifications along the macroelectrode's main axis. The designated subthalamic 'beta' area projected predominantly to motor and premotor cortical regions additional to connections to limbic and associative areas. More ventral subthalamic areas showed predominant connectivity to medial temporal regions including amygdala and hippocampus. We interpret our findings as evidence for the convergence of different functional circuits within subthalamic nucleus' portions deemed to be appropriate as deep brain stimulation target to treat motor symptoms in Parkinson's disease. Potential clinical implications of our study are illustrated by an index case where deep brain stimulation of estimated predominant non-motor subthalamic nucleus induced hypomanic behaviour. © The

The Roots of Alzheimer's Disease: Are High-Expanding Cortical Areas Preferentially Targeted?†.

PubMed

Fjell, Anders M; Amlien, Inge K; Sneve, Markus H; Grydeland, Håkon; Tamnes, Christian K; Chaplin, Tristan A; Rosa, Marcello G P; Walhovd, Kristine B

2015-09-01

Alzheimer's disease (AD) is regarded a human-specific condition, and it has been suggested that brain regions highly expanded in humans compared with other primates are selectively targeted. We calculated shared and unique variance in the distribution of AD atrophy accounted for by cortical expansion between macaque and human, affiliation to the default mode network (DMN), ontogenetic development and normal aging. Cortical expansion was moderately related to atrophy, but a critical discrepancy was seen in the medial temporo-parietal episodic memory network. Identification of "hotspots" and "coldspots" of expansion across several primate species did not yield compelling evidence for the hypothesis that highly expanded regions are specifically targeted. Controlling for distribution of atrophy in aging substantially attenuated the expansion-AD relationship. A path model showed that all variables explained unique variance in AD atrophy but were generally mediated through aging. This supports a systems-vulnerability model, where critical networks are subject to various negative impacts, aging in particular, rather than being selectively targeted in AD. An alternative approach is suggested, focused on the interplay of the phylogenetically old and preserved medial temporal lobe areas with more highly expanded association cortices governed by different principles of plasticity and stability. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study.

PubMed

Gopalakrishnan, Raghavan; Burgess, Richard C; Malone, Donald A; Lempka, Scott F; Gale, John T; Floden, Darlene P; Baker, Kenneth B; Machado, Andre G

2018-06-01

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action

Targeted Delivery of Drugs to Brain Tumors (LBNL Summer Lecture Series)

ScienceCinema

Forte, Trudy [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Children’s Hospital Oakland Research Inst. (CHORI), Oakland, CA (United States)

2017-12-15

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.

Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide.

PubMed

Pluta, Ryszard; Jabłoński, Mirosław; Czuczwar, Stanisław J

2012-01-01

The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with

Evaluation of brain targeting and mucosal integrity of nasally administrated nanostructured carriers of a CNS active drug, clonazepam.

PubMed

Abdel-Bar, Hend Mohamed; Abdel-Reheem, Amal Youssef; Awad, Gehanne Abdel Samie; Mortada, Nahed Daoud

2013-01-01

The aim of the study was to target clonazepam, a CNS active drug, to the brain through the non-invasive intranasal (in) route using of nanocarriers with proven safety in clonazepam nanocarriers were prepared by mixing isopropyl myristate, Tween 80, Cremophor EL or lecithin, polyethylene glycol 200, propylene glycol or ethanol in different ratios with water. in-vitro characterization of the nanocarriers was done by various methods including: polarized light microscopy, particle size determination, viscosity measurements and drug release studies. in-vivo study comparing intranasal and intravenous administration was performed. The drug targeting efficiency (DTE %) and direct nose to brain transport percentage (DTP %) were calculated and nasal integrity assessment was carried out. The obtained formulae had particle size below 100 nm favoring rapid direct nose to brain transport and the time for 100% drug release (T100%) depended on systems composition. Plasma Tmax of clonazepam nanostructured carriers varied from 10-30 min., while their brain Tmax did not exceed 10 min, in comparison with 30 min for iv solution. Although there was no significant difference (p>0.05) between the plasma AUC0-∞ of the different tested nanocarriers and intravenous one, the increase in brain AUC 0 -∞ of different nasal formulations in comparison to that of iv administration (3.6 -7.2 fold) confirms direct nose to brain transport via olfactory region. Furthermore, DTE and DTP% confirmed brain targeting of clonazepam following intranasal administration. The results confirmed that intranasal nanocarriers were proved to be safe alternative for iv clonazepam delivery with rapid nose to brain transport.

MO-F-CAMPUS-T-02: Optimizing Orientations of Hundreds of Intensity-Modulated Beams to Treat Multiple Brain Targets

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

Ma, L; Dong, P; Larson, D

Purpose: To investigate a new modulated beam orientation optimization (MBOO) approach maximizing treatment planning quality for the state-of-the-art flattening filter free (FFF) beam that has enabled rapid treatments of multiple brain targets. Methods: MBOO selects and optimizes a large number of intensity-modulated beams (400 or more) from all accessible beam angles surrounding a patient’s skull. The optimization algorithm was implemented on a standalone system that interfaced with the 3D Dicom images and structure sets. A standard published data set that consisted of 1 to 12 metastatic brain tumor combinations was selected for MBOO planning. The planning results from various coplanarmore » and non-coplanar configurations via MBOO were then compared with the results obtained from a clinical volume modulated arc therapy (VMAT) delivery system (Truebeam RapidArc, Varian Oncology). Results: When planning a few number of targets (n<4), MBOO produced results equivalent to non-coplanar multi-arc VMAT planning in terms of target volume coverage and normal tissue sparing. For example, the 12-Gy and 4-Gy normal brain volumes for the 3-target plans differed by less than 1 mL ( 3.0 mLvs 3.8 mL; and 35.2 mL vs 36.3 mL, respectively) for MBOO versus VMAT. However, when planning a larger number of targets (n≥4), MBOO significantly reduced the dose to the normal brain as compared to VMAT, though the target volume coverage was equivalent. For example, the 12-Gy and 4-Gy normal brain volumes for the 12-target plans were 10.8 mL vs. 18.0 mL and 217.9 mL vs. 390.0 mL, respectively for the non-coplanar MBOO versus the non-coplanar VMAT treatment plans, yielding a reduction in volume of more than 60% for the case. Conclusion: MBOO is a unique approach for maximizing normal tissue sparing when treating a large number (n≥4) of brain tumors with FFF linear accelerators. Dr Ma and Dr Sahgal are currently on the board of international society of stereotactic radiosurgery. Dr Sahgal

Segmentation of the Globus Pallidus Internus Using Probabilistic Diffusion Tractography for Deep Brain Stimulation Targeting in Parkinson Disease.

PubMed

Middlebrooks, E H; Tuna, I S; Grewal, S S; Almeida, L; Heckman, M G; Lesser, E R; Foote, K D; Okun, M S; Holanda, V M

2018-06-01

Although globus pallidus internus deep brain stimulation is a widely accepted treatment for Parkinson disease, there is persistent variability in outcomes that is not yet fully understood. In this pilot study, we aimed to investigate the potential role of globus pallidus internus segmentation using probabilistic tractography as a supplement to traditional targeting methods. Eleven patients undergoing globus pallidus internus deep brain stimulation were included in this retrospective analysis. Using multidirection diffusion-weighted MR imaging, we performed probabilistic tractography at all individual globus pallidus internus voxels. Each globus pallidus internus voxel was then assigned to the 1 ROI with the greatest number of propagated paths. On the basis of deep brain stimulation programming settings, the volume of tissue activated was generated for each patient using a finite element method solution. For each patient, the volume of tissue activated within each of the 10 segmented globus pallidus internus regions was calculated and examined for association with a change in the Unified Parkinson Disease Rating Scale, Part III score before and after treatment. Increasing volume of tissue activated was most strongly correlated with a change in the Unified Parkinson Disease Rating Scale, Part III score for the primary motor region (Spearman r = 0.74, P = .010), followed by the supplementary motor area/premotor cortex (Spearman r = 0.47, P = .15). In this pilot study, we assessed a novel method of segmentation of the globus pallidus internus based on probabilistic tractography as a supplement to traditional targeting methods. Our results suggest that our method may be an independent predictor of deep brain stimulation outcome, and evaluation of a larger cohort or prospective study is warranted to validate these findings. © 2018 by American Journal of Neuroradiology.

Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound

PubMed Central

Mead, Brian P.; Mastorakos, Panagiotis; Suk, Jung Soo; Klibanov, Alexander L.; Hanes, Justin; Price, Richard J.

2016-01-01

Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact “brain penetrating” nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24 h post administration and lasted for at least 28 days. In the FUS-treated region ~42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non-FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain. PMID:26732553

Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier.

PubMed

Ghadiri, Maryam; Vasheghani-Farahani, Ebrahim; Atyabi, Fatemeh; Kobarfard, Farzad; Mohamadyar-Toupkanlou, Farzaneh; Hosseinkhani, Hossein

2017-10-01

Application of many vital hydrophilic medicines have been restricted by blood-brain barrier (BBB) for treatment of brain diseases. In this study, a targeted drug delivery system based on dextran-spermine biopolymer was developed for drug transport across BBB. Drug loaded magnetic dextran-spermine nanoparticles (DS-NPs) were prepared via ionic gelation followed by transferrin (Tf) conjugation as targeting moiety. The characteristics of Tf conjugated nanoparticles (TDS-NPs) were analyzed by different methods and their cytotoxicity effects on U87MG cells were tested. The superparamagnetic characteristic of TDS-NPs was verified by vibration simple magnetometer. Capecitabine loaded TDS-NPs exhibited pH-sensitive release behavior with enhanced cytotoxicity against U87MG cells, compared to DS-NPs and free capecitabine. Prussian-blue staining and TEM-imaging showed the significant cellular uptake of TDS-NPs. Furthermore, a remarkable increase of Fe concentrations in brain was observed following their biodistribution and histological studies in vivo, after 1 and 7 days of post-injection. Enhanced drug transport across BBB and pH-triggered cellular uptake of TDS-NPs indicated that these theranostic nanocarriers are promising candidate for the brain malignance treatment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2851-2864, 2017. © 2017 Wiley Periodicals, Inc.

Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis

DTIC Science & Technology

2016-03-01

Currently, no effective drug treatments are available for brain metastasis. In this proposal, we hypothesize: interactions with reactive brain astrocytes...neurological drugs . In this project, we propose two specific aims to explore the functional importance of the early metastatic evolution and the...feasibility of targeting metastatic evolution by repurposing neurological drugs . Aim 1: Study the spatial and temporal interactions between brain

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening.

PubMed

Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel; Konofagou, Elisa E

2017-04-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

Development of novel bioadhesive granisetron hydrochloride spanlastic gel and insert for brain targeting and study their effects on rats.

PubMed

Abdelmonem, Rehab; El Nabarawi, Mohamed; Attia, Alshaimaa

2018-11-01

The aim of this study was to formulate granisetron hydrochloride (GH) spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve GH bioavailability and brain targeting. Carpapol 934 and HPMC were incorporated in GH spanlastic in nasal gels (GHSpNGs). Gelatin and HPMC as matrix former, glycine as a collapse protecting and mannitol as an insert filler and sweeting agent were used to prepare GH spanlastic loaded in lyophilized inserts (GHSpNIs). The prepared GHSpNGs were characterized for pH measurement, drug content, rheology, and in vitro drug release. The prepared GHSpNIs were characterized for drug content, surface pH, GH release, and mucoadhesion. Biological investigations including pharmacokinetics studies and brain drug targeting efficiency dimensions were performed on rats (LC-MS/MS). The results showed thixotropic pseudoplastic gels and white insert with pH values in a physiological range, drug content (89.9-98.6%), (82.4-98.38%) for gel and insert, respectively and rapid release rate of GH. Biological studies showed that C max and AUC 0-6 h in brain and plasma after intranasal administration of gel and insert were higher compared to IV administration of GH solution. A high brain targeting efficiency (199.3%, 230%) for gel and insert, respectively and a direct nose to brain transport (49.8%, 56.95%) for gel and insert, respectively confirmed that there is a direct nose to brain transport of GH following nasal administration of GH spanlastic loaded in nasal gel and insert. GHSpNIs can be considered as potential novel drug delivery system intended for brain targeting via the nasal rout of administration than GHSpNGs.

Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases.

PubMed

Falzone, Nadia; Ackerman, Nicole L; Rosales, Liset de la Fuente; Bernal, Mario A; Liu, Xiaoxuan; Peeters, Sarah Gja; Soto, Manuel Sarmiento; Corroyer-Dulmont, Aurélien; Bernaudin, Myriam; Grimoin, Elisa; Touzani, Omar; Sibson, Nicola R; Vallis, Katherine A

2018-01-01

Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, 149 Tb, 211 At, 212 Pb, 213 Bi and 225 Ac; β-emitting radionuclides, 90 Y, 161 Tb and 177 Lu; and Auger electron (AE)-emitters 67 Ga, 89 Zr, 111 In and 124 I, for targeted radionuclide therapy (TRT). Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative β- and α-emitters, 177 Lu and 212 Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. 177 Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212 Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products, 212 Bi and 212 Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212 Pb may be more effective for short range targeting of early micrometastatic lesions than 177 Lu. MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of α-, β- and AE-emitting radionuclides for TRT. 212 Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.

OPS MCC level B/C formulation requirements: Area targets and space volumes processor

NASA Technical Reports Server (NTRS)

Bishop, M. J., Jr.

1979-01-01

The level B/C mathematical specifications for the area targets and space volumes processor (ATSVP) are described. The processor is designed to compute the acquisition-of-signal (AOS) and loss-of-signal (LOS) times for area targets and space volumes. The characteristics of the area targets and space volumes are given. The mathematical equations necessary to determine whether the spacecraft lies within the area target or space volume are given. These equations provide a detailed model of the target geometry. A semianalytical technique for predicting the AOS and LOS time periods is disucssed. This technique was designed to bound the actual visibility period using a simplified target geometry model and unperturbed orbital motion. Functional overview of the ATSVP is presented and it's detailed logic flow is described.

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

PubMed

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

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. 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). 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 this basis, we have designed a Phase 1 clinical study of EGFR-targeted

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

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.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways.

PubMed

Newton, Herbert B

2003-10-01

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.

Assistance to neurosurgical planning: using a fuzzy spatial graph model of the brain for locating anatomical targets in MRI

NASA Astrophysics Data System (ADS)

Villéger, Alice; Ouchchane, Lemlih; Lemaire, Jean-Jacques; Boire, Jean-Yves

2007-03-01

Symptoms of neurodegenerative pathologies such as Parkinson's disease can be relieved through Deep Brain Stimulation. This neurosurgical technique relies on high precision positioning of electrodes in specific areas of the basal ganglia and the thalamus. These subcortical anatomical targets must be located at pre-operative stage, from a set of MRI acquired under stereotactic conditions. In order to assist surgical planning, we designed a semi-automated image analysis process for extracting anatomical areas of interest. Complementary information, provided by both patient's data and expert knowledge, is represented as fuzzy membership maps, which are then fused by means of suitable possibilistic operators in order to achieve the segmentation of targets. More specifically, theoretical prior knowledge on brain anatomy is modelled within a 'virtual atlas' organised as a spatial graph: a list of vertices linked by edges, where each vertex represents an anatomical structure of interest and contains relevant information such as tissue composition, whereas each edge represents a spatial relationship between two structures, such as their relative directions. The model is built using heterogeneous sources of information such as qualitative descriptions from the expert, or quantitative information from prelabelled images. For each patient, tissue membership maps are extracted from MR data through a classification step. Prior model and patient's data are then matched by using a research algorithm (or 'strategy') which simultaneously computes an estimation of the location of every structures. The method was tested on 10 clinical images, with promising results. Location and segmentation results were statistically assessed, opening perspectives for enhancements.

Inflammatory Responses in Brain Ischemia

PubMed Central

Kawabori, Masahito; Yenari, Midori A.

2017-01-01

Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of ischemic pathology. Because secondary damage by brain inflammation may have a longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentall progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke. PMID:25666795

Brain-Targeted (Pro)Renin Receptor Knockdown attenuates Angiotensin II-Dependent Hypertension

PubMed Central

Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, Sarah. J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yumei

2012-01-01

The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID:22526255

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

Alterations of whole-brain cortical area and thickness in mild cognitive impairment and Alzheimer's disease.

PubMed

Li, Chuanming; Wang, Jian; Gui, Li; Zheng, Jian; Liu, Chen; Du, Hanjian

2011-01-01

Gray matter volume and density of several brain regions, determined by magnetic resonance imaging (MRI), are decreased in Alzheimer's disease (AD). Animal studies have indicated that changes in cortical area size is relevant to thinking and behavior, but alterations of cortical area and thickness in the brains of individuals with AD or its likely precursor, mild cognitive impairment (MCI), have not been reported. In this study, 25 MCI subjects, 30 AD subjects, and 30 age-matched normal controls were recruited for brain MRI scans and Functional Activities Questionnaire (FAQ) assessments. Based on the model using FreeSurfer software, two brain lobes were divided into various regions according to the Desikan-Killiany atlas and the cortical area and thickness of every region was compared and analyzed. We found a significant increase in cortical area of several regions in the frontal and temporal cortices, which correlated negatively with MMSE scores, and a significant decrease in cortical area of several regions in the parietal cortex and the cingulate gyrus in AD subjects. Increased cortical area was also seen in some regions of the frontal and temporal cortices in MCI subjects, whereas the cortical thickness of the same regions was decreased. Our observations suggest characteristic differences of the cortical area and thickness in MCI, AD, and normal control subjects, and these changes may help diagnose both MCI and AD.

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

PubMed Central

Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel

2016-01-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo. PMID:27278929

G5G2.5 core-shell tecto-dendrimer specifically targets reactive glia in brain ischemia.

PubMed

Murta, Veronica; Schilrreff, Priscila; Rosciszewski, Gerardo; Morilla, Maria Jose; Ramos, Alberto Javier

2018-03-01

Secondary neuronal death is a serious stroke complication. This process is facilitated by the conversion of glial cells to the reactive pro-inflammatory phenotype that induces neurodegeneration. Therefore, regulation of glial activation is a compelling strategy to reduce brain damage after stroke. However, drugs have difficulties to access the CNS, and to specifically target glial cells. In the present work, we explored the use core-shell polyamidoamine tecto-dendrimer (G5G2.5 PAMAM) and studied its ability to target distinct populations of stroke-activated glial cells. We found that G5G2.5 tecto-dendrimer is actively engulfed by primary glial cells in a time- and dose-dependent manner showing high cellular selectivity and lysosomal localization. In addition, oxygen-glucose deprivation or lipopolysaccharides exposure in vitro and brain ischemia in vivo increase glial G5G2.5 uptake; not being incorporated by neurons or other cell types. We conclude that G5G2.5 tecto-dendrimer is a highly suitable carrier for targeted drug delivery to reactive glial cells in vitro and in vivo after brain ischemia. © 2017 International Society for Neurochemistry.

RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4 Induced Mouse Model

DTIC Science & Technology

2017-10-01

mouse genetic breeding, provided genotyping, immunostaining, histological analysis, and molecular expertise. Funding Support NIH/NHLBI Name: Bert...AWARD NUMBER: W81XWH-16-1-0665 TITLE: RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4-Induced Mouse...2016 - 29 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in

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

PubMed Central

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. PMID:22619515

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.

Who is who: areas of the brain associated with recognizing and naming famous faces.

PubMed

Giussani, Carlo; Roux, Franck-Emmanuel; Bello, Lorenzo; Lauwers-Cances, Valérie; Papagno, Costanza; Gaini, Sergio M; Puel, Michelle; Démonet, Jean-François

2009-02-01

It has been hypothesized that specific brain regions involved in face naming may exist in the brain. To spare these areas and to gain a better understanding of their organization, the authors studied patients who underwent surgery by using direct electrical stimulation mapping for brain tumors, and they compared an object-naming task to a famous face-naming task. Fifty-six patients with brain tumors (39 and 17 in the left and right hemispheres, respectively) and with no significant preoperative overall language deficit were prospectively studied over a 2-year period. Four patients who had a partially selective famous face anomia and 2 with prosopagnosia were not included in the final analysis. Face-naming interferences were exclusively localized in small cortical areas (< 1 cm2). Among 35 patients whose dominant left hemisphere was studied, 26 face-naming specific areas (that is, sites of interference in face naming only and not in object naming) were found. These face naming-specific sites were significantly detected in 2 regions: in the left frontal areas of the superior, middle, and inferior frontal gyri (p < 0.001) and in the anterior part of the superior and middle temporal gyri (p < 0.01). Variable patterns of interference were observed (speech arrest, anomia, phonemic, or semantic paraphasia) probably related to the different stages in famous face processing. Only 4 famous face-naming interferences were found in the right hemisphere. Relative anatomical segregation of naming categories within language areas was detected. This study showed that famous face naming was preferentially processed in the left frontal and anterior temporal gyri. The authors think it is necessary to adapt naming tasks in neurosurgical patients to the brain region studied.

Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex

PubMed Central

Mars, Rogier B.; Sallet, Jérôme; Neubert, Franz-Xaver; Rushworth, Matthew F. S.

2013-01-01

The human ability to infer the thoughts and beliefs of others, often referred to as “theory of mind,” as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of-mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor. PMID:23754406

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.

Testosterone affects language areas of the adult human brain.

PubMed

Hahn, Andreas; Kranz, Georg S; Sladky, Ronald; Kaufmann, Ulrike; Ganger, Sebastian; Hummer, Allan; Seiger, Rene; Spies, Marie; Vanicek, Thomas; Winkler, Dietmar; Kasper, Siegfried; Windischberger, Christian; Swaab, Dick F; Lanzenberger, Rupert

2016-05-01

Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high-dose hormone application in adult female-to-male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel-based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting-state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone-dependent neuroplastic adaptations in adulthood within language-specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738-1748, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Brain hyper-reactivity to auditory novel targets in children with high-functioning autism.

PubMed

Gomot, Marie; Belmonte, Matthew K; Bullmore, Edward T; Bernard, Frédéric A; Baron-Cohen, Simon

2008-09-01

Although communication and social difficulties in autism have received a great deal of research attention, the other key diagnostic feature, extreme repetitive behaviour and unusual narrow interests, has been addressed less often. Also known as 'resistance to change' this may be related to atypical processing of infrequent, novel stimuli. This can be tested at sensory and neural levels. Our aims were to (i) examine auditory novelty detection and its neural basis in children with autism spectrum conditions (ASC) and (ii) test for brain activation patterns that correlate quantitatively with number of autistic traits as a test of the dimensional nature of ASC. The present study employed event-related fMRI during a novel auditory detection paradigm. Participants were twelve 10- to 15-year-old children with ASC and a group of 12 age-, IQ- and sex-matched typical controls. The ASC group responded faster to novel target stimuli. Group differences in brain activity mainly involved the right prefrontal-premotor and the left inferior parietal regions, which were more activated in the ASC group than in controls. In both groups, activation of prefrontal regions during target detection was positively correlated with Autism Spectrum Quotient scores measuring the number of autistic traits. These findings suggest that target detection in autism is associated not only with superior behavioural performance (shorter reaction time) but also with activation of a more widespread network of brain regions. This pattern also shows quantitative variation with number of autistic traits, in a continuum that extends to the normal population. This finding may shed light on the neurophysiological process underlying narrow interests and what clinically is called 'need for sameness'.

Brain-Targeted Delivery of Trans-Activating Transcriptor-Conjugated Magnetic PLGA/Lipid Nanoparticles

PubMed Central

Zhang, Yifang; Sun, Tingting; Zhang, Fang; Wu, Jian; Fu, Yanyan; Du, Yang; Zhang, Lei; Sun, Ying; Liu, YongHai; Ma, Kai; Liu, Hongzhi; Song, Yuanjian

2014-01-01

Magnetic poly (D,L-lactide-co-glycolide) (PLGA)/lipid nanoparticles (MPLs) were fabricated from PLGA, L-α-phosphatidylethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino (polyethylene glycol) (DSPE-PEG-NH2), and magnetic nanoparticles (NPs), and then conjugated to trans-activating transcriptor (TAT) peptide. The TAT-MPLs were designed to target the brain by magnetic guidance and TAT conjugation. The drugs hesperidin (HES), naringin (NAR), and glutathione (GSH) were encapsulated in MPLs with drug loading capacity (>10%) and drug encapsulation efficiency (>90%). The therapeutic efficacy of the drug-loaded TAT-MPLs in bEnd.3 cells was compared with that of drug-loaded MPLs. The cells accumulated higher levels of TAT-MPLs than MPLs. In addition, the accumulation of QD-loaded fluorescein isothiocyanate (FITC)-labeled TAT-MPLs in bEnd.3 cells was dose and time dependent. Our results show that TAT-conjugated MPLs may function as an effective drug delivery system that crosses the blood brain barrier to the brain. PMID:25187980

Brain-targeted delivery of trans-activating transcriptor-conjugated magnetic PLGA/lipid nanoparticles.

PubMed

Wen, Xiangru; Wang, Kai; Zhao, Ziming; Zhang, Yifang; Sun, Tingting; Zhang, Fang; Wu, Jian; Fu, Yanyan; Du, Yang; Zhang, Lei; Sun, Ying; Liu, YongHai; Ma, Kai; Liu, Hongzhi; Song, Yuanjian

2014-01-01

Magnetic poly (D,L-lactide-co-glycolide) (PLGA)/lipid nanoparticles (MPLs) were fabricated from PLGA, L-α-phosphatidylethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino (polyethylene glycol) (DSPE-PEG-NH2), and magnetic nanoparticles (NPs), and then conjugated to trans-activating transcriptor (TAT) peptide. The TAT-MPLs were designed to target the brain by magnetic guidance and TAT conjugation. The drugs hesperidin (HES), naringin (NAR), and glutathione (GSH) were encapsulated in MPLs with drug loading capacity (>10%) and drug encapsulation efficiency (>90%). The therapeutic efficacy of the drug-loaded TAT-MPLs in bEnd.3 cells was compared with that of drug-loaded MPLs. The cells accumulated higher levels of TAT-MPLs than MPLs. In addition, the accumulation of QD-loaded fluorescein isothiocyanate (FITC)-labeled TAT-MPLs in bEnd.3 cells was dose and time dependent. Our results show that TAT-conjugated MPLs may function as an effective drug delivery system that crosses the blood brain barrier to the brain.

Demyelination as a rational therapeutic target for ischemic or traumatic brain injury.

PubMed

Shi, Hong; Hu, Xiaoming; Leak, Rehana K; Shi, Yejie; An, Chengrui; Suenaga, Jun; Chen, Jun; Gao, Yanqin

2015-10-01

Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Blood-Brain Barrier Integrity and Glial Support: Mechanisms that can be targeted for Novel Therapeutic Approaches in Stroke

PubMed Central

Ronaldson, Patrick T.; Davis, Thomas P.

2014-01-01

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this “barrier,” brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a “neurovascular unit.” Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB in an effort to identify novel targets for optimization of CNS delivery of therapeutics in the setting of ischemic stroke. PMID:22574987

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.

Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest

PubMed Central

2015-01-01

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. PMID:24499315

Processing of targets in smooth or apparent motion along the vertical in the human brain: an fMRI study.

PubMed

Maffei, Vincenzo; Macaluso, Emiliano; Indovina, Iole; Orban, Guy; Lacquaniti, Francesco

2010-01-01

Neural substrates for processing constant speed visual motion have been extensively studied. Less is known about the brain activity patterns when the target speed changes continuously, for instance under the influence of gravity. Using functional MRI (fMRI), here we compared brain responses to accelerating/decelerating targets with the responses to constant speed targets. The target could move along the vertical under gravity (1g), under reversed gravity (-1g), or at constant speed (0g). In the first experiment, subjects observed targets moving in smooth motion and responded to a GO signal delivered at a random time after target arrival. As expected, we found that the timing of the motor responses did not depend significantly on the specific motion law. Therefore brain activity in the contrast between different motion laws was not related to motor timing responses. Average BOLD signals were significantly greater for 1g targets than either 0g or -1g targets in a distributed network including bilateral insulae, left lingual gyrus, and brain stem. Moreover, in these regions, the mean activity decreased monotonically from 1g to 0g and to -1g. In the second experiment, subjects intercepted 1g, 0g, and -1g targets either in smooth motion (RM) or in long-range apparent motion (LAM). We found that the sites in the right insula and left lingual gyrus, which were selectively engaged by 1g targets in the first experiment, were also significantly more active during 1g trials than during -1g trials both in RM and LAM. The activity in 0g trials was again intermediate between that in 1g trials and that in -1g trials. Therefore in these regions the global activity modulation with the law of vertical motion appears to hold for both RM and LAM. Instead, a region in the inferior parietal lobule showed a preference for visual gravitational motion only in LAM but not RM.

Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.

PubMed

Flatscher-Bader, T; Zuvela, N; Landis, N; Wilce, P A

2008-01-01

Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilized gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area (VTA) of the human brain. Alcohol-responsive genes encoded proteins primarily involved in structural plasticity and neurotransmitter transport and release. In particular, genes involved with brain-derived neurotrophic factor signalling and glutamatergic transmission were found to be affected. The possibility that glutamate transport was a target of chronic alcohol and/or tobacco abuse was further investigated in an extended case set by measurement of mRNA and protein expression. Expression levels of vesicular glutamate transporters SLC17A6 and SLC17A7 were robustly induced by smoking, an effect that was reduced by alcohol co-exposure. Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. We conclude that enduring plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine and co-abuse have distinct impacts on glutamatergic transmission with important implications for the control of this core mesolimbic structure.

Bilinguals Use Language-Control Brain Areas More Than Monolinguals to Perform Non-Linguistic Switching Tasks

PubMed Central

Rodríguez-Pujadas, Aina; Sanjuán, Ana; Ventura-Campos, Noelia; Román, Patricia; Martin, Clara; Barceló, Francisco; Costa, Albert; Ávila, César

2013-01-01

We tested the hypothesis that early bilinguals use language-control brain areas more than monolinguals when performing non-linguistic executive control tasks. We do so by exploring the brain activity of early bilinguals and monolinguals in a task-switching paradigm using an embedded critical trial design. Crucially, the task was designed such that the behavioural performance of the two groups was comparable, allowing then to have a safer comparison between the corresponding brain activity in the two groups. Despite the lack of behavioural differences between both groups, early bilinguals used language-control areas – such as left caudate, and left inferior and middle frontal gyri – more than monolinguals, when performing the switching task. Results offer direct support for the notion that, early bilingualism exerts an effect in the neural circuitry responsible for executive control. This effect partially involves the recruitment of brain areas involved in language control when performing domain-general executive control tasks, highlighting the cross-talk between these two domains. PMID:24058456

Pseudotyped Lentiviral Vectors for Retrograde Gene Delivery into Target Brain Regions

PubMed Central

Kobayashi, Kenta; Inoue, Ken-ichi; Tanabe, Soshi; Kato, Shigeki; Takada, Masahiko; Kobayashi, Kazuto

2017-01-01

Gene transfer through retrograde axonal transport of viral vectors offers a substantial advantage for analyzing roles of specific neuronal pathways or cell types forming complex neural networks. This genetic approach may also be useful in gene therapy trials by enabling delivery of transgenes into a target brain region distant from the injection site of the vectors. Pseudotyping of a lentiviral vector based on human immunodeficiency virus type 1 (HIV-1) with various fusion envelope glycoproteins composed of different combinations of rabies virus glycoprotein (RV-G) and vesicular stomatitis virus glycoprotein (VSV-G) enhances the efficiency of retrograde gene transfer in both rodent and nonhuman primate brains. The most recently developed lentiviral vector is a pseudotype with fusion glycoprotein type E (FuG-E), which demonstrates highly efficient retrograde gene transfer in the brain. The FuG-E–pseudotyped vector permits powerful experimental strategies for more precisely investigating the mechanisms underlying various brain functions. It also contributes to the development of new gene therapy approaches for neurodegenerative disorders, such as Parkinson’s disease, by delivering genes required for survival and protection into specific neuronal populations. In this review article, we report the properties of the FuG-E–pseudotyped vector, and we describe the application of the vector to neural circuit analysis and the potential use of the FuG-E vector in gene therapy for Parkinson’s disease. PMID:28824385

The brain is a target organ after acute exposure to depleted uranium.

PubMed

Lestaevel, P; Houpert, P; Bussy, C; Dhieux, B; Gourmelon, P; Paquet, F

2005-09-01

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144+/-10 microg DU kg-1 as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6 microg of DU g-1 of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70+/-8 microg DU kg-1), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed.

Evolving Concepts in Posterior Subthalamic Area Deep Brain Stimulation for Treatment of Tremor: Surgical Neuroanatomy and Practical Considerations.

PubMed

Ramirez-Zamora, Adolfo; Smith, Heather; Kumar, Vignessh; Prusik, Julia; Phookan, Sujoy; Pilitsis, Julie G

2016-01-01

Although thalamic deep brain stimulation (DBS) has been established as an effective therapy for refractory tremor in Parkinson's disease and essential tremor, reports investigating the efficacy of posterior subthalamic area (PSA) DBS for severe, debilitating tremors continue to emerge. However, questions regarding the optimal anatomical target, surgical approach, programming paradigms and effectiveness compared to other targets remain. In this report, we aimed to review the current literature to assess different stereotactic techniques, anatomical considerations, adverse effects and stimulation settings in PSA DBS. A comprehensive literature review was performed searching for articles discussing tremors and PSA stimulation. We performed a quantitative analysis comparing different DBS tremor targets. Tremor improvement is consistently documented in most reports with an average reduction in tremor of 79% depending on the specific tremor syndrome. Tremor benefit in patients with multiple sclerosis (MS) tremor was significantly higher than for other stimulation targets. Transient paresthesias, imbalance, dizziness and dysarthria are the most common side effects with PSA DBS. PSA DBS is an effective and safe treatment for tremor control and should be considered in patients with refractory tremors with associated cerebellar or dystonic features, proximal tremors and MS tremor. © 2016 S. Karger AG, Basel.

MRI-Based Measurement of Brain Stem Cross-Sectional Area in Relapsing-Remitting Multiple Sclerosis.

PubMed

Chivers, Tomos R; Constantinescu, Cris S; Tench, Christopher R

2015-01-01

To determine if patients with relapsing-remitting multiple sclerosis (RRMS) have a reduced brain stem cross-sectional area (CSA) compared to age- and sex-matched controls. The brain stem is a common site of involvement in MS. However, relatively few imaging studies have investigated brain stem atrophy. Brain magnetic resonance imaging (MRI) was performed on patients and controls using a 1.5T MRI scanner with a quadrature head coil. Three-dimensional magnetization-prepared rapid acquisition gradient-echo (MPRAGE) images with 128 contiguous slices, covering the whole brain and brain stem and a T2-weighted image with 3 mm transverse contiguous images were acquired. We measured the brain stem CSA at three sites, the midbrain, the pons, and the medulla oblongata in 35 RRMS patients and 35 controls using a semiautomated algorithm. CSA readings were normalized using the total external cranial volume to reduce normal population variance and increase statistical power. A significant CSA reduction was found in the midbrain (P ≤ .001), pons (P ≤ .001), and the medulla oblongata (P = .047) postnormalization. A CSA reduction of 9.3% was found in the midbrain, 8.7% in the pons, and 6.5% in the medulla oblongata. A significantly reduced, normalized brain stem CSA was detected in all areas of the brain stem of the RRMS patients, when compared to age- and gender-matched controls. Lack of detectable upper cervical cord atrophy in the same patients suggests some independence of the MS pathology in these regions. Copyright © 2015 by the American Society of Neuroimaging.

Testosterone affects language areas of the adult human brain

PubMed Central

Hahn, Andreas; Kranz, Georg S.; Sladky, Ronald; Kaufmann, Ulrike; Ganger, Sebastian; Hummer, Allan; Seiger, Rene; Spies, Marie; Vanicek, Thomas; Winkler, Dietmar; Kasper, Siegfried; Windischberger, Christian; Swaab, Dick F.

2016-01-01

Abstract Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high‐dose hormone application in adult female‐to‐male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel‐based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting‐state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone‐dependent neuroplastic adaptations in adulthood within language‐specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738–1748, 2016. © 2016 Wiley Periodicals, Inc. PMID:26876303

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

Optimal staining methods for delineation of cortical areas and neuron counts in human brains.

PubMed

Uylings, H B; Zilles, K; Rajkowska, G

1999-04-01

For cytoarchitectonic delineation of cortical areas in human brain, the Gallyas staining for somata with its sharp contrast between cell bodies and neuropil is preferable to the classical Nissl staining, the more so when an image analysis system is used. This Gallyas staining, however, does not appear to be appropriate for counting neuron numbers in pertinent brain areas, due to the lack of distinct cytological features between small neurons and glial cells. For cell counting Nissl is preferable. In an optimal design for cell counting at least both the Gallyas and the Nissl staining must be applied, the former staining for cytoarchitectural delineaton of cortical areas and the latter for counting the number of neurons in the pertinent cortical areas. Copyright 1999 Academic Press.

Not single brain areas but a network is involved in language: Applications in presurgical planning.

PubMed

Alemi, Razieh; Batouli, Seyed Amir Hossein; Behzad, Ebrahim; Ebrahimpoor, Mitra; Oghabian, Mohammad Ali

2018-02-01

Language is an important human function, and is a determinant of the quality of life. In conditions such as brain lesions, disruption of the language function may occur, and lesion resection is a solution for that. Presurgical planning to determine the language-related brain areas would enhance the chances of language preservation after the operation; however, availability of a normative language template is essential. In this study, using data from 60 young individuals who were meticulously checked for mental and physical health, and using fMRI and robust imaging and data analysis methods, functional brain maps for the language production, perception and semantic were produced. The obtained templates showed that the language function should be considered as the product of the collaboration of a network of brain regions, instead of considering only few brain areas to be involved in that. This study has important clinical applications, and extends our knowledge on the neuroanatomy of the language function. Copyright © 2018 Elsevier B.V. All rights reserved.

Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy.

PubMed

Fang, Jen-Hung; Chiu, Tsung-Lang; Huang, Wei-Chen; Lai, Yen-Ho; Hu, Shang-Hsiu; Chen, You-Yin; Chen, San-Yuan

2016-03-01

Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed Central

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

2015-01-01

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. PMID:25970776

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.

Brain activation underlying threat detection to targets of different races.

PubMed

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

2015-01-01

The current study examined blood oxygen level-dependent signal underlying racial differences in threat detection. During functional magnetic resonance imaging, 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.

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.

Preparation of surface multiple-coated polylactide acid drug-loaded nanoparticles for intranasal delivery and evaluation on its brain-targeting efficiency.

PubMed

Bian, Junjie; Yuan, Zhixiang; Chen, Xiaoliang; Gao, Yuan; Xu, Chaoqun; Shi, Jianyou

2016-01-01

To prepare a mixture of multiple-coated aniracetam nasal polylactic-acid nanoparticles (M-C-PLA-NP) and evaluate its stability preliminarily in vitro and its brain-targeting efficiency in vivo. The solvent diffusion-evaporation combined with magnetic stirring method has been chosen for the entrapment of aniracetam. The M-C-PLA-NP was characterized with respect to its morphology, particle size, size distribution and aniracetam entrapment efficiency. The in vivo distribution was studied in male SD rats after an intranasal administration. In vitro release of M-C-PLA-NP showed two components with an initial rapid release due to the surface-associated drug and followed by a slower exponential release of aniracetam, which was dissolved in the core. The AUC0 → 30 min of M-C-PLA-NP in brain tissues resulted in a 5.19-fold increase compared with aniracetam solution. The ratios of AUC in brain to that in other tissues obtained after nasal application of M-C-PLA-NP were significantly higher than those of aniracetam solution. Therefore, it can be concluded that M-C-PLA-NP demonstrated its potential on increasing the brain-targeting efficiency of drugs and will be used as novel brain-targeting agent for nasal drug delivery.

Brain Activity Changes in Somatosensory and Emotion-Related Areas With Medial Patellofemoral Ligament Deficiency.

PubMed

Kadowaki, Masaru; Tadenuma, Taku; Kumahashi, Nobuyuki; Uchio, Yuji

2017-11-01

Patellar instability with medial patellofemoral ligament (MPFL) deficiency is a common sports injury among young people. Although nonoperative and surgical treatment can provide stability of the patella, patients often have anxiety related to the knee. We speculate that neural dysfunction may be related to anxiety in these patients; however, the mechanism in the brain that generates this anxiety remains unknown. (1) How does brain activity in patients with MPFL deficiency change in the areas related to somatic sensation against lateral shift of the patella? (2) How does patella instability, which can lead to continuous fear or apprehension for dislocation, influence brain activity in the areas related to emotion? Nineteen patients with MPFL deficiency underwent surgical reconstruction in our hospital from April 2012 to March 2014. Excluding seven patients with osteochondral lesions, 12 patients (five males and seven females; mean age, 20 years) with MPFL deficiency were sequentially included in this study. Eleven control subjects (four males and seven females; mean age, 23 years) were recruited from medical students who had no history of knee injury. Diagnosis of the MPFL deficiency was made with MR images, which confirmed the rupture, and by proving the instability with a custom-made biomechanical device. Brain activity during passive lateral stress to the patella was assessed by functional MRI. Functional and anatomic images were analyzed using statistical parametric mapping. Differences in functional MRI outcome measures from the detected activated brain regions between the patients with MPFL deficiency and controls were assessed using t tests. Intergroup analysis showed less activity in several sensorimotor cortical areas, including the contralateral primary somatosensory areas (% signal change for MPFL group 0.49% versus 1.1% for the control group; p < 0.001), thalamus (0.2% versus 0.41% for the MPFL versus control, respectively; p < 0.001), ipsilateral

A Novel Human Body Area Network for Brain Diseases Analysis.

PubMed

Lin, Kai; Xu, Tianlang

2016-10-01

Development of wireless sensor and mobile communication technology provide an unprecedented opportunity for realizing smart and interactive healthcare systems. Designing such systems aims to remotely monitor the health and diagnose the diseases for users. In this paper, we design a novel human body area network for brain diseases analysis, which is named BABDA. Considering the brain is one of the most complex organs in the human body, the BABDA system provides four function modules to ensure the high quality of the analysis result, which includes initial data collection, data correction, data transmission and comprehensive data analysis. The performance evaluation conducted in a realistic environment with several criteria shows the availability and practicability of the BABDA system.

A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment

PubMed Central

Zhang, Cheng-Xiang; Zhao, Wei-Yu; Liu, Lei; Ju, Rui-Jun; Mu, Li-Min; Zhao, Yao; Zeng, Fan; Xie, Hong-Jun; Yan, Yan; Lu, Wan-Liang

2015-01-01

The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin β3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas. PMID:26418720

Audiovisual synchrony enhances BOLD responses in a brain network including multisensory STS while also enhancing target-detection performance for both modalities

PubMed Central

Marchant, Jennifer L; Ruff, Christian C; Driver, Jon

2012-01-01

The brain seeks to combine related inputs from different senses (e.g., hearing and vision), via multisensory integration. Temporal information can indicate whether stimuli in different senses are related or not. A recent human fMRI study (Noesselt et al. [2007]: J Neurosci 27:11431–11441) used auditory and visual trains of beeps and flashes with erratic timing, manipulating whether auditory and visual trains were synchronous or unrelated in temporal pattern. A region of superior temporal sulcus (STS) showed higher BOLD signal for the synchronous condition. But this could not be related to performance, and it remained unclear if the erratic, unpredictable nature of the stimulus trains was important. Here we compared synchronous audiovisual trains to asynchronous trains, while using a behavioral task requiring detection of higher-intensity target events in either modality. We further varied whether the stimulus trains had predictable temporal pattern or not. Synchrony (versus lag) between auditory and visual trains enhanced behavioral sensitivity (d') to intensity targets in either modality, regardless of predictable versus unpredictable patterning. The analogous contrast in fMRI revealed BOLD increases in several brain areas, including the left STS region reported by Noesselt et al. [2007: J Neurosci 27:11431–11441]. The synchrony effect on BOLD here correlated with the subject-by-subject impact on performance. Predictability of temporal pattern did not affect target detection performance or STS activity, but did lead to an interaction with audiovisual synchrony for BOLD in inferior parietal cortex. PMID:21953980

Specific Binding, Uptake, and Transport of ICAM-1-Targeted Nanocarriers Across Endothelial and Subendothelial Cell Components of the Blood-Brain Barrier

PubMed Central

Hsu, Janet; Rappaport, Jeff; Muro, Silvia

2014-01-01

Purpose The blood-brain barrier (BBB) represents a target for therapeutic intervention and an obstacle for brain drug delivery. Targeting endocytic receptors on brain endothelial cells (ECs) helps transporting drugs and carriers into and across this barrier. While most receptors tested are associated with clathrin-mediated pathways, clathrin-independent routes are rather unexplored. We have examined the potential for one of these pathways, cell adhesion molecule (CAM)-mediated endocytosis induced by targeting intercellular adhesion molecule 1 (ICAM-1), to transport drug carriers into and across BBB models. Methods Model polymer nanocarriers (NCs) coated with control IgG or antibodies against ICAM-1 (IgG NCs vs. anti-ICAM NCs; ~250-nm) were incubated with human brain ECs, astrocytes (ACs), or pericytes (PCs) grown as monocultures or bilayered (endothelial+subendothelial) co-cultures. Results ICAM-1 was present and overexpressed in disease-like conditions on ECs and, at a lesser extent, on ACs and PCs which are BBB subendothelial components. Specific targeting and CAM-mediated uptake of anti-ICAM NCs occurred in these cells, although this was greater for ECs. Anti-ICAM NCs were transported across endothelial monolayers and endothelial+subendothelial co-cultures modeling the BBB. Conclusions CAM-mediated transport induced by ICAM-1 targeting operates in endothelial and subendothelial cellular components of the BBB, which may provide an avenue to overcome this barrier. PMID:24558007

Specific binding, uptake, and transport of ICAM-1-targeted nanocarriers across endothelial and subendothelial cell components of the blood-brain barrier.

PubMed

Hsu, Janet; Rappaport, Jeff; Muro, Silvia

2014-07-01

The blood-brain barrier (BBB) represents a target for therapeutic intervention and an obstacle for brain drug delivery. Targeting endocytic receptors on brain endothelial cells (ECs) helps transport drugs and carriers into and across this barrier. While most receptors tested are associated with clathrin-mediated pathways, clathrin-independent routes are rather unexplored. We have examined the potential for one of these pathways, cell adhesion molecule (CAM)-mediated endocytosis induced by targeting intercellular adhesion molecule -1 (ICAM-1), to transport drug carriers into and across BBB models. Model polymer nanocarriers (NCs) coated with control IgG or antibodies against ICAM-1 (IgG NCs vs. anti-ICAM NCs; ~250-nm) were incubated with human brain ECs, astrocytes (ACs), or pericytes (PCs) grown as monocultures or bilayered (endothelial+subendothelial) co-cultures. ICAM-1 was present and overexpressed in disease-like conditions on ECs and, at a lesser extent, on ACs and PCs which are BBB subendothelial components. Specific targeting and CAM-mediated uptake of anti-ICAM NCs occurred in these cells, although this was greater for ECs. Anti-ICAM NCs were transported across endothelial monolayers and endothelial+subendothelial co-cultures modeling the BBB. CAM-mediated transport induced by ICAM-1 targeting operates in endothelial and subendothelial cellular components of the BBB, which may provide an avenue to overcome this barrier.

100-N Area Decision Unit Target Analyte List Development for Soil

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

Ovink, R.

2012-09-18

This report documents the process used to identify source area target analytes in support of the 100-N Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

Inter-species activity correlations reveal functional correspondences between monkey and human brain areas

PubMed Central

Mantini, Dante; Hasson, Uri; Betti, Viviana; Perrucci, Mauro G.; Romani, Gian Luca; Corbetta, Maurizio; Orban, Guy A.; Vanduffel, Wim

2012-01-01

Evolution-driven functional changes in the primate brain are typically assessed by aligning monkey and human activation maps using cortical surface expansion models. These models use putative homologous areas as registration landmarks, assuming they are functionally correspondent. In cases where functional changes have occurred in an area, this assumption prohibits to reveal whether other areas may have assumed lost functions. Here we describe a method to examine functional correspondences across species. Without making spatial assumptions, we assess similarities in sensory-driven functional magnetic resonance imaging responses between monkey (Macaca mulatta) and human brain areas by means of temporal correlation. Using natural vision data, we reveal regions for which functional processing has shifted to topologically divergent locations during evolution. We conclude that substantial evolution-driven functional reorganizations have occurred, not always consistent with cortical expansion processes. This novel framework for evaluating changes in functional architecture is crucial to building more accurate evolutionary models. PMID:22306809

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.

Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment.

PubMed

Vizi, E S; Fekete, A; Karoly, R; Mike, A

2010-06-01

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic-extrasynaptic receptor trafficking, neuron-glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.

Target surface area effects on hot electron dynamics from high intensity laser–plasma interactions

DOE PAGES

Zulick, C.; Raymond, A.; McKelvey, A.; ...

2016-06-15

Reduced surface area targets were studied using an ultra-high intensity femtosecond laser in order to determine the effect of electron sheath field confinement on electron dynamics. X-ray emission due to energetic electrons was imaged using a K α imaging crystal. Electrons were observed to travel along the surface of wire targets, and were slowed mainly by the induced fields. Targets with reduced surface areas were correlated with increased hot electron densities and proton energies. Furthermore, Hybrid Vlasov–Fokker–Planck simulations demonstrated increased electric sheath field strength in reduced surface area targets.

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.

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging.

PubMed

Bhaskar, Sonu; Tian, Furong; Stoeger, Tobias; Kreyling, Wolfgang; de la Fuente, Jesús M; Grazú, Valeria; Borm, Paul; Estrada, Giovani; Ntziachristos, Vasilis; Razansky, Daniel

2010-03-03

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as

Tailoring Lipid and Polymeric Nanoparticles as siRNA Carriers towards the Blood-Brain Barrier - from Targeting to Safe Administration.

PubMed

Gomes, Maria João; Fernandes, Carlos; Martins, Susana; Borges, Fernanda; Sarmento, Bruno

2017-03-01

Blood-brain barrier is a tightly packed layer of endothelial cells surrounding the brain that acts as the main obstacle for drugs enter the central nervous system (CNS), due to its unique features, as tight junctions and drug efflux systems. Therefore, since the incidence of CNS disorders is increasing worldwide, medical therapeutics need to be improved. Consequently, aiming to surpass blood-brain barrier and overcome CNS disabilities, silencing P-glycoprotein as a drug efflux transporter at brain endothelial cells through siRNA is considered a promising approach. For siRNA enzymatic protection and efficient delivery to its target, two different nanoparticles platforms, solid lipid (SLN) and poly-lactic-co-glycolic (PLGA) nanoparticles were used in this study. Polymeric PLGA nanoparticles were around 115 nm in size and had 50 % of siRNA association efficiency, while SLN presented 150 nm and association efficiency close to 52 %. Their surface was functionalized with a peptide-binding transferrin receptor, in a site-oriented manner confirmed by NMR, and their targeting ability against human brain endothelial cells was successfully demonstrated by fluorescence microscopy and flow cytometry. The interaction of modified nanoparticles with brain endothelial cells increased 3-fold compared to non-modified lipid nanoparticles, and 4-fold compared to non-modified PLGA nanoparticles, respectively. These nanosystems, which were also demonstrated to be safe for human brain endothelial cells, without significant cytotoxicity, bring a new hopeful breath to the future of brain diseases therapies.

Benevolent sexism alters executive brain responses.

PubMed

Dardenne, Benoit; Dumont, Muriel; Sarlet, Marie; Phillips, Christophe; Balteau, Evelyne; Degueldre, Christian; Luxen, André; Salmon, Eric; Maquet, Pierre; Collette, Fabienne

2013-07-10

Benevolence is widespread in our societies. It is defined as considering a subordinate group nicely but condescendingly, that is, with charity. Deleterious consequences for the target have been reported in the literature. In this experiment, we used functional MRI (fMRI) to identify whether being the target of (sexist) benevolence induces changes in brain activity associated with a working memory task. Participants were confronted by benevolent, hostile, or neutral comments before and while performing a reading span test in an fMRI environment. fMRI data showed that brain regions associated previously with intrusive thought suppression (bilateral, dorsolateral, prefrontal, and anterior cingulate cortex) reacted specifically to benevolent sexism compared with hostile sexism and neutral conditions during the performance of the task. These findings indicate that, despite being subjectively positive, benevolence modifies task-related brain networks by recruiting supplementary areas likely to impede optimal cognitive performance.

In Utero Administration of Drugs Targeting Microglia Improves the Neurodevelopmental Outcome Following Cytomegalovirus Infection of the Rat Fetal Brain

PubMed Central

Cloarec, Robin; Bauer, Sylvian; Teissier, Natacha; Schaller, Fabienne; Luche, Hervé; Courtens, Sandra; Salmi, Manal; Pauly, Vanessa; Bois, Emilie; Pallesi-Pocachard, Emilie; Buhler, Emmanuelle; Michel, François J.; Gressens, Pierre; Malissen, Marie; Stamminger, Thomas; Streblow, Daniel N.; Bruneau, Nadine; Szepetowski, Pierre

2018-01-01

Congenital cytomegalovirus (CMV) infections represent one leading cause of neurodevelopmental disorders. Recently, we reported on a rat model of CMV infection of the developing brain in utero, characterized by early and prominent infection and alteration of microglia—the brain-resident mononuclear phagocytes. Besides their canonical function against pathogens, microglia are also pivotal to brain development. Here we show that CMV infection of the rat fetal brain recapitulated key postnatal phenotypes of human congenital CMV including increased mortality, sensorimotor impairment reminiscent of cerebral palsy, hearing defects, and epileptic seizures. The possible influence of early microglia alteration on those phenotypes was then questioned by pharmacological targeting of microglia during pregnancy. One single administration of clodronate liposomes in the embryonic brains at the time of CMV injection to deplete microglia, and maternal feeding with doxycyxline throughout pregnancy to modify microglia in the litters' brains, were both associated with dramatic improvements of survival, body weight gain, sensorimotor development and with decreased risk of epileptic seizures. Improvement of microglia activation status did not persist postnatally after doxycycline discontinuation; also, active brain infection remained unchanged by doxycycline. Altogether our data indicate that early microglia alteration, rather than brain CMV load per se, is instrumental in influencing survival and the neurological outcomes of CMV-infected rats, and suggest that microglia might participate in the neurological outcome of congenital CMV in humans. Furthermore this study represents a first proof-of-principle for the design of microglia-targeted preventive strategies in the context of congenital CMV infection of the brain. PMID:29559892

Functional Brain Connectivity as a New Feature for P300 Speller.

PubMed

Kabbara, Aya; Khalil, Mohamad; El-Falou, Wassim; Eid, Hassan; Hassan, Mahmoud

2016-01-01

The brain is a large-scale complex network often referred to as the "connectome". Cognitive functions and information processing are mainly based on the interactions between distant brain regions. However, most of the 'feature extraction' methods used in the context of Brain Computer Interface (BCI) ignored the possible functional relationships between different signals recorded from distinct brain areas. In this paper, the functional connectivity quantified by the phase locking value (PLV) was introduced to characterize the evoked responses (ERPs) obtained in the case of target and non-targets visual stimuli. We also tested the possibility of using the functional connectivity in the context of 'P300 speller'. The proposed approach was compared to the well-known methods proposed in the state of the art of "P300 Speller", mainly the peak picking, the area, time/frequency based features, the xDAWN spatial filtering and the stepwise linear discriminant analysis (SWLDA). The electroencephalographic (EEG) signals recorded from ten subjects were analyzed offline. The results indicated that phase synchrony offers relevant information for the classification in a P300 speller. High synchronization between the brain regions was clearly observed during target trials, although no significant synchronization was detected for a non-target trial. The results showed also that phase synchrony provides higher performance than some existing methods for letter classification in a P300 speller principally when large number of trials is available. Finally, we tested the possible combination of both approaches (classical features and phase synchrony). Our findings showed an overall improvement of the performance of the P300-speller when using Peak picking, the area and frequency based features. Similar performances were obtained compared to xDAWN and SWLDA when using large number of trials.

A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection.

PubMed

Sil, Susmita; Ghosh, Rupsa; Sanyal, Moumita; Guha, Debjani; Ghosh, Tusharkanti

2016-01-01

Colchicine induces neurodegeneration, but the extent of neurodegeneration in different areas of the brain in relation to neuroinflammation remains unclear. Such information may be useful to allow for the development of a model to compare colchicine-induced neurodegeneration with other neurodegenerative diseases such as Alzheimer's Disease (AD). The present study was designed to investigate the extent of neurodegeneration along with neuroinflammation in different areas of the brain, e.g. frontal cortex, parietal cortex, occipital cortex, corpus striatum, amygdala and hippocampus, in rats along with memory impairment 21 days after a single intracerebroventricular (icv) injection of colchicine. Memory parameters were measured before and after icv colchicine injection in all test groups of rats (control, sham-operated, colchicine-injected [ICIR] rats). On Day 21 post-injection, rats from all groups were anesthesized and tissues from the various brain areas were collected for assessment of biomarkers of neuroinflammation (i.e. levels of ROS, nitrite and proinflammatory cytokines TNFα and IL-1β) and neurodegeneration (assessed histologically). The single injection of colchicine resulted in impaired memory and neurodegeneration (significant presence of plaques, Nissl granule chromatolysis) in various brain areas (frontal cortex, amygdala, parietal cortex, corpus striatum), with maximum severity in the hippocampus. While IL-1β, TNFα, ROS and nitrite levels were altered in different brain areas in the ICIR rats, these parameters had their greatest change in the hippocampus. This study showed that icv injection of colchicine caused strong neurodegeneration and neuroinflammation in the hippocampus of rats and the increases in neurodegeneration were corroborated with those of neuroinflammation at the site. The present study also showed that the extent of neurodegeneration and neuroinflammation in different brain areas of the colchicine-injected rats were AD-like and

Brain pattern of histone H3 phosphorylation after acute amphetamine administration: its relationship to brain c-fos induction is strongly dependent on the particular brain area.

PubMed

Rotllant, David; Armario, Antonio

2012-02-01

Recent evidence strongly suggests a critical role of chromatin remodelling in the acute and chronic effects of addictive drugs. We reasoned that Immunohistochemical detection of certain histone modifications may be a more specific tool than induction of immediate early genes (i.e. c-fos) to detect brain areas and neurons that are critical for the action of addictive drugs. Thus, in the present work we studied in adult male rats the effects of a high dose of amphetamine on brain pattern of histone H3 phosphorylation in serine 10 (pH3S(10)) and c-fos expression. We firstly observed that amphetamine-induced an increase in the number of pH3S(10) positive neurons in a restricted number of brain areas, with maximum levels at 30 min after the drug administration that declined at 90 min in most areas. In a second experiment we studied colocalization of pH3S(10) immunoreactivity (pH3S(10)-IR) and c-fos expression. Amphetamine increased c-fos expression in medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens (Acb), major Island of Calleja (ICjM), central amygdala (CeA), bed nucleus of stria terminalis lateral dorsal (BSTld) and paraventricular nucleus of the hypothalamus (PVN). Whereas no evidence for increase in pH3S(10) positive neurons was found in the mPFC and the PVN, in the striatum and the Acb basically all pH3S(10) positive neurons showed colocalization with c-fos. In ICjM, CeA and BSTld a notable degree of colocalization was found, but an important number of neurons expressing c-fos were negative for pH3S(10). The present results give support to the hypothesis that amphetamine-induced pH3S(10)-IR showed a more restricted pattern than brain c-fos induction, being this difference strongly dependent on the particular brain area studied. It is likely that those nuclei and neurons showing pH3S(10)-IR are more specifically associated to important effects of the drug, including neural plasticity. This article is part of a Special Issue entitled 'Post

Widespread Brain Areas Engaged during a Classical Auditory Streaming Task Revealed by Intracranial EEG

PubMed Central

Dykstra, Andrew R.; Halgren, Eric; Thesen, Thomas; Carlson, Chad E.; Doyle, Werner; Madsen, Joseph R.; Eskandar, Emad N.; Cash, Sydney S.

2011-01-01

The auditory system must constantly decompose the complex mixture of sound arriving at the ear into perceptually independent streams constituting accurate representations of individual sources in the acoustic environment. How the brain accomplishes this task is not well understood. The present study combined a classic behavioral paradigm with direct cortical recordings from neurosurgical patients with epilepsy in order to further describe the neural correlates of auditory streaming. Participants listened to sequences of pure tones alternating in frequency and indicated whether they heard one or two “streams.” The intracranial EEG was simultaneously recorded from sub-dural electrodes placed over temporal, frontal, and parietal cortex. Like healthy subjects, patients heard one stream when the frequency separation between tones was small and two when it was large. Robust evoked-potential correlates of frequency separation were observed over widespread brain areas. Waveform morphology was highly variable across individual electrode sites both within and across gross brain regions. Surprisingly, few evoked-potential correlates of perceptual organization were observed after controlling for physical stimulus differences. The results indicate that the cortical areas engaged during the streaming task are more complex and widespread than has been demonstrated by previous work, and that, by-and-large, correlates of bistability during streaming are probably located on a spatial scale not assessed – or in a brain area not examined – by the present study. PMID:21886615

In vivo brain electrophoresis - a novel method for chemotherapy of CNS diseases.

PubMed

Ammirati, Mario; Lamki, Tariq; Chitnis, Girish; Yang, Xiangyu; Russell, Duncan; Coble, Dondrae; Kaur, Balveen; Knopp, Michael; Moore, Sarah; Ziaie, Babak

2015-05-01

The blood-brain barrier (BBB) is a protective mechanism that does its job superbly. So much so, that hitherto, brain chemotherapy has been limited by it. In fact, very few agents are effective against brain disease due to the inherent difficulties of penetrating the BBB. We describe a novel, extremely focused method for delivering drugs to specific diseased areas. This innovative method directly delivers putative substances to the pathological area, bypassing the BBB. Treatment of brain diseases could be improved by targeted, controlled delivery of therapeutic substances to diseased cerebral areas. Our described novel method - in vivo electrophoresis - achieves this. This technique was evaluated in beagles after craniotomy was performed and a custom-designed plate with electrodes inserted. The delivery of charged substances to selected areas with predictably guided movement was achieved via a created electrical field. Gadolinium, a compound unable to cross the BBB, was injected intracerebrally whereas an electrical field was created using the implanted electrodes surrounding the injection area. The electrical field-guided Gadolinium movement was evaluated using MRI. Gadolinium was moved predictably using the created electrical field without complications. The experiment successfully demonstrated controlled movement of the substance. This technique can significantly change treatment of brain diseases because substances: i) may be moved in a controlled, predictable way - exponentially increasing therapeutic interactions with the target; and ii) no longer need to conform to constraints dictated by the BBB (molecular mass < 500 d; lipophilic), thereby increasing potential number of usable substances.

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.

Prolonged Repeated Acupuncture Stimulation Induces Habituation Effects in Pain-Related Brain Areas: An fMRI Study

PubMed Central

Li, Chuanfu; Yang, Jun; Park, Kyungmo; Wu, Hongli; Hu, Sheng; Zhang, Wei; Bu, Junjie; Xu, Chunsheng; Qiu, Bensheng; Zhang, Xiaochu

2014-01-01

Most previous studies of brain responses to acupuncture were designed to investigate the acupuncture instant effect while the cumulative effect that should be more important in clinical practice has seldom been discussed. In this study, the neural basis of the acupuncture cumulative effect was analyzed. For this experiment, forty healthy volunteers were recruited, in which more than 40 minutes of repeated acupuncture stimulation was implemented at acupoint Zhusanli (ST36). Three runs of acupuncture fMRI datasets were acquired, with each run consisting of two blocks of acupuncture stimulation. Besides general linear model (GLM) analysis, the cumulative effects of acupuncture were analyzed with analysis of covariance (ANCOVA) to find the association between the brain response and the cumulative duration of acupuncture stimulation in each stimulation block. The experimental results showed that the brain response in the initial stage was the strongest although the brain response to acupuncture was time-variant. In particular, the brain areas that were activated in the first block and the brain areas that demonstrated cumulative effects in the course of repeated acupuncture stimulation overlapped in the pain-related areas, including the bilateral middle cingulate cortex, the bilateral paracentral lobule, the SII, and the right thalamus. Furthermore, the cumulative effects demonstrated bimodal characteristics, i.e. the brain response was positive at the beginning, and became negative at the end. It was suggested that the cumulative effect of repeated acupuncture stimulation was consistent with the characteristic of habituation effects. This finding may explain the neurophysiologic mechanism underlying acupuncture analgesia. PMID:24821143

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. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The auditory and non-auditory brain areas involved in tinnitus. An emergent property of multiple parallel overlapping subnetworks

PubMed Central

Vanneste, Sven; De Ridder, Dirk

2012-01-01

Tinnitus is the perception of a sound in the absence of an external sound source. It is characterized by sensory components such as the perceived loudness, the lateralization, the tinnitus type (pure tone, noise-like) and associated emotional components, such as distress and mood changes. Source localization of quantitative electroencephalography (qEEG) data demonstrate the involvement of auditory brain areas as well as several non-auditory brain areas such as the anterior cingulate cortex (dorsal and subgenual), auditory cortex (primary and secondary), dorsal lateral prefrontal cortex, insula, supplementary motor area, orbitofrontal cortex (including the inferior frontal gyrus), parahippocampus, posterior cingulate cortex and the precuneus, in different aspects of tinnitus. Explaining these non-auditory brain areas as constituents of separable subnetworks, each reflecting a specific aspect of the tinnitus percept increases the explanatory power of the non-auditory brain areas involvement in tinnitus. Thus, the unified percept of tinnitus can be considered an emergent property of multiple parallel dynamically changing and partially overlapping subnetworks, each with a specific spontaneous oscillatory pattern and functional connectivity signature. PMID:22586375

Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.

PubMed

van Vliet, Danique; Bruinenberg, Vibeke M; Mazzola, Priscila N; van Faassen, Martijn Hjr; de Blaauw, Pim; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Kema, Ido P; Heiner-Fokkema, M Rebecca; van der Zee, Eddy A; van Spronsen, Francjan J

2016-11-01

Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus

Geothermal Target Areas in Colorado as Identified by Remote Sensing Techniques

DOE Data Explorer

Khalid Hussein

2012-02-01

This layer contains the areas identified as targets of potential geothermal activity. The Criteria used to identify the target areas include: hot/warm surface exposures modeled from ASTER/Landsat satellite imagery and geological characteristics, alteration mineral commonly associated with hot springs (clays, Si, and FeOx) modeled from ASTER and Landsat data, Colorado Geological Survey (CGS) known thermal hot springs/wells and heat-flow data points, Colorado deep-seated fault zones, weakened basement identified from isostatic gravity data, and Colorado sedimentary and topographic characteristics.

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.

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. Copyright © 2016 Elsevier B.V. All rights reserved.

Brain-lung crosstalk in critical care: how protective mechanical ventilation can affect the brain homeostasis.

PubMed

Mazzeo, A T; Fanelli, V; Mascia, L

2013-03-01

The maintenance of brain homeostasis against multiple internal and external challenges occurring during the acute phase of acute brain injury may be influenced by critical care management, especially in its respiratory, hemodynamic and metabolic components. The occurrence of acute lung injury represents the most frequent extracranial complication after brain injury and deserves special attention in daily practice as optimal ventilatory strategy for patients with acute brain and lung injury are potentially in conflict. Protecting the lung while protecting the brain is thus a new target in the modern neurointensive care. This article discusses the essentials of brain-lung crosstalk and focuses on how mechanical ventilation may exert an active role in the process of maintaining or treatening brain homeostasis after acute brain injury, highlighting the following points: 1) the role of inflammation as common pathomechanism of both acute lung and brain injury; 2) the recognition of ventilatory induced lung injury as determinant of systemic inflammation affecting distal organs, included the brain; 3) the possible implication of protective mechanical ventilation strategy on the patient with an acute brain injury as an undiscovered area of research in both experimental and clinical settings.

Convection-enhanced delivery of targeted quantum dot-immunoliposome hybrid nanoparticles to intracranial brain tumor models.

PubMed

Weng, Kevin C; Hashizume, Rintaro; Noble, Charles O; Serwer, Laura P; Drummond, Daryl C; Kirpotin, Dmitri B; Kuwabara, Anne M; Chao, Lucy X; Chen, Fanqing F; James, Charles D; Park, John W

2013-12-01

The aim of this work is to evaluate combining targeting strategy and convection-enhanced delivery in brain tumor models by imaging quantum dot-immunoliposome hybrid nanoparticles. An EGF receptor-targeted, quantum dot-immunoliposome hybrid nanoparticle (QD-IL) was synthesized. In vitro uptake was measured by flow cytometry and intracellular localization was imaged by confocal microscopy. In the in vivo study, QD-ILs were delivered to intracranial xenografts via convection-enhanced delivery and fluorescence was monitored noninvasively in real-time. QD-ILs exhibited specific and efficient uptake in vitro and exhibited approximately 1.3- to 5.0-fold higher total fluorescence compared with nontargeted counterpart in intracranial brain tumor xenografts in vivo. QD-ILs serve as an effective imaging agent in vitro and in vivo, and the data suggest that ligand-directed liposomal nanoparticles in conjunction with convection-enhanced delivery may offer therapeutic benefits for glioblastoma treatment as a result of specific and efficient uptake by malignant cells.

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

Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment

PubMed Central

Vizi, ES; Fekete, A; Karoly, R; Mike, A

2010-01-01

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the ‘what’ of brain function, the ‘how’ of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the ‘how’ that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic–extrasynaptic receptor trafficking, neuron–glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them. PMID:20136842

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

PubMed

Priceman, Saul J; Tilakawardane, Dileshni; Jeang, Brook; Aguilar, Brenda; Murad, John P; Park, Anthony K; Chang, Wen-Chung; Ostberg, Julie R; Neman, Josh; Jandial, Rahul; Portnow, Jana; Forman, Stephen J; Brown, Christine E

2018-01-01

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR . ©2017 American Association for Cancer Research.

Area, age and gender dependence of the nucleoside system in the brain: a review of current literature.

PubMed

Kovács, Zsolt; Juhász, Gábor; Palkovits, Miklós; Dobolyi, Arpád; Kékesi, Katalin A

2011-01-01

Nucleosides, such as uridine, inosine, guanosine and adenosine, may participate in the regulation of sleep, cognition, memory and nociception, the suppression of seizures, and have also been suggested to play a role in the pathophysiology of some neurodegenerative and neuropsychiatric diseases. Under pathological conditions, levels of nucleosides change extremely in the brain, indicating their participation in the pathophysiology of disorders like Alzheimer's disease, Parkinson's disease and schizophrenia. These findings have resulted in an increasing attention to the roles of nucleosides in the central nervous system. The specific effects of nucleosides depend on the expression of their receptors and transporters in neuronal and glial cells, as well as their extracellular concentrations in the brain. A complex interlinked metabolic network and transporters of nucleosides may balance nucleoside levels in the brain tissue under normal conditions and enable the fine modulation of neuronal and glial processes via nucleoside receptor signaling mechanisms. Brain levels of nucleosides were found to vary when measured in a variety of different brain regions. In addition, nucleoside levels also depend on age and gender. Furthermore, distributions of nucleoside transporters and receptors as well as nucleoside metabolic enzyme activities demonstrate the area, age and gender dependence of the nucleoside system, suggesting different roles of nucleosides in functionally different brain areas. The aim of this review article is to summarize our present knowledge of the area-, age- and gender-dependent distribution of nucleoside levels, nucleoside metabolic enzyme activity, nucleoside receptors and nucleoside transporters in the brain.

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

Rat model of blood-brain barrier disruption to allow targeted neurovascular therapeutics.

PubMed

Martin, Jacob A; Maris, Alexander S; Ehtesham, Moneeb; Singer, Robert J

2012-11-30

Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier(1). The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders. A number of chemotherapeutic drugs, for example, will not effectively cross the blood-brain barrier to reach tumor cells(2). Thus, improving the delivery of drugs across the blood-brain barrier is an area of interest. The most prevalent methods for enhancing the delivery of drugs to the brain are direct cerebral infusion and blood-brain barrier disruption(3). Direct intracerebral infusion guarantees that therapies reach the brain; however, this method has a limited ability to disperse the drug(4). Blood-brain barrier disruption (BBBD) allows drugs to flow directly from the circulatory system into the brain and thus more effectively reach dispersed tumor cells. Three methods of barrier disruption include osmotic barrier disruption, pharmacological barrier disruption, and focused ultrasound with microbubbles. Osmotic disruption, pioneered by Neuwelt, uses a hypertonic solution of 25% mannitol that dehydrates the cells of the blood-brain barrier causing them to shrink and disrupt their tight junctions. Barrier disruption can also be accomplished pharmacologically with vasoactive compounds such as histamine(5) and bradykinin(6). This method, however, is selective primarily for the brain-tumor barrier(7). Additionally, RMP-7, an analog of the peptide bradykinin, was found to be inferior when compared head-to-head with osmotic BBBD with 25% mannitol(8). Another method, focused ultrasound (FUS) in conjunction with microbubble ultrasound contrast agents, has also been shown to reversibly open the blood-brain barrier(9). In comparison to FUS, though, 25% mannitol has a longer history of safety in human patients

Camelid single-domain antibodies: A versatile tool for in vivo imaging of extracellular and intracellular brain targets.

PubMed

Li, Tengfei; Vandesquille, Matthias; Koukouli, Fani; Dudeffant, Clémence; Youssef, Ihsen; Lenormand, Pascal; Ganneau, Christelle; Maskos, Uwe; Czech, Christian; Grueninger, Fiona; Duyckaerts, Charles; Dhenain, Marc; Bay, Sylvie; Delatour, Benoît; Lafaye, Pierre

2016-12-10

Detection of intracerebral targets with imaging probes is challenging due to the non-permissive nature of blood-brain barrier (BBB). The present work describes two novel single-domain antibodies (VHHs or nanobodies) that specifically recognize extracellular amyloid deposits and intracellular tau neurofibrillary tangles, the two core lesions of Alzheimer's disease (AD). Following intravenous administration in transgenic mouse models of AD, in vivo real-time two-photon microscopy showed gradual extravasation of the VHHs across the BBB, diffusion in the parenchyma and labeling of amyloid deposits and neurofibrillary tangles. Our results demonstrate that VHHs can be used as specific BBB-permeable probes for both extracellular and intracellular brain targets and suggest new avenues for therapeutic and diagnostic applications in neurology. Copyright © 2016 Elsevier B.V. All rights reserved.

AN EARLY STAGE IN THE PLANT RECOLONIZATION OF A NUCLEAR TARGET AREA

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

Rickard, W.H.; Shields, L.M.

1963-01-01

Vegetational analyses were conducted three years postdetonation in a nuclear target area in a Grayia spinosa-Lycium andersonii community in Yucca Fiat, Nevada. Annual plants dominated the early stage of recolonization and were quantitatively more abundant in the disturbed areas than in an adjacent undisturbed shrub community. Ment zelia albicaulis and Chaenactis steviodes occurred in both disturbed and undisturbed areas, however; Mentzelia was more abundant in disturbed areas while Chaenactis was more abundant in the undisturbed community. Salsola kali was confined to disturbed areas while Phacelia vallismortae was more often encountered in the undisturbed community. The plant recolonization of a mechanicallymore » disturbed area was quantitatively and qualitatively more like that of the interior zone of the nuclear target area than less disturbed habitats. These data support a conclusion that soil displacement presents a more rigorous habitat for plant recolonization than disturbances created by the wider ranging destructive components of a nuclear detonation. (auth)« less

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. Copyright © 2016 Elsevier B.V. All rights reserved.

The effects of figure/ground, perceived area, and target saliency on the luminosity threshold.

PubMed

Bonato, F; Cataliotti, J

2000-02-01

Observers adjusted the luminance of a target region until it began to appear self-luminous, or glowing. In Experiment 1, the target was either a face-shaped region (figure) or a non-face-shaped region (ground) of identical area that appeared to be the face's background. In Experiment 2, the target was a square or a trapezoid of identical area that appeared as a tilted rectangle. In Experiment 3, the target was a square surrounded by square, circular, or diamond-shaped elements. Targets that (1) were perceived as figures, (2) were phenomenally small in area, or (3) did not group well with other elements in the array because of shape appeared self-luminous at significantly lower luminance levels. These results indicate that like lightness perception, the luminosity threshold is influenced by perceptual organization and is not based on low-level retinal processes alone.

Brain-to-brain coupling during handholding is associated with pain reduction.

PubMed

Goldstein, Pavel; Weissman-Fogel, Irit; Dumas, Guillaume; Shamay-Tsoory, Simone G

2018-03-13

The mechanisms underlying analgesia related to social touch are not clear. While recent research highlights the role of the empathy of the observer to pain relief in the target, the contribution of social interaction to analgesia is unknown. The current study examines brain-to-brain coupling during pain with interpersonal touch and tests the involvement of interbrain synchrony in pain alleviation. Romantic partners were assigned the roles of target (pain receiver) and observer (pain observer) under pain-no-pain and touch-no-touch conditions concurrent with EEG recording. Brain-to-brain coupling in alpha-mu band (8-12 Hz) was estimated by a three-step multilevel analysis procedure based on running window circular correlation coefficient and post hoc power of the findings was calculated using simulations. Our findings indicate that hand-holding during pain administration increases brain-to-brain coupling in a network that mainly involves the central regions of the pain target and the right hemisphere of the pain observer. Moreover, brain-to-brain coupling in this network was found to correlate with analgesia magnitude and observer's empathic accuracy. These findings indicate that brain-to-brain coupling may be involved in touch-related analgesia.

A pentapeptide monocyte locomotion inhibitory factor protects brain ischemia injury by targeting the eEF1A1/endothelial nitric oxide synthase pathway.

PubMed

Zhang, Yuefan; Chen, Jun; Li, Fan; Li, Dong; Xiong, Qinhui; Lin, Yang; Zhang, Dazhi; Wang, Xiao-Fan; Yang, Pengyuan; Rui, Yao-Cheng

2012-10-01

Ischemic stroke is a major cause of death worldwide but lacks viable treatment or treatment targets. Monocyte locomotion inhibitory factor (MLIF) is a small heat-stable pentapeptide produced by Entamoeba histolytica in axenic culture, which is supposed to protect the brain from ischemic injury; the mechanism, however, remains unknown. In this study, we further investigated the mechanism underlying the protective role of MLIF in brain ischemia. A middle cerebral artery occlusion model in rats was used for detecting the effect of MLIF in the brain ischemia in vivo. To identify targets of MLIF in brain endothelial cells, we performed immunoprecipitation of biotin-conjugated MLIF and mass spectrometry. MLIF can protect the brain from ischemic injury in vivo, yielding decreased ischemic volume, prolonged survival, and improved neurological outcome. In vitro studies showed that MLIF displayed protective effects through inhibition of expression of pathological inflammatory adhesion molecules and enhancing endothelial nitric oxide synthase expression and nitric oxide release in the cerebrovascular endothelium. The target screening experiments demonstrated binding of MLIF to the ribosomal protein translation elongation factor eEF1A1. MLIF enhanced endothelial nitric oxide synthase expression through stabilization of endothelial nitric oxide synthase mRNA, and eEF1A1 was shown to be necessary for this enhanced expression. Knockdown of eEF1A1 or inhibition of endothelial nitric oxide synthase attenuated MLIF-mediated inhibition of adhesion molecule expression. In this study, we identified a new potential pharmacologically targetable mechanism underlying MLIF's protective effects in brain ischemia through the eEF1A1/endothelial nitric oxide synthase pathway.

Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration

PubMed Central

Chertok, Beata; David, Allan E.; Yang, Victor C.

2010-01-01

This study aimed to examine the applicability of polyethyleneimine (PEI)-modified magnetic nanoparticles (GPEI) as a potential vascular drug/gene carrier to brain tumors. In vitro, GPEI exhibited high cell association and low cell toxicity – properties which are highly desirable for intracellular drug/gene delivery. In addition, a high saturation magnetization of 93 emu/g Fe was expected to facilitate magnetic targeting of GPEI to brain tumor lesions. However, following intravenous administration, GPEI could not be magnetically accumulated in tumors of rats harboring orthotopic 9L-gliosarcomas due to its poor pharmacokinetic properties, reflected by a negligibly low plasma AUC of 12 ± 3 μg Fe/ml*min. To improve “passive” GPEI presentation to brain tumor vasculature for subsequent “active” magnetic capture, we examined the intra-carotid route as an alternative for nanoparticle administration. Intra-carotid administration in conjunction with magnetic targeting resulted in 30-fold (p = 0.002) increase in tumor entrapment of GPEI compared to that seen with intravenous administration. In addition, magnetic accumulation of cationic GPEI (ζ-potential = + 37.2 mV) in tumor lesions was 5.2-fold higher (p = 0.004) than that achieved with slightly anionic G100 (ζ-potential = −12 mV) following intra-carotid administration, while no significant accumulation difference was detected between the two types of nanoparticles in the contra-lateral brain (p = 0.187). These promising results warrant further investigation of GPEI as a potential cell-permeable, magnetically-responsive platform for brain tumor delivery of drugs and genes. PMID:20494439

Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration.

PubMed

Chertok, Beata; David, Allan E; Yang, Victor C

2010-08-01

This study aimed to examine the applicability of polyethyleneimine (PEI)-modified magnetic nanoparticles (GPEI) as a potential vascular drug/gene carrier to brain tumors. In vitro, GPEI exhibited high cell association and low cell toxicity--properties which are highly desirable for intracellular drug/gene delivery. In addition, a high saturation magnetization of 93 emu/g Fe was expected to facilitate magnetic targeting of GPEI to brain tumor lesions. However, following intravenous administration, GPEI could not be magnetically accumulated in tumors of rats harboring orthotopic 9L-gliosarcomas due to its poor pharmacokinetic properties, reflected by a negligibly low plasma AUC of 12 +/- 3 microg Fe/ml min. To improve "passive" GPEI presentation to brain tumor vasculature for subsequent "active" magnetic capture, we examined the intra-carotid route as an alternative for nanoparticle administration. Intra-carotid administration in conjunction with magnetic targeting resulted in 30-fold (p=0.002) increase in tumor entrapment of GPEI compared to that seen with intravenous administration. In addition, magnetic accumulation of cationic GPEI (zeta-potential = + 37.2 mV) in tumor lesions was 5.2-fold higher (p=0.004) than that achieved with slightly anionic G100 (zeta-potential= -12 mV) following intra-carotid administration, while no significant accumulation difference was detected between the two types of nanoparticles in the contra-lateral brain (p=0.187). These promising results warrant further investigation of GPEI as a potential cell-permeable, magnetically-responsive platform for brain tumor delivery of drugs and genes. 2010 Elsevier Ltd. All rights reserved.

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. Copyright © 2013 Elsevier B.V. All rights reserved.

A microinjection technique for targeting regions of embryonic and neonatal mouse brain in vivo

PubMed Central

Davidson, Steve; Truong, Hai; Nakagawa, Yasushi; Giesler, Glenn J

2009-01-01

A simple pressure injection technique was developed to deliver substances into specific regions of the embryonic and neonatal mouse brain in vivo. The retrograde tracers Fluorogold and cholera toxin B subunit were used to test the validity of the technique. Injected animals survived the duration of transport (24–48 hrs) and then were sacrificed and perfused with fixative. Small injections (≤ 50 nL) were contained within targeted structures of the perinatal brain and labeled distant cells of origin in several model neural pathways. Traced neural pathways in the perinatal mouse were further examined with immunohistochemical methods to test the feasibility of double labeling experiments during development. Several experimental situations in which this technique would be useful are discussed, for example, to label projection neurons in slice or culture preparations of mouse embryos and neonates. The administration of pharmacological or genetic vectors directly into specific neural targets during development should also be feasible. An examination of the form of neural pathways during early stages of life may lead to insights regarding the functional changes that occur during critical periods of development and provide an anatomic basis for some neurodevelopmental disorders. PMID:19840780

Finding influential nodes for integration in brain networks using optimal percolation theory.

PubMed

Del Ferraro, Gino; Moreno, Andrea; Min, Byungjoon; Morone, Flaviano; Pérez-Ramírez, Úrsula; Pérez-Cervera, Laura; Parra, Lucas C; Holodny, Andrei; Canals, Santiago; Makse, Hernán A

2018-06-11

Global integration of information in the brain results from complex interactions of segregated brain networks. Identifying the most influential neuronal populations that efficiently bind these networks is a fundamental problem of systems neuroscience. Here, we apply optimal percolation theory and pharmacogenetic interventions in vivo to predict and subsequently target nodes that are essential for global integration of a memory network in rodents. The theory predicts that integration in the memory network is mediated by a set of low-degree nodes located in the nucleus accumbens. This result is confirmed with pharmacogenetic inactivation of the nucleus accumbens, which eliminates the formation of the memory network, while inactivations of other brain areas leave the network intact. Thus, optimal percolation theory predicts essential nodes in brain networks. This could be used to identify targets of interventions to modulate brain function.

Black Holes as Brains: Neural Networks with Area Law Entropy

NASA Astrophysics Data System (ADS)

Dvali, Gia

2018-04-01

Motivated by the potential similarities between the underlying mechanisms of the enhanced memory storage capacity in black holes and in brain networks, we construct an artificial quantum neural network based on gravity-like synaptic connections and a symmetry structure that allows to describe the network in terms of geometry of a d-dimensional space. We show that the network possesses a critical state in which the gapless neurons emerge that appear to inhabit a (d-1)-dimensional surface, with their number given by the surface area. In the excitations of these neurons, the network can store and retrieve an exponentially large number of patterns within an arbitrarily narrow energy gap. The corresponding micro-state entropy of the brain network exhibits an area law. The neural network can be described in terms of a quantum field, via identifying the different neurons with the different momentum modes of the field, while identifying the synaptic connections among the neurons with the interactions among the corresponding momentum modes. Such a mapping allows to attribute a well-defined sense of geometry to an intrinsically non-local system, such as the neural network, and vice versa, it allows to represent the quantum field model as a neural network.

Strong Functional Connectivity among Homotopic Brain Areas Is Vital for Motor Control in Unilateral Limb Movement.

PubMed

Wei, Pengxu; Zhang, Zuting; Lv, Zeping; Jing, Bin

2017-01-01

The mechanism underlying brain region organization for motor control in humans remains poorly understood. In this functional magnetic resonance imaging (fMRI) study, right-handed volunteers were tasked to maintain unilateral foot movements on the right and left sides as consistently as possible. We aimed to identify the similarities and differences between brain motor networks of the two conditions. We recruited 18 right-handed healthy volunteers aged 25 ± 2.3 years and used a whole-body 3T system for magnetic resonance (MR) scanning. Image analysis was performed using SPM8, Conn toolbox and Brain Connectivity Toolbox. We determined a craniocaudally distributed, mirror-symmetrical modular structure. The functional connectivity between homotopic brain areas was generally stronger than the intrahemispheric connections, and such strong connectivity led to the abovementioned modular structure. Our findings indicated that the interhemispheric functional interaction between homotopic brain areas is more intensive than the interaction along the conventional top-down and bottom-up pathways within the brain during unilateral limb movement. The detected strong interhemispheric horizontal functional interaction is an important aspect of motor control but often neglected or underestimated. The strong interhemispheric connectivity may explain the physiological phenomena and effects of promising therapeutic approaches. Further accurate and effective therapeutic methods may be developed on the basis of our findings.

Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.

PubMed

Molino, Yves; David, Marion; Varini, Karine; Jabès, Françoise; Gaudin, Nicolas; Fortoul, Aude; Bakloul, Karima; Masse, Maxime; Bernard, Anne; Drobecq, Lucile; Lécorché, Pascaline; Temsamani, Jamal; Jacquot, Guillaume; Khrestchatisky, Michel

2017-05-01

The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from wild-type and LDLR-knockout animals ( ldlr -/- ) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier. © FASEB.

Altered intraoperative cerebrovascular reactivity in brain areas of high-grade glioma recurrence.

PubMed

Fierstra, Jorn; van Niftrik, Bas; Piccirelli, Marco; Burkhardt, Jan Karl; Pangalu, Athina; Kocian, Roman; Valavanis, Antonios; Weller, Michael; Regli, Luca; Bozinov, Oliver

2016-07-01

Current MRI sequences are limited in identifying brain areas at risk for high grade glioma recurrence. We employed intraoperative 3-Tesla functional MRI to assess cerebrovascular reactivity (CVR) after high-grade glioma resection and analyzed regional CVR responses in areas of tumor recurrence on clinical follow-up imaging. Five subjects with high-grade glioma that underwent an intraoperative Blood Oxygen-Level Dependent (BOLD) MRI CVR examination and had a clinical follow-up of at least 18months were selected from a prospective database. For this study, location of tumor recurrence was spatially matched to the intraoperative imaging to assess CVR response in that particular area. CVR is defined as the percent BOLD signal change during repeated cycles of apnea. Of the 5 subjects (mean age 44, 2 females), 4 were diagnosed with a WHO grade III and 1 subject with a WHO grade IV glioma. Three subjects exhibited a tumor recurrence on clinical follow-up MRI (mean: 15months). BOLD CVR measured in the spatially matched area of tumor recurrence was on average 94% increased (range-32% to 183%) as compared to contralateral hemisphere CVR response, 1.50±0.81 versus 1.03±0.46 respectively (p=0.31). For this first analysis in a small cohort, we found altered intraoperative CVR in brain areas exhibiting high grade glioma recurrence on clinical follow-up imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Emerging Drugs for the Treatment of Breast Cancer Brain Metastasis: A Review of Patent Literature.

PubMed

Anaya-Ruiz, Maricruz; Bandala, Cindy; Martinez-Morales, Patricia; Landeta, Gerardo; Martinez-Contreras, Rebeca D; Martinez-Montiel, Nancy; Perez-Santos, Martin

2018-04-29

Despite dramatic advances in cancer treatment that lead to long-term survival, there is an increasing number of patients presenting with clinical manifestations of cerebral metastasis in breast cancer, for whom only palliative treatment options exist. The present review aims to provide to identify recent patens of breast cancer brain metastasis that may have application in improving cancer treatment. Recent patents regarding the breast cancer brain metastasis were obtained from USPTO patent databases, Esp@cenet, Patentscope and Patent Inspiration®. A total of 55 patent documents and 35 drug targets were recovered. Of these, a total of 45 patents and 10 patents were biotech drugs and chemical drugs, respectively. Among the target drugs analyzed were neurotrophin-3, protocadherin 7, CXCR4, PTEN, GABA receptor 3, L1CAM, PI3K-Akt / mTOR, VEGFR2, Claudin-5, Occludin, and NKG2A, among others. In this study we found 35 drug targets for metastasis to the brain in breast cancer, with 60% of them including only one patent, which establishes that this area of research is very recent, and that these targets have recently been linked to metastasis to the brain. On the other hand, 19 drug targets, among them VEGF, VEGFR2, CXCL12, and CXCR4, have been addressed for the first time until 6 years ago, confirming that the development of drugs for brain metastasis in breast cancer is an incipient area, but with interesting potential. Interestingly, the stage of inside the brain, was the stage with the lowest amount of drug targets, which places it as a priority for research and drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

From the "little brain" gastrointestinal infection to the "big brain" neuroinflammation: a proposed fast axonal transport pathway involved in multiple sclerosis.

PubMed

Deretzi, Georgia; Kountouras, Jannis; Grigoriadis, Nikolaos; Zavos, Christos; Chatzigeorgiou, Stavros; Koutlas, Evangelos; Tsiptsios, Iakovos

2009-11-01

The human central nervous system (CNS) is targeted by different pathogens which, apart from pathogens' intranasal inoculation or trafficking into the brain through infected blood cells, may use a distinct pathway to bypass the blood-brain barrier by using the gastrointestinal tract (GIT) retrograde axonal transport through sensory or motor fibres. The recent findings regarding the enteric nervous system (often called the "little brain") similarities with CNS and GIT axonal transport of infections resulting in CNS neuroinflammation are mainly reviewed in this article. We herein propose that the GIT is the vulnerable area through which pathogens (such as Helicobacter pylori) may influence the brain and induce multiple sclerosis pathologies, mainly via the fast axonal transport by the afferent neurones connecting the GIT to brain.

Technical Note: Immunohistochemical evaluation of mouse brain irradiation targeting accuracy with 3D-printed immobilization device.

PubMed

Zarghami, Niloufar; Jensen, Michael D; Talluri, Srikanth; Foster, Paula J; Chambers, Ann F; Dick, Frederick A; Wong, Eugene

2015-11-01

Small animal immobilization devices facilitate positioning of animals for reproducible imaging and accurate focal radiation therapy. In this study, the authors demonstrate the use of three-dimensional (3D) printing technology to fabricate a custom-designed mouse head restraint. The authors evaluate the accuracy of this device for the purpose of mouse brain irradiation. A mouse head holder was designed for a microCT couch using cad software and printed in an acrylic based material. Ten mice received half-brain radiation while positioned in the 3D-printed head holder. Animal placement was achieved using on-board image guidance and computerized asymmetric collimators. To evaluate the precision of beam localization for half-brain irradiation, mice were sacrificed approximately 30 min after treatment and brain sections were stained for γ-H2AX, a marker for DNA breaks. The distance and angle of the γ-H2AX radiation beam border to longitudinal fissure were measured on histological samples. Animals were monitored for any possible trauma from the device. Visualization of the radiation beam on ex vivo brain sections with γ-H2AX immunohistochemical staining showed a sharp radiation field within the tissue. Measurements showed a mean irradiation targeting error of 0.14±0.09 mm (standard deviation). Rotation between the beam axis and mouse head was 1.2°±1.0° (standard deviation). The immobilization device was easily adjusted to accommodate different sizes of mice. No signs of trauma to the mice were observed from the use of tooth block and ear bars. The authors designed and built a novel 3D-printed mouse head holder with many desired features for accurate and reproducible radiation targeting. The 3D printing technology was found to be practical and economical for producing a small animal imaging and radiation restraint device and allows for customization for study specific needs.

Dynamics of brain activity in motor and frontal cortical areas during music listening: a magnetoencephalographic study.

PubMed

Popescu, Mihai; Otsuka, Asuka; Ioannides, Andreas A

2004-04-01

There are formidable problems in studying how 'real' music engages the brain over wide ranges of temporal scales extending from milliseconds to a lifetime. In this work, we recorded the magnetoencephalographic signal while subjects listened to music as it unfolded over long periods of time (seconds), and we developed and applied methods to correlate the time course of the regional brain activations with the dynamic aspects of the musical sound. We showed that frontal areas generally respond with slow time constants to the music, reflecting their more integrative mode; motor-related areas showed transient-mode responses to fine temporal scale structures of the sound. The study combined novel analysis techniques designed to capture and quantify fine temporal sequencing from the authentic musical piece (characterized by a clearly defined rhythm and melodic structure) with the extraction of relevant features from the dynamics of the regional brain activations. The results demonstrated that activity in motor-related structures, specifically in lateral premotor areas, supplementary motor areas, and somatomotor areas, correlated with measures of rhythmicity derived from the music. These correlations showed distinct laterality depending on how the musical performance deviated from the strict tempo of the music score, that is, depending on the musical expression.

In vivo real-time fluorescence visualization and brain-targeting mechanisms of lipid nanocarriers with different fatty ester:oil ratios.

PubMed

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

2011-11-01

The objective of the present work was to investigate the influence of the inner cores of lipid nanocarriers on the efficiency of brain targeting. Cetyl palmitate and squalene were respectively chosen as the solid lipid and liquid oil in the inner phase of the nanocarriers. Nanoparticulate systems with different cetyl palmitate/squalene ratios were compared by evaluating the size, zeta potential, molecular environment, and mobility of lipids in the systems. The particulate diameter ranged from 190 to 210 nm, with systems containing 100% cetyl palmitate in the matrix (solid lipid nanoparticles [SLN]) showing the smallest size, followed by systems with both cetyl palmitate and squalene (nanostructured lipid carriers [NLC]) and with 100% squalene (lipid emulsions [LE]). A cationic surfactant, Forestall, was used to produce a positive surface charge of 40-55 mW. The in vitro release was evaluated using various dyes located in different phases of the nanocarriers. The release of sulforhodamine B occurred in a sustained manner from the shell of the nanocarriers. The in vivo brain distribution of lipid nanosystems after an intravenous injection into rats was monitored by a real-time fluorescence imaging system. LE showed higher brain accumulation than SLN and NLC. NLC only exhibited a slightly higher brain accumulation compared with the aqueous control. Incorporation of sulforhodamine B into LE could prolong its retention in the brain from 20 to 50 min. The results were further confirmed by imaging the entire brain and brain slices. The specific association of lipid nanocarriers with rat brain endothelial cells (bEnd3) was demonstrated using fluorescence microscopy. The cellular uptake of LE and SLN was higher compared with NLC and the aqueous control. LE were observed to be internalized by cells through caveola-mediated and macropinocytotic energy-dependent endocytosis. The experimental profiles indicated that LE with moderate additives are a promising brain-targeting

Advances in Decoding Breast Cancer Brain Metastasis

PubMed Central

Zhang, Chenyu; Yu, Dihua

2016-01-01

The past decade has witnessed impressive advances in cancer treatment ushered in by targeted and immunotherapies. However, with significantly prolonged survival, upon recurrence, more patients become inflicted by brain metastasis, which is mostly refractory to all currently available therapeutic regimens. Historically, brain metastasis is an understudied area in cancer research, partly due to the dearth of appropriate experimental models that closely simulate the special biological features of metastasis in the unique brain environment; and to the sophistication of techniques required to perform in-depth studies of the extremely complex and challenging brain metastasis. Yet, with increasing clinical demand for more effective treatment options, brain metastasis research has rapidly advanced in recent years. The present review spotlights the recent major progresses in basic and translational studies of brain metastasis with focuses on new animal models, novel imaging technologies, omics “big data” resources, and some new and exciting biological insights on brain metastasis. PMID:27873078

Targeting the Brain with a Neuroprotective Omega-3 Fatty Acid to Enhance Neurogenesis in Hypoxic Condition in Culture.

PubMed

Lo Van, Amanda; Sakayori, Nobuyuki; Hachem, Mayssa; Belkouch, Mounir; Picq, Madeleine; Fourmaux, Baptiste; Lagarde, Michel; Osumi, Noriko; Bernoud-Hubac, Nathalie

2018-06-01

Docosahexaenoic acid (DHA, 22:6n-3) is an essential omega-3 polyunsaturated fatty acid (PUFA) that is required for proper brain development and cerebral functions. While DHA deficiency in the brain was shown to be linked to the emergence of cerebral diseases, a dietary intake of omega-3 PUFA could prevent or attenuate neurologic disturbances linked with aging or neurodegenerative diseases. In this context, targeting the brain with DHA might offer great promise in developing new therapeutics for neurodegenerative diseases. We previously synthesized a stabilized form of DHA-containing lysophosphatidylcholine a major vector of DHA transportation to the brain, which is 1-acetyl,2-docoshexaenoyl-glycerophosphocholine, named AceDoPC®. Injection of AceDoPC® or DHA after experimental ischemic stroke showed that both molecules had neuroprotective effects but AceDoPC® was the most potent. This study aims to investigate the beneficial effects of DHA either unesterified or esterified within AceDoPC® on a model of neurogenesis in vitro, under physiological or pathological conditions. The effect of protectin DX (PDX, a double lipoxygenase product of DHA) was also tested. We cultured neural stem progenitor cells (NSPCs) derived from the adult mouse brain under normal or hypoxigenic (ischemic) conditions in vitro. Neurogenesis study of cell cultures with AceDoPC® showed enhanced neurogenesis compared to addition of unesterified DHA, PDX, or vehicle control, especially under pathological conditions. Our studies of the potential mechanisms involved in neuroprotection hinted that AceDoPC® neuroprotective and regenerative effects might be due in part to its anti-oxidative effects. These results indicate the potential for novel therapeutics against stroke that target the brain.

Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells

PubMed Central

Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi

2015-01-01

Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. PMID:25910782

Targeting the Cerebellum by Noninvasive Neurostimulation: a Review.

PubMed

van Dun, Kim; Bodranghien, Florian; Manto, Mario; Mariën, Peter

2017-06-01

Transcranial magnetic and electric stimulation of the brain are novel and highly promising techniques currently employed in both research and clinical practice. Improving or rehabilitating brain functions by modulating excitability with these noninvasive tools is an exciting new area in neuroscience. Since the cerebellum is closely connected with the cerebral regions subserving motor, associative, and affective functions, the cerebello-thalamo-cortical pathways are an interesting target for these new techniques. Targeting the cerebellum represents a novel way to modulate the excitability of remote cortical regions and their functions. This review brings together the studies that have applied cerebellar stimulation, magnetic and electric, and presents an overview of the current knowledge and unsolved issues. Some recommendations for future research are implemented as well.

33 CFR 334.120 - Delaware Bay off Milford Neck; naval aircraft bombing target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Delaware Bay off Milford Neck; naval aircraft bombing target area. 334.120 Section 334.120 Navigation and Navigable Waters CORPS OF....120 Delaware Bay off Milford Neck; naval aircraft bombing target area. (a) The danger zone. A circular...

33 CFR 334.120 - Delaware Bay off Milford Neck; naval aircraft bombing target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Delaware Bay off Milford Neck; naval aircraft bombing target area. 334.120 Section 334.120 Navigation and Navigable Waters CORPS OF....120 Delaware Bay off Milford Neck; naval aircraft bombing target area. (a) The danger zone. A circular...

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

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

Vose, Sarah C.; Center for Children's Environmental Health Research, School of Public Health, University of California, Berkeley, CA 94720; Holland, Nina T.

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} valuesmore » 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.« less

Modified egg as a nutritional supplement during peak brain development: a new target for fortification.

PubMed

Shapira, Niva

2009-01-01

Though eggs have the unique capacity, like breastmilk, to concentrate essential nutrients required for early growth and brain development of offspring - i.e. n-3 PUFA, increasingly deficient and sources contaminated - cholesterol and allergy concerns often exclude them from perinatal recommendations. Egg's potential contribution of key nutrients required for peak brain development are re-evaluated vis-à-vis fortification, accessibility, and risks. Contributions of standard (USDA) and fortified (selected market-available) egg compositions to perinatal requirements for critical brain-supporting nutrients were compared to human and cow milks, and risks and recommendations evaluated. Standard egg has already higher concentrations/kcal of iron, selenium, zinc, choline, vitamins B12 and E, and essential amino acids (plus taurine) than human milk. Fortified egg could further yield significant n-3 PUFA % recommendations for pregnancy-lactation (total n-3 69.6-75.0% [DRI=1400-1300 mg/day]), including DHA (120.1-129.3%, mostly approximately 80% [calculated DRI=140-130 mg/day]), plus antioxidant vitamins A (9.0-15.2%) and E (51.6-65.3%), and minerals iodine (33.6-44.5%) and selenium (33.7-39.3%); % recommendations for children (1-3 y) even more. Cholesterol, important for nerve membranes and learning, may not be generally contraindicated in childbearing-aged women (approximately 10.5% hypercholesterolemia), and early-life egg exposure may increase tolerance. Egg-inclusive perinatal nutrition programs have shown significant contributions. Eggs, especially target-fortified, may provide a unique nutritional supplement for peak brain development continously during pregnancy, nursing, and infancy (from 6 months), especially vs. insufficiencies. Missing nutritional opportunities by egg exclusion vs. concerns of hypercholesterolemia or allergy could be addressed individually, rather than as general recommendations, warranting further research and targeted egg design.

Philippine protected areas are not meeting the biodiversity coverage and management effectiveness requirements of Aichi Target 11.

PubMed

Mallari, Neil Aldrin D; Collar, Nigel J; McGowan, Philip J K; Marsden, Stuart J

2016-04-01

Aichi Target 11 of the Convention on Biological Diversity urges, inter alia, that nations protect at least 17 % of their land, and that protection is effective and targets areas of importance for biodiversity. Five years before reporting on Aichi targets is due, we assessed the Philippines' current protected area system for biodiversity coverage, appropriateness of management regimes and capacity to deliver protection. Although protected estate already covers 11 % of the Philippines' land area, 64 % of its key biodiversity areas (KBAs) remain unprotected. Few protected areas have appropriate management and governance infrastructures, funding streams, management plans and capacity, and a serious mismatch exists between protected area land zonation regimes and conservation needs of key species. For the Philippines to meet the biodiversity coverage and management effectiveness elements of Aichi Target 11, protected area and KBA boundaries should be aligned, management systems reformed to pursue biodiversity-led targets and effective management capacity created.

Drug delivery across the blood-brain barrier using focused ultrasound

PubMed Central

Burgess, Alison; Hynynen, Kullervo H.

2015-01-01

Introduction The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a non-invasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. Areas Covered The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. Expert Opinion The introduction of MRI guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient, and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development. PMID:24650132

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules.

PubMed

He, Bo; Jabouille, Arnaud; Steri, Veronica; Johansson-Percival, Anna; Michael, Iacovos P; Kotamraju, Venkata Ramana; Junckerstorff, Reimar; Nowak, Anna K; Hamzah, Juliana; Lee, Gabriel; Bergers, Gabriele; Ganss, Ruth

2018-06-01

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The Multidimensional Therapeutic Potential of Targeting the Brain Oxytocin System for the Treatment of Substance Use Disorders.

PubMed

Bowen, Michael T; Neumann, Inga D

2017-09-24

The neuropeptide oxytocin is released both into the blood and within the brain in response to reproductive stimuli, such as birth, suckling and sex, but also in response to social interaction and stressors. Substance use disorders, or addictions, are chronic, relapsing brain disorders and are one of the major causes of global burden of disease. Unfortunately, current treatment options for substance use disorders are extremely limited and a treatment breakthrough is sorely needed. There is mounting preclinical evidence that targeting the brain oxytocin system may provide that breakthrough. Substance use disorders are characterised by a viscous cycle of bingeing and intoxication, followed by withdrawal and negative affect, and finally preoccupation and anticipation that triggers relapse and further consumption. Administration of oxytocin has been shown to have a potential therapeutic benefit at each stage of this addiction cycle for numerous drugs of abuse. This multidimensional therapeutic utility is likely due to oxytocin's interactions with key biological systems that underlie the development and maintenance of addiction. Only a few human trials of oxytocin in addicted populations have been completed with the results thus far being mixed. There are numerous other trials underway, and the results are eagerly awaited. However, the ability to fully harness the potential therapeutic benefit of targeting the brain oxytocin system may depend on the development of molecules that selectively stimulate the oxytocin system, but that have superior pharmacokinetic properties to oxytocin itself.

Deep brain stimulation in uncommon tremor disorders: indications, targets, and programming.

PubMed

Artusi, Carlo Alberto; Farooqi, Ashar; Romagnolo, Alberto; Marsili, Luca; Balestrino, Roberta; Sokol, Leonard L; Wang, Lily L; Zibetti, Maurizio; Duker, Andrew P; Mandybur, George T; Lopiano, Leonardo; Merola, Aristide

2018-03-06

In uncommon tremor disorders, clinical efficacy and optimal anatomical targets for deep brain stimulation (DBS) remain inadequately studied and insufficiently quantified. We performed a systematic review of PubMed.gov and ClinicalTrials.gov. Relevant articles were identified using the following keywords: "tremor", "Holmes tremor", "orthostatic tremor", "multiple sclerosis", "multiple sclerosis tremor", "neuropathy", "neuropathic tremor", "fragile X-associated tremor/ataxia syndrome", and "fragile X." We identified a total of 263 cases treated with DBS for uncommon tremor disorders. Of these, 44 had Holmes tremor (HT), 18 orthostatic tremor (OT), 177 multiple sclerosis (MS)-associated tremor, 14 neuropathy-associated tremor, and 10 fragile X-associated tremor/ataxia syndrome (FXTAS). DBS resulted in favorable, albeit partial, clinical improvements in HT cases receiving Vim-DBS alone or in combination with additional targets. A sustained improvement was reported in OT cases treated with bilateral Vim-DBS, while the two cases treated with unilateral Vim-DBS demonstrated only a transient effect. MS-associated tremor responded to dual-target Vim-/VO-DBS, but the inability to account for the progression of MS-associated disability impeded the assessment of its long-term clinical efficacy. Neuropathy-associated tremor substantially improved with Vim-DBS. In FXTAS patients, while Vim-DBS was effective in improving tremor, equivocal results were observed in those with ataxia. DBS of select targets may represent an effective therapeutic strategy for uncommon tremor disorders, although the level of evidence is currently in its incipient form and based on single cases or limited case series. An international registry is, therefore, warranted to clarify selection criteria, long-term results, and optimal surgical targets.

The evolution of Homo sapiens denisova and Homo sapiens neanderthalensis miRNA targeting genes in the prenatal and postnatal brain.

PubMed

Gunbin, Konstantin V; Afonnikov, Dmitry A; Kolchanov, Nikolay A; Derevianko, Anatoly P; Rogaev, Eugeny I

2015-01-01

As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain. A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development. Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.

The evolution of Homo sapiens denisova and Homo sapiens neanderthalensis miRNA targeting genes in the prenatal and postnatal brain

PubMed Central

2015-01-01

Background As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain. Results A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development. Conclusions Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines. PMID:26693966

Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase

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

Read, David J.; Li Yong; Chao, Moses V.

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 maymore » 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.« less

Can older "at risk" adults benefit from psychoeducation targeting healthy brain aging?

PubMed

Norrie, Louisa M; Diamond, Keri; Hickie, Ian B; Rogers, Naomi L; Fearns, Samantha; Naismith, Sharon L

2011-04-01

Multifactorial strategies that prevent or delay the onset or progress of cognitive decline and dementia are needed, and should include education regarding recognized risk factors. The current study sought to investigate whether older adults "at risk" of cognitive decline benefit from psychoeducation targeting healthy brain aging. 65 participants (mean age 64.8 years, SD 9.6) with a lifetime history of major depression; vascular risk as evidenced by at least one vascular risk factor; and/or subjective or objective memory impairment were allocated to weekly psychoeducation sessions or a waitlist control group. The small group sessions were conducted over ten weeks by a team of medical and allied health professionals with expertise in late-life depression and cognition. Sessions focused on modifiable risk factors for cognitive decline including vascular risk, diet, exercise, depression, anxiety and sleep disturbance, as well as providing practical strategies for memory and cognition. Both the psychoeducation and waitlist group completed a 20-item knowledge test at baseline and follow-up. Participants in the psychoeducation group were asked to complete follow-up self-report satisfaction questionnaires. Repeated measures ANOVA showed a significant interaction effect depicting improvements in knowledge associated with psychoeducation, corresponding to an improvement of 15% from baseline. Satisfaction data additionally showed that 92.3% of participants rated the program as "good" to "excellent", and over 90% suggested they would recommend it to others. A group-based psychoeducation program targeting healthy brain aging is effective in improving knowledge. Additionally, it is acceptable and rated highly by participants.

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.

Brain development during adolescence: A mixed-longitudinal investigation of cortical thickness, surface area, and volume.

PubMed

Vijayakumar, Nandita; Allen, Nicholas B; Youssef, George; Dennison, Meg; Yücel, Murat; Simmons, Julian G; Whittle, Sarah

2016-06-01

What we know about cortical development during adolescence largely stems from analyses of cross-sectional or cohort-sequential samples, with few studies investigating brain development using a longitudinal design. Further, cortical volume is a product of two evolutionarily and genetically distinct features of the cortex - thickness and surface area, and few studies have investigated development of these three characteristics within the same sample. The current study examined maturation of cortical thickness, surface area and volume during adolescence, as well as sex differences in development, using a mixed longitudinal design. 192 MRI scans were obtained from 90 healthy (i.e., free from lifetime psychopathology) adolescents (11-20 years) at three time points (with different MRI scanners used at time 1 compared to 2 and 3). Developmental trajectories were estimated using linear mixed models. Non-linear increases were present across most of the cortex for surface area. In comparison, thickness and volume were both characterised by a combination of non-linear decreasing and increasing trajectories. While sex differences in volume and surface area were observed across time, no differences in thickness were identified. Furthermore, few regions exhibited sex differences in the cortical development. Our findings clearly illustrate that volume is a product of surface area and thickness, with each exhibiting differential patterns of development during adolescence, particularly in regions known to contribute to the development of social-cognition and behavioral regulation. These findings suggest that thickness and surface area may be driven by different underlying mechanisms, with each measure potentially providing independent information about brain development. Hum Brain Mapp 37:2027-2038, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

[Effects of methomyl on acetylcholinesterase in erythrocyte membrane and various brain areas].

PubMed

Zhao, Fei; Li, Tao; Zhang, Changchun; Xu, Yiping; Xu, Hangong; Shi, Nian

2015-06-01

To study the toxicity of methomyl to acetylcholinesterase (AChE) in different regions. The optimal temperature and time for measurement of AChE activity were determined in vitro. The dose- and time-response relationships of methomyl with AChE activity in human erythrocyte membrane, rat erythrocyte membrane, cortical synapses, cerebellar synapses, hippocampal synapses, and striatal synapses were evaluated. The half maximal inhibitory concentration (IC50) and bimolecular rate constant (K) of methomyl for AChE activity in different regions were calculated, and the type of inhibition of AChE activity by methomyl was determined. AChE achieved the maximum activity at 370 °C, and the optimal time to determine initial reaction velocity was 0-17 min. There were dose- and time-response relationships between methomyl and AChE activity in the erythrocyte membrane and various brain areas. The IC50 value of methomyl for AChE activity in human erythrocyte membrane was higher than that in rat erythrocyte membrane, while the Ki value of methomyl for AChE activity in rat erythrocyte membrane was higher than that in human erythrocyte membrane. Among synapses in various brain areas, the striatum had the highest IC50 value, followed by the cerebellum, cerebral cortex, and hippocampus, while the cerebral cortex had the highest Ki value, followed by the hippocampus, striatum, and cerebellum. Lineweaver-Burk diagram demonstrated that with increasing concentration of methomyl, the maximum reaction velocity (Vmax) of AChE decreased, and the Michaelis constant (Km) remained the same. Methomyl is a reversible non-competitive inhibitor of AChE. AChE of rat erythrocyte membrane is more sensitive to methomyl than that of human erythrocyte membrane; the cerebral cortical synapses have the most sensitive AChE to methomyl among synapses in various brain areas.

Drugs, Biogenic Amine Targets and the Developing Brain

PubMed Central

Frederick, Aliya L.; Stanwood, Gregg D.

2009-01-01

Defects in the development of the brain have profound impacts on mature brain functions and underlie psychopathology. Classical neurotransmitters and neuromodulators, such as dopamine, serotonin, norepinephrine, acetycholine, 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 a variety of illicit drugs of abuse, 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. PMID:19372683

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis*

PubMed Central

Dun, Matthew D.; Chalkley, Robert J.; Faulkner, Sam; Keene, Sheridan; Avery-Kiejda, Kelly A.; Scott, Rodney J.; Falkenby, Lasse G.; Cairns, Murray J.; Larsen, Martin R.; Bradshaw, Ralph A.; Hondermarck, Hubert

2015-01-01

Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and l-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation. PMID:26041846

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false San Pablo Bay, Calif.; target... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a..., Mare Island Naval Shipyard, Vallejo, California, will conduct target practice in the area at intervals...

33 CFR 334.1160 - San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false San Pablo Bay, Calif.; target... REGULATIONS § 334.1160 San Pablo Bay, Calif.; target practice area, Mare Island Naval Shipyard, Vallejo. (a..., Mare Island Naval Shipyard, Vallejo, California, will conduct target practice in the area at intervals...

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. © 2012 Wiley Periodicals, Inc.

The stomach-brain axis.

PubMed

Holtmann, Gerald; Talley, Nicholas J

2014-12-01

The stomach has distinct functions in relation to the ingestion and handling of solids and liquids. These functions include storage of the food before it is gradually emptied into the duodenum, mechanical crushing of larger food particles to increase the surface area, secretion of an acidic enzyme rich gastric juice and mixing the ingested food with the gastric juice. In addition, the stomach 'senses' the composition of the gastric content and this information is passed via the vagal nerve to the lateral hypothalamus and the limbic system, most likely as palatability signals that influence eating behaviour. Other sensory qualities related to the stimulation of gastric tension receptors are satiety and fullness. Receptors that respond to macronutrient content or gastric wall tension influence appetite and meal related hormone responses. The ingestion of food - in contrast to an infusion of nutrients into the stomach - has distinct effects on the activation of specific brain regions. Brain areas such as thalamus, amygdala, putamen and praecuneus are activated by the ingestion of food. Gastric nutrient infusion evokes greater activation in the hippocampus and anterior cingulate. The brain integrates these interrelated neural and hormonal signals arising from the stomach as well as visual, olfactory and anticipatory stimuli that ultimately influence eating and other behavioural patterns. Furthermore, there is now good evidence from experimental studies that gastric afferents influence mood, and animal studies point towards the possibility that gastric dysfunction may be a risk factor for mood disorders such as anxiety and depression. The stomach is also not only colonised by Helicobacter pylori but a large array of bacteria. While there is sufficient evidence to suggest that H. pylori may alter caloric intake and mood, the role of other gastric microbiome for the brain function is unknown. To address this appropriate targeted gastric microbiome studies would be

Analysis of risk and predictors of brain radiation necrosis after radiosurgery.

PubMed

Zhuang, Hongqing; Zheng, Yi; Wang, Junjie; Chang, Joe Y; Wang, Xiaoguang; Yuan, Zhiyong; Wang, Ping

2016-02-16

In this study, we examined the factors contributing to brain radiation necrosis and its predictors of patients treated with Cyberknife radiosurgery. A total of 94 patients with primary or metastatic brain tumours having been treated with Cyberknife radiotherapy from Sep. 2006 to Oct. 2011 were collected and retrospectively analyzed. Skull based tracking was used to deliver radiation to 104 target sites. and the prescribed radiation doses ranged from 1200 to 4500 cGy in 1 to 8 fractions with a 60% to 87% isodose line. Radiation necrosis was confirmed by imaging or pathological examination. Associations between cerebral radiation necrosis and factors including diabetes, cardio-cerebrovascular disease, target volume, isodose line, prescribed dosage, number of fractions, combination with whole brain radiation and biologically equivalent dose (BED) were determined by logistic regression. ROC curves were created to measure the predictive accuracy of influence factors and identify the threshold for brain radiation necrosis. Our results showed that radiation necrosis occurred in 12 targets (11.54%). Brain radiation necrosis was associated by BED, combination with whole brain radiotherapy, and fractions (areas under the ROC curves = 0.892±0.0335, 0.650±0.0717, and 0.712±0.0637 respectively). Among these factors, only BED had the capability to predict brain radiation necrosis, and the threshold dose was 7410 cGy. In conclusion, BED is the most effective predictor of brain radiation necrosis, with a dose of 7410 cGy being identified as the threshold.

A cytoarchitecture-driven myelin model reveals area-specific signatures in human primary and secondary areas using ultra-high resolution in-vivo brain MRI.

PubMed

Dinse, J; Härtwich, N; Waehnert, M D; Tardif, C L; Schäfer, A; Geyer, S; Preim, B; Turner, R; Bazin, P-L

2015-07-01

This work presents a novel approach for modelling laminar myelin patterns in the human cortex in brain MR images on the basis of known cytoarchitecture. For the first time, it is possible to estimate intracortical contrast visible in quantitative ultra-high resolution MR images in specific primary and secondary cytoarchitectonic areas. The presented technique reveals different area-specific signatures which may help to study the spatial distribution of cortical T1 values and the distribution of cortical myelin in general. It may lead to a new discussion on the concordance of cyto- and myeloarchitectonic boundaries, given the absence of such concordance atlases. The modelled myelin patterns are quantitatively compared with data from human ultra-high resolution in-vivo 7T brain MR images (9 subjects). In the validation, the results are compared to one post-mortem brain sample and its ex-vivo MRI and histological data. Details of the analysis pipeline are provided. In the context of the increasing interest in advanced methods in brain segmentation and cortical architectural studies, the presented model helps to bridge the gap between the microanatomy revealed by classical histology and the macroanatomy visible in MRI. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Two areas for familiar face recognition in the primate brain.

PubMed

Landi, Sofia M; Freiwald, Winrich A

2017-08-11

Familiarity alters face recognition: Familiar faces are recognized more accurately than unfamiliar ones and under difficult viewing conditions when unfamiliar face recognition fails. The neural basis for this fundamental difference remains unknown. Using whole-brain functional magnetic resonance imaging, we found that personally familiar faces engage the macaque face-processing network more than unfamiliar faces. Familiar faces also recruited two hitherto unknown face areas at anatomically conserved locations within the perirhinal cortex and the temporal pole. These two areas, but not the core face-processing network, responded to familiar faces emerging from a blur with a characteristic nonlinear surge, akin to the abruptness of familiar face recognition. In contrast, responses to unfamiliar faces and objects remained linear. Thus, two temporal lobe areas extend the core face-processing network into a familiar face-recognition system. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Brain/MINDS: brain-mapping project in Japan

PubMed Central

Okano, Hideyuki; Miyawaki, Atsushi; Kasai, Kiyoto

2015-01-01

There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (Callithrix jacchus). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas. PMID:25823872

Combining Functional Neuroimaging with Off-Line Brain Stimulation: Modulation of Task-Related Activity in Language Areas

ERIC Educational Resources Information Center

Andoh, Jamila; Paus, Tomas

2011-01-01

Repetitive TMS (rTMS) provides a noninvasive tool for modulating neural activity in the human brain. In healthy participants, rTMS applied over the language-related areas in the left hemisphere, including the left posterior temporal area of Wernicke (LTMP) and inferior frontal area of Broca, have been shown to affect performance on word…

Biochemical Fractionation and Stable Isotope Dilution Liquid Chromatography-mass Spectrometry for Targeted and Microdomain-specific Protein Quantification in Human Postmortem Brain Tissue*

PubMed Central

MacDonald, Matthew L.; Ciccimaro, Eugene; Prakash, Amol; Banerjee, Anamika; Seeholzer, Steven H.; Blair, Ian A.; Hahn, Chang-Gyu

2012-01-01

Synaptic architecture and its adaptive changes require numerous molecular events that are both highly ordered and complex. A majority of neuropsychiatric illnesses are complex trait disorders, in which multiple etiologic factors converge at the synapse via many signaling pathways. Investigating the protein composition of synaptic microdomains from human patient brain tissues will yield valuable insights into the interactions of risk genes in many disorders. These types of studies in postmortem tissues have been limited by the lack of proper study paradigms. Thus, it is necessary not only to develop strategies to quantify protein and post-translational modifications at the synapse, but also to rigorously validate them for use in postmortem human brain tissues. In this study we describe the development of a liquid chromatography-selected reaction monitoring method, using a stable isotope-labeled neuronal proteome standard prepared from the brain tissue of a stable isotope-labeled mouse, for the multiplexed quantification of target synaptic proteins in mammalian samples. Additionally, we report the use of this method to validate a biochemical approach for the preparation of synaptic microdomain enrichments from human postmortem prefrontal cortex. Our data demonstrate that a targeted mass spectrometry approach with a true neuronal proteome standard facilitates accurate and precise quantification of over 100 synaptic proteins in mammalian samples, with the potential to quantify over 1000 proteins. Using this method, we found that protein enrichments in subcellular fractions prepared from human postmortem brain tissue were strikingly similar to those prepared from fresh mouse brain tissue. These findings demonstrate that biochemical fractionation methods paired with targeted proteomic strategies can be used in human brain tissues, with important implications for the study of neuropsychiatric disease. PMID:22942359

Technical Note: Immunohistochemical evaluation of mouse brain irradiation targeting accuracy with 3D-printed immobilization device

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

Zarghami, Niloufar, E-mail: nzargham@uwo.ca; Jensen, Michael D.; Talluri, Srikanth

Purpose: Small animal immobilization devices facilitate positioning of animals for reproducible imaging and accurate focal radiation therapy. In this study, the authors demonstrate the use of three-dimensional (3D) printing technology to fabricate a custom-designed mouse head restraint. The authors evaluate the accuracy of this device for the purpose of mouse brain irradiation. Methods: A mouse head holder was designed for a microCT couch using CAD software and printed in an acrylic based material. Ten mice received half-brain radiation while positioned in the 3D-printed head holder. Animal placement was achieved using on-board image guidance and computerized asymmetric collimators. To evaluate themore » precision of beam localization for half-brain irradiation, mice were sacrificed approximately 30 min after treatment and brain sections were stained for γ-H2AX, a marker for DNA breaks. The distance and angle of the γ-H2AX radiation beam border to longitudinal fissure were measured on histological samples. Animals were monitored for any possible trauma from the device. Results: Visualization of the radiation beam on ex vivo brain sections with γ-H2AX immunohistochemical staining showed a sharp radiation field within the tissue. Measurements showed a mean irradiation targeting error of 0.14 ± 0.09 mm (standard deviation). Rotation between the beam axis and mouse head was 1.2° ± 1.0° (standard deviation). The immobilization device was easily adjusted to accommodate different sizes of mice. No signs of trauma to the mice were observed from the use of tooth block and ear bars. Conclusions: The authors designed and built a novel 3D-printed mouse head holder with many desired features for accurate and reproducible radiation targeting. The 3D printing technology was found to be practical and economical for producing a small animal imaging and radiation restraint device and allows for customization for study specific needs.« less

Toward intracellular targeted delivery of cancer therapeutics: progress and clinical outlook for brain tumor therapy.

PubMed

Pandya, Hetal; Debinski, Waldemar

2012-08-01

A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells.

Brain and lung metastasis of alveolar echinococcosis in a refugee from a hyperendemic area.

PubMed

Tappe, Dennis; Weise, David; Ziegler, Uwe; Müller, Andreas; Müllges, Wolfgang; Stich, August

2008-11-01

Alveolar echinococcosis (AE) of the liver with cerebral and pulmonary metastasis was diagnosed in a Tibetan monk who initially presented with severe headache to an emergency department in Germany. Multiple lesions with perifocal oedema and severe compression of the third ventricle were seen with computed tomography (CT) of the brain. Glioma or cerebral metastasis of a hitherto undiagnosed abdominal or pulmonary malignancy was suspected. CT scans of the lung and liver demonstrated further tumorous masses. Magnetic resonance imaging of the brain revealed the cystic nature of the cerebral lesions and the patient had a highly positive serology for AE. The echinococcal aetiology of the brain lesions was confirmed by PCR for this refugee from an area where two disease entities, AE and cystic echinococcosis, are hyperendemic.

The microenvironmental landscape of brain tumors

PubMed Central

Quail, Daniela F.; Joyce, Johanna A.

2017-01-01

The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases. PMID:28292436

78 FR 35612 - Agency Information Collection Activities; Comment Request; Targeted Teacher Shortage Areas...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-13

... address the targeted teacher deferment provision of the Higher Education Act of 1965, as amended. The... DEPARTMENT OF EDUCATION [Docket No. ED-2013-ICCD-0076] Agency Information Collection Activities; Comment Request; Targeted Teacher Shortage Areas Nationwide Listing AGENCY: Office of Postsecondary...

Targeted Imaging and Chemo-Phototherapy of Brain Cancer by a Multifunctional Drug Delivery System.

PubMed

Hao, Yongwei; Wang, Lei; Zhao, Yalin; Meng, Dehui; Li, Dong; Li, Haixia; Zhang, Bingxiang; Shi, Jinjin; Zhang, Hongling; Zhang, Zhenzhong; Zhang, Yun

2015-11-01

The aim of this study was to develop multifunctional poly lactide-co-glycolide (PLGA) nanoparticles with the ability to simultaneously deliver indocyanine green (ICG) and docetaxel (DTX) to the brain by surface decoration with the brain-targeting peptide angiopep-2 to achieve combined chemo-phototherapy for glioma under near-infrared (NIR) imaging. ICG was selected as a near-infrared imaging and phototherapy agent and DTX was employed as a chemotherapeutic agent. ICG and DTX were simultaneously incorporated into PLGA nanoparticles with higher stability. These nanoparticles were further decorated with angiopep-2 via the outer maleimide group of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]-maleinimide incorporated in the nanoparticles. The NIR image-guided chemo-phototherapy of the angiopep-2 modified PLGA/DTX/ICG nanoparticles (ANG/PLGA/DTX/ICG NPs) not only highly induced U87MG cell death in vitro, but also efficiently prolonged the life span of the brain orthotopic U87MG glioma xenograft-bearing mice in vivo. Thus, this study suggests that ANG/PLGA/DTX/ICG NPs have the potential for combinatorial chemotherapy and phototherapy for glioma. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Neural Substrates of Visual Spatial Coding and Visual Feedback Control for Hand Movements in Allocentric and Target-Directed Tasks

PubMed Central

Thaler, Lore; Goodale, Melvyn A.

2011-01-01

Neuropsychological evidence suggests that different brain areas may be involved in movements that are directed at visual targets (e.g., pointing or reaching), and movements that are based on allocentric visual information (e.g., drawing or copying). Here we used fMRI to investigate the neural correlates of these two types of movements in healthy volunteers. Subjects (n = 14) performed right hand movements in either a target-directed task (moving a cursor to a target dot) or an allocentric task (moving a cursor to reproduce the distance and direction between two distal target dots) with or without visual feedback about their hand movement. Movements were monitored with an MR compatible touch panel. A whole brain analysis revealed that movements in allocentric conditions led to an increase in activity in the fundus of the left intra-parietal sulcus (IPS), in posterior IPS, in bilateral dorsal premotor cortex (PMd), and in the lateral occipital complex (LOC). Visual feedback in both target-directed and allocentric conditions led to an increase in activity in area MT+, superior parietal–occipital cortex (SPOC), and posterior IPS (all bilateral). In addition, we found that visual feedback affected brain activity differently in target-directed as compared to allocentric conditions, particularly in the pre-supplementary motor area, PMd, IPS, and parieto-occipital cortex. Our results, in combination with previous findings, suggest that the LOC is essential for allocentric visual coding and that SPOC is involved in visual feedback control. The differences in brain activity between target-directed and allocentric visual feedback conditions may be related to behavioral differences in visual feedback control. Our results advance the understanding of the visual coordinate frame used by the LOC. In addition, because of the nature of the allocentric task, our results have relevance for the understanding of neural substrates of magnitude estimation and vector coding of

Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target.

PubMed

Lichtensteiger, Walter; Bassetti-Gaille, Catherine; Faass, Oliver; Axelstad, Marta; Boberg, Julie; Christiansen, Sofie; Rehrauer, Hubert; Georgijevic, Jelena Kühn; Hass, Ulla; Kortenkamp, Andreas; Schlumpf, Margret

2015-04-01

The study addressed the question whether gene expression patterns induced by different mixtures of endocrine disrupting chemicals (EDCs) administered in a higher dose range, corresponding to 450×, 200×, and 100× high-end human exposure levels, could be characterized in developing brain with respect to endocrine activity of mixture components, and which developmental processes were preferentially targeted. Three EDC mixtures, A-Mix (anti-androgenic mixture) with 8 antiandrogenic chemicals (di-n-butylphthalate, diethylhexylphthalate, vinclozolin, prochloraz, procymidone, linuron, epoxiconazole, and DDE), E-Mix (estrogenic mixture) with 4 estrogenic chemicals (bisphenol A, 4-methylbenzylidene camphor, 2-ethylhexyl 4-methoxycinnamate, and butylparaben), a complex mixture, AEP-Mix, containing the components of A-Mix and E-Mix plus paracetamol, and paracetamol alone, were administered by oral gavage to rat dams from gestation day 7 until weaning. General developmental endpoints were not affected by EDC mixtures or paracetamol. Gene expression was analyzed on postnatal day 6, during sexual brain differentiation, by exon microarray in medial preoptic area in the high-dose group, and by real-time RT-PCR in medial preoptic area and ventromedial hypothalamus in all dose groups. Expression patterns were mixture, sex, and region specific. Effects of the analgesic drug paracetamol, which exhibits antiandrogenic activity in peripheral systems, differed from those of A-Mix. All mixtures had a strong, mixture-specific impact on genes encoding for components of excitatory glutamatergic synapses and genes controlling migration and pathfinding of glutamatergic and GABAergic neurons, as well as genes linked with increased risk of autism spectrum disorders. Because development of glutamatergic synapses is regulated by sex steroids also in hippocampus, this may represent a general target of ECD mixtures.

Linking neocortical, cognitive, and genetic variability in autism with alterations of brain plasticity: the Trigger-Threshold-Target model.

PubMed

Mottron, Laurent; Belleville, Sylvie; Rouleau, Guy A; Collignon, Olivier

2014-11-01

The phenotype of autism involves heterogeneous adaptive traits (strengths vs. disabilities), different domains of alterations (social vs. non-social), and various associated genetic conditions (syndromic vs. nonsyndromic autism). Three observations suggest that alterations in experience-dependent plasticity are an etiological factor in autism: (1) the main cognitive domains enhanced in autism are controlled by the most plastic cortical brain regions, the multimodal association cortices; (2) autism and sensory deprivation share several features of cortical and functional reorganization; and (3) genetic mutations and/or environmental insults involved in autism all appear to affect developmental synaptic plasticity, and mostly lead to its upregulation. We present the Trigger-Threshold-Target (TTT) model of autism to organize these findings. In this model, genetic mutations trigger brain reorganization in individuals with a low plasticity threshold, mostly within regions sensitive to cortical reallocations. These changes account for the cognitive enhancements and reduced social expertise associated with autism. Enhanced but normal plasticity may underlie non-syndromic autism, whereas syndromic autism may occur when a triggering mutation or event produces an altered plastic reaction, also resulting in intellectual disability and dysmorphism in addition to autism. Differences in the target of brain reorganization (perceptual vs. language regions) account for the main autistic subgroups. In light of this model, future research should investigate how individual and sex-related differences in synaptic/regional brain plasticity influence the occurrence of autism. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Separate and overlapping brain areas encode subjective value during delay and effort discounting.

PubMed

Massar, Stijn A A; Libedinsky, Camilo; Weiyan, Chee; Huettel, Scott A; Chee, Michael W L

2015-10-15

Making decisions about rewards that involve delay or effort requires the integration of value and cost information. The brain areas recruited in this integration have been well characterized for delay discounting. However only a few studies have investigated how effort costs are integrated into value signals to eventually determine choice. In contrast to previous studies that have evaluated fMRI signals related to physical effort, we used a task that focused on cognitive effort. Participants discounted the value of delayed and effortful rewards. The value of cognitively effortful rewards was represented in the anterior portion of the inferior frontal gyrus and dorsolateral prefrontal cortex. Additionally, the value of the chosen option was encoded in the anterior cingulate cortex, caudate, and cerebellum. While most brain regions showed no significant dissociation between effort discounting and delay discounting, the ACC was significantly more activated in effort compared to delay discounting tasks. Finally, overlapping regions within the right orbitofrontal cortex and lateral temporal and parietal cortices encoded the value of the chosen option during both delay and effort discounting tasks. These results indicate that encoding of rewards discounted by cognitive effort and delay involves partially dissociable brain areas, but a common representation of chosen value is present in the orbitofrontal, temporal and parietal cortices. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

[Neurological and technical aspects of deep brain stimulation].

PubMed

Voges, J; Krauss, J K

2010-06-01

Deep brain stimulation (DBS) is an important component of the therapy of movement disorders and has almost completely replaced high-frequency coagulation of brain tissue in stereotactic neurosurgery. Despite the functional efficacy of DBS, which in parts is documented on the highest evidence level, the underlying mechanisms are still not completely understood. According to the current state of knowledge electrophysiological and functional data give evidence that high-frequency DBS has an inhibitory effect around the stimulation electrode whilst at the same time axons entering or leaving the stimulated brain area are excited leading to modulation of neuronal networks. The latter effect modifies pathological discharges of neurons in key structures of the basal ganglia network (e.g. irregular bursting activity, oscillations or synchronization) which are found in particular movement disorders such as Parkinson' s disease or dystonia. The introduction of technical standards, such as the integration of high resolution MRI into computer-assisted treatment planning, in combination with special treatment planning software have contributed significantly to the reduction of severe surgical complications (frequency of intracranial hemorrhaging 1-3%) in recent years. Future developments will address the modification of hardware components of the stimulation system, the evaluation of new brain target areas, the simultaneous stimulation of different brain areas and the assessment of different stimulation paradigms (high-frequency vs low-frequency DBS).

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

Defining Face Perception Areas in the Human Brain: A Large-Scale Factorial fMRI Face Localizer Analysis

ERIC Educational Resources Information Center

Rossion, Bruno; Hanseeuw, Bernard; Dricot, Laurence

2012-01-01

A number of human brain areas showing a larger response to faces than to objects from different categories, or to scrambled faces, have been identified in neuroimaging studies. Depending on the statistical criteria used, the set of areas can be overextended or minimized, both at the local (size of areas) and global (number of areas) levels. Here…

MO-F-CAMPUS-T-01: Radiosurgery of Multiple Brain Metastases with Single-Isocenter VMAT: Optimizing Treatment Geometry to Reduce Normal Brain Dose

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

Wu, Q; Snyder, K; Liu, C

Purpose: To develop an optimization algorithm to reduce normal brain dose by optimizing couch and collimator angles for single isocenter multiple targets treatment of stereotactic radiosurgery. Methods: Three metastatic brain lesions were retrospectively planned using single-isocenter volumetric modulated arc therapy (VMAT). Three matrices were developed to calculate the projection of each lesion on Beam’s Eye View (BEV) by the rotating couch, collimator and gantry respectively. The island blocking problem was addressed by computing the total area of open space between any two lesions with shared MLC leaf pairs. The couch and collimator angles resulting in the smallest open areas weremore » the optimized angles for each treatment arc. Two treatment plans with and without couch and collimator angle optimization were developed using the same objective functions and to achieve 99% of each target volume receiving full prescription dose of 18Gy. Plan quality was evaluated by calculating each target’s Conformity Index (CI), Gradient Index (GI), and Homogeneity index (HI), and absolute volume of normal brain V8Gy, V10Gy, V12Gy, and V14Gy. Results: Using the new couch/collimator optimization strategy, dose to normal brain tissue was reduced substantially. V8, V10, V12, and V14 decreased by 2.3%, 3.6%, 3.5%, and 6%, respectively. There were no significant differences in the conformity index, gradient index, and homogeneity index between two treatment plans with and without the new optimization algorithm. Conclusion: We have developed a solution to the island blocking problem in delivering radiation to multiple brain metastases with shared isocenter. Significant reduction in dose to normal brain was achieved by using optimal couch and collimator angles that minimize total area of open space between any of the two lesions with shared MLC leaf pairs. This technique has been integrated into Eclipse treatment system using scripting API.« less

Differential investment in visual and olfactory brain areas reflects behavioural choices in hawk moths

PubMed Central

Stöckl, Anna; Heinze, Stanley; Charalabidis, Alice; el Jundi, Basil; Warrant, Eric; Kelber, Almut

2016-01-01

Nervous tissue is one of the most metabolically expensive animal tissues, thus evolutionary investments that result in enlarged brain regions should also result in improved behavioural performance. Indeed, large-scale comparative studies in vertebrates and invertebrates have successfully linked differences in brain anatomy to differences in ecology and behaviour, but their precision can be limited by the detail of the anatomical measurements, or by only measuring behaviour indirectly. Therefore, detailed case studies are valuable complements to these investigations, and have provided important evidence linking brain structure to function in a range of higher-order behavioural traits, such as foraging experience or aggressive behaviour. Here, we show that differences in the size of both lower and higher-order sensory brain areas reflect differences in the relative importance of these senses in the foraging choices of hawk moths, as suggested by previous anatomical work in Lepidopterans. To this end we combined anatomical and behavioural quantifications of the relative importance of vision and olfaction in two closely related hawk moth species. We conclude that differences in sensory brain volume in these hawk moths can indeed be interpreted as differences in the importance of these senses for the animal’s behaviour. PMID:27185464

Nano to micro delivery systems: targeting angiogenesis in brain tumors.

PubMed

Gilert, Ariel; Machluf, Marcelle

2010-10-08

Treating brain tumors using inhibitors of angiogenesis is extensively researched and tested in clinical trials. Although anti-angiogenic treatment holds a great potential for treating primary and secondary brain tumors, no clinical treatment is currently approved for brain tumor patients. One of the main hurdles in treating brain tumors is the blood brain barrier - a protective barrier of the brain, which prevents drugs from entering the brain parenchyma. As most therapeutics are excluded from the brain there is an urgent need to develop delivery platforms which will bypass such hurdles and enable the delivery of anti-angiogenic drugs into the tumor bed. Such delivery systems should be able to control release the drug or a combination of drugs at a therapeutic level for the desired time. In this mini-review we will discuss the latest improvements in nano and micro drug delivery platforms that were designed to deliver inhibitors of angiogenesis to the brain.

Nano to micro delivery systems: targeting angiogenesis in brain tumors

PubMed Central

2010-01-01

Treating brain tumors using inhibitors of angiogenesis is extensively researched and tested in clinical trials. Although anti-angiogenic treatment holds a great potential for treating primary and secondary brain tumors, no clinical treatment is currently approved for brain tumor patients. One of the main hurdles in treating brain tumors is the blood brain barrier - a protective barrier of the brain, which prevents drugs from entering the brain parenchyma. As most therapeutics are excluded from the brain there is an urgent need to develop delivery platforms which will bypass such hurdles and enable the delivery of anti-angiogenic drugs into the tumor bed. Such delivery systems should be able to control release the drug or a combination of drugs at a therapeutic level for the desired time. In this mini-review we will discuss the latest improvements in nano and micro drug delivery platforms that were designed to deliver inhibitors of angiogenesis to the brain. PMID:20932320

Common brain areas engaged in false belief reasoning and visual perspective taking: a meta-analysis of functional brain imaging studies.

PubMed

Schurz, Matthias; Aichhorn, Markus; Martin, Anna; Perner, Josef

2013-01-01

We performed a quantitative meta-analysis of functional neuroimaging studies to identify brain areas which are commonly engaged in social and visuo-spatial perspective taking. Specifically, we compared brain activation for visual-perspective taking to activation for false belief reasoning, which requires awareness of perspective to understand someone's mistaken belief about the world which contrasts with reality. In support of a previous account by Perner and Leekam (2008), our meta-analytic conjunction analysis found common activation for false belief reasoning and visual perspective taking in the left but not the right dorsal temporo-parietal junction (TPJ). This fits with the idea that the left dorsal TPJ is responsible for representing different perspectives in a domain-general fashion. Moreover, our conjunction analysis found activation in the precuneus and the left middle occipital gyrus close to the putative Extrastriate Body Area (EBA). The precuneus is linked to mental-imagery which may aid in the construction of a different perspective. The EBA may be engaged due to imagined body-transformations when another's viewpoint is adopted.

Common brain areas engaged in false belief reasoning and visual perspective taking: a meta-analysis of functional brain imaging studies

PubMed Central

Schurz, Matthias; Aichhorn, Markus; Martin, Anna; Perner, Josef

2013-01-01

We performed a quantitative meta-analysis of functional neuroimaging studies to identify brain areas which are commonly engaged in social and visuo-spatial perspective taking. Specifically, we compared brain activation for visual-perspective taking to activation for false belief reasoning, which requires awareness of perspective to understand someone's mistaken belief about the world which contrasts with reality. In support of a previous account by Perner and Leekam (2008), our meta-analytic conjunction analysis found common activation for false belief reasoning and visual perspective taking in the left but not the right dorsal temporo-parietal junction (TPJ). This fits with the idea that the left dorsal TPJ is responsible for representing different perspectives in a domain-general fashion. Moreover, our conjunction analysis found activation in the precuneus and the left middle occipital gyrus close to the putative Extrastriate Body Area (EBA). The precuneus is linked to mental-imagery which may aid in the construction of a different perspective. The EBA may be engaged due to imagined body-transformations when another's viewpoint is adopted. PMID:24198773

A dual-targeting liposome conjugated with transferrin and arginine-glycine-aspartic acid peptide for glioma-targeting therapy.

PubMed

Qin, Li; Wang, Cheng-Zheng; Fan, Hui-Jie; Zhang, Chong-Jian; Zhang, Heng-Wei; Lv, Min-Hao; Cui, Shu-DE

2014-11-01

The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy.

[Target chemotherapy of intestinal nematode infection in area with low endemicity].

PubMed

Zhang, Tao; Shen, Yi-ping; Liu, Ying; Yang, Wei-ping; Shao, Jing-ou; Ju, Shao-you; Dong, Kai; Xu, Ju-ling; Jiang, Ji-min

2002-01-01

To evaluate the control measures for intestinal nematodiasis in endemic area with low prevalence and intensity of infection. Target chemotherapy was carried out in high-risk population based on the epidemiological characteristics such as age and clinical findings. Albendazole and mebendazole were administered each 200 mg once daily every year for 3 or 5 years. Saturated brine floatation and Kato-Katz thick smear techniques were used for stool examination to evaluate the efficacy of treatment. Two hundred residents from each of the three investigation villages were selected for target chemotherapy once a year for three years. The prevalence of intestinal nematodes decreased from 6.2% in 1995 to 5.4% in 1996 and 3.2% in 1997, and remained at 2.3% after three years in 2000. One control village where only primary school students were treated once a year for 5 years, the prevalence of Ascaris and Trichuris infection also decreased from 1.4% and 4.2% in 1995 to 0.9% and 1.4% in 2000, respectively. The target chemotherapy on the predisposed population to hookworm infection showed that the prevalence in the population above 41 years old was declined from 19.4% to 10.9%. The target chemotherapy is an economical and effective approach for the control of intestinal nematode infection in endemic area with low prevalence and intensity of infection.

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

PubMed Central

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

2011-01-01

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. PMID:21382469

MRI Guided Brain Stimulation without the Use of a Neuronavigation System

PubMed Central

Vaghefi, Ehsan; Byblow, Winston D.; Stinear, Cathy M.; Thompson, Benjamin

2015-01-01

A key issue in the field of noninvasive brain stimulation (NIBS) is the accurate localization of scalp positions that correspond to targeted cortical areas. The current gold standard is to combine structural and functional brain imaging with a commercially available “neuronavigation” system. However, neuronavigation systems are not commonplace outside of specialized research environments. Here we describe a technique that allows for the use of participant-specific functional and structural MRI data to guide NIBS without a neuronavigation system. Surface mesh representations of the head were generated using Brain Voyager and vectors linking key anatomical landmarks were drawn on the mesh. Our technique was then used to calculate the precise distances on the scalp corresponding to these vectors. These calculations were verified using actual measurements of the head and the technique was used to identify a scalp position corresponding to a brain area localized using functional MRI. PMID:26413537

Target Surface Area Effects on Hot Electron Dynamics from High Intensity Laser-Plasma Interactions

DTIC Science & Technology

2016-08-19

New J. Phys. 18 (2016) 063020 doi:10.1088/1367-2630/18/6/063020 PAPER Target surface area effects on hot electron dynamics from high intensity laser ...Science, University ofMichigan, AnnArbor,MI 48109-2099, USA E-mail: czulick@umich.edu Keywords: laser -plasma,mass-limited, fast electrons, sheath...field Abstract Reduced surface area targets were studied using an ultra-high intensity femtosecond laser in order to determine the effect of electron

7 CFR 3402.4 - Food and agricultural sciences areas targeted for National Needs Graduate and Postdoctoral...

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 15 2010-01-01 2010-01-01 false Food and agricultural sciences areas targeted for..., AND EXTENSION SERVICE, DEPARTMENT OF AGRICULTURE FOOD AND AGRICULTURAL SCIENCES NATIONAL NEEDS... sciences areas targeted for National Needs Graduate and Postdoctoral Fellowship Grants Program support...

Purines: forgotten mediators in traumatic brain injury.

PubMed

Jackson, Edwin K; Boison, Detlev; Schwarzschild, Michael A; Kochanek, Patrick M

2016-04-01

Recently, the topic of traumatic brain injury has gained attention in both the scientific community and lay press. Similarly, there have been exciting developments on multiple fronts in the area of neurochemistry specifically related to purine biology that are relevant to both neuroprotection and neurodegeneration. At the 2105 meeting of the National Neurotrauma Society, a session sponsored by the International Society for Neurochemistry featured three experts in the field of purine biology who discussed new developments that are germane to both the pathomechanisms of secondary injury and development of therapies for traumatic brain injury. This included presentations by Drs. Edwin Jackson on the novel 2',3'-cAMP pathway in neuroprotection, Detlev Boison on adenosine in post-traumatic seizures and epilepsy, and Michael Schwarzschild on the potential of urate to treat central nervous system injury. This mini review summarizes the important findings in these three areas and outlines future directions for the development of new purine-related therapies for traumatic brain injury and other forms of central nervous system injury. In this review, novel therapies based on three emerging areas of adenosine-related pathobiology in traumatic brain injury (TBI) were proposed, namely, therapies targeting 1) the 2',3'-cyclic adenosine monophosphate (cAMP) pathway, 2) adenosine deficiency after TBI, and 3) augmentation of urate after TBI. © 2016 International Society for Neurochemistry.

Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases

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

Atalar, Banu; Modlin, Leslie A.; Choi, Clara Y.H.

Purpose: We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. Methods and Materials: We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), andmore » histology (lung, colon, breast, melanoma, gynecologic, other). Results: With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). Conclusions: In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.« less

Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control

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

Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.

2012-10-01

Purpose: Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity. Patients and Methods: We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competingmore » risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests. Results: The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients. Conclusion: Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin.« less

Efficacy of NGR peptide-modified PEGylated quantum dots for crossing the blood-brain barrier and targeted fluorescence imaging of glioma and tumor vasculature.

PubMed

Huang, Ning; Cheng, Si; Zhang, Xiang; Tian, Qi; Pi, Jiangli; Tang, Jun; Huang, Qing; Wang, Feng; Chen, Jin; Xie, Zongyi; Xu, Zhongye; Chen, Weifu; Zheng, Huzhi; Cheng, Yuan

2017-01-01

Delivery of imaging agents to brain glioma is challenging because the blood-brain barrier (BBB) functions as a physiological checkpoint guarding the central nervous system from circulating large molecules. Moreover, the ability of existing probes to target glioma has been insufficient and needs to be improved. In present study, PEG-based long circulation, CdSe/ZnS quantum dots (QDs)-based nanoscale and fluorescence, asparagines-glycine-arginine peptides (NGR)-based specific CD13 recognition were integrated to design and synthesize a novel nanoprobe by conjugating biotinylated NGR peptides to avidin-PEG-coated QDs. Our data showed that the NGR-PEG-QDs were nanoscale with less than 100 nm and were stable in various pH (4.0~8.0). These nanomaterials with non-toxic concentrations could cross the BBB and target CD13-overexpressing glioma and tumor vasculature in vitro and in vivo, contributing to fluorescence imaging of this brain malignancy. These achievements allowed groundbreaking technological advances in targeted fluorescence imaging for the diagnosis and surgical removal of glioma, facilitating potential transformation toward clinical nanomedicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Current and emerging treatments for brain metastases.

PubMed

Lin, Jenny; Jandial, Rahul; Nesbit, Amanda; Badie, Behnam; Chen, Mike

2015-04-01

Brain metastasis in patients with cancer can be indicative of multisystem spread or lead to neurological demise if not locally controlled, and is associated with poor survival and high morbidity. Compared with metastasis to other areas of the body, brain metastasis possesses a unique biology that confers high resistance to systemic therapies. This phenomenon has been historically attributed to the inability of chemotherapeutic agents to pass through the blood-brain barrier. Recent studies challenge this premise, revealing other potentially targetable mechanism(s). Therapies that exploit recent advances in the understanding of brain metastasis are still in early stages of development. Encouragingly, and discovered by happenstance, some molecularly targeted drugs already appear to have efficacy against certain tumors and accompanying cerebral edema. In the meantime, conventional treatment modalities such as surgery and radiation have iteratively reached new levels of refinement. However, these achievements are somewhat muted by the emergence of magnetic resonance (MR)-guided laser interstitial thermal therapy, a minimally invasive neuroablative technique. On the horizon, MR-guided focused ultrasound surgery is similarly intriguing. Even in the absence of further advances, local control is frequently achieved with state-of-the-art therapies. Dramatic improvements will likely require sophisticated approaches that account for the particular effects of the microenvironment of the central nervous system on metastasis.

Brain Responses to High-Protein Diets12

PubMed Central

Journel, Marion; Chaumontet, Catherine; Darcel, Nicolas; Fromentin, Gilles; Tomé, Daniel

2012-01-01

Proteins are suspected to have a greater satiating effect than the other 2 macronutrients. After protein consumption, peptide hormones released from the gastrointestinal tract (mainly anorexigenic gut peptides such as cholecystokinin, glucagon peptide 1, and peptide YY) communicate information about the energy status to the brain. These hormones and vagal afferents control food intake by acting on brain regions involved in energy homeostasis such as the brainstem and the hypothalamus. In fact, a high-protein diet leads to greater activation than a normal-protein diet in the nucleus tractus solitarius and in the arcuate nucleus. More specifically, neural mechanisms triggered particularly by leucine consumption involve 2 cellular energy sensors: the mammalian target of rapamycin and AMP-activated protein kinase. In addition, reward and motivation aspects of eating behavior, controlled mainly by neurons present in limbic regions, play an important role in the reduced hedonic response of a high-protein diet. This review examines how metabolic signals emanating from the gastrointestinal tract after protein ingestion target the brain to control feeding, energy expenditure, and hormones. Understanding the functional roles of brain areas involved in the satiating effect of proteins and their interactions will demonstrate how homeostasis and reward are integrated with the signals from peripheral organs after protein consumption. PMID:22585905

Image-based in vivo assessment of targeting accuracy of stereotactic brain surgery in experimental rodent models

NASA Astrophysics Data System (ADS)

Rangarajan, Janaki Raman; Vande Velde, Greetje; van Gent, Friso; de Vloo, Philippe; Dresselaers, Tom; Depypere, Maarten; van Kuyck, Kris; Nuttin, Bart; Himmelreich, Uwe; Maes, Frederik

2016-11-01

Stereotactic neurosurgery is used in pre-clinical research of neurological and psychiatric disorders in experimental rat and mouse models to engraft a needle or electrode at a pre-defined location in the brain. However, inaccurate targeting may confound the results of such experiments. In contrast to the clinical practice, inaccurate targeting in rodents remains usually unnoticed until assessed by ex vivo end-point histology. We here propose a workflow for in vivo assessment of stereotactic targeting accuracy in small animal studies based on multi-modal post-operative imaging. The surgical trajectory in each individual animal is reconstructed in 3D from the physical implant imaged in post-operative CT and/or its trace as visible in post-operative MRI. By co-registering post-operative images of individual animals to a common stereotaxic template, targeting accuracy is quantified. Two commonly used neuromodulation regions were used as targets. Target localization errors showed not only variability, but also inaccuracy in targeting. Only about 30% of electrodes were within the subnucleus structure that was targeted and a-specific adverse effects were also noted. Shifting from invasive/subjective 2D histology towards objective in vivo 3D imaging-based assessment of targeting accuracy may benefit a more effective use of the experimental data by excluding off-target cases early in the study.

Partially Overlapping Brain Networks for Singing and Cello Playing.

PubMed

Segado, Melanie; Hollinger, Avrum; Thibodeau, Joseph; Penhune, Virginia; Zatorre, Robert J

2018-01-01

This research uses an MR-Compatible cello to compare functional brain activation during singing and cello playing within the same individuals to determine the extent to which arbitrary auditory-motor associations, like those required to play the cello, co-opt functional brain networks that evolved for singing. Musical instrument playing and singing both require highly specific associations between sounds and movements. Because these are both used to produce musical sounds, it is often assumed in the literature that their neural underpinnings are highly similar. However, singing is an evolutionarily old human trait, and the auditory-motor associations used for singing are also used for speech and non-speech vocalizations. This sets it apart from the arbitrary auditory-motor associations required to play musical instruments. The pitch range of the cello is similar to that of the human voice, but cello playing is completely independent of the vocal apparatus, and can therefore be used to dissociate the auditory-vocal network from that of the auditory-motor network. While in the MR-Scanner, 11 expert cellists listened to and subsequently produced individual tones either by singing or cello playing. All participants were able to sing and play the target tones in tune (<50C deviation from target). We found that brain activity during cello playing directly overlaps with brain activity during singing in many areas within the auditory-vocal network. These include primary motor, dorsal pre-motor, and supplementary motor cortices (M1, dPMC, SMA),the primary and periprimary auditory cortices within the superior temporal gyrus (STG) including Heschl's gyrus, anterior insula (aINS), anterior cingulate cortex (ACC), and intraparietal sulcus (IPS), and Cerebellum but, notably, exclude the periaqueductal gray (PAG) and basal ganglia (Putamen). Second, we found that activity within the overlapping areas is positively correlated with, and therefore likely contributing to, both

Partially Overlapping Brain Networks for Singing and Cello Playing

PubMed Central

Segado, Melanie; Hollinger, Avrum; Thibodeau, Joseph; Penhune, Virginia; Zatorre, Robert J.

2018-01-01

This research uses an MR-Compatible cello to compare functional brain activation during singing and cello playing within the same individuals to determine the extent to which arbitrary auditory-motor associations, like those required to play the cello, co-opt functional brain networks that evolved for singing. Musical instrument playing and singing both require highly specific associations between sounds and movements. Because these are both used to produce musical sounds, it is often assumed in the literature that their neural underpinnings are highly similar. However, singing is an evolutionarily old human trait, and the auditory-motor associations used for singing are also used for speech and non-speech vocalizations. This sets it apart from the arbitrary auditory-motor associations required to play musical instruments. The pitch range of the cello is similar to that of the human voice, but cello playing is completely independent of the vocal apparatus, and can therefore be used to dissociate the auditory-vocal network from that of the auditory-motor network. While in the MR-Scanner, 11 expert cellists listened to and subsequently produced individual tones either by singing or cello playing. All participants were able to sing and play the target tones in tune (<50C deviation from target). We found that brain activity during cello playing directly overlaps with brain activity during singing in many areas within the auditory-vocal network. These include primary motor, dorsal pre-motor, and supplementary motor cortices (M1, dPMC, SMA),the primary and periprimary auditory cortices within the superior temporal gyrus (STG) including Heschl's gyrus, anterior insula (aINS), anterior cingulate cortex (ACC), and intraparietal sulcus (IPS), and Cerebellum but, notably, exclude the periaqueductal gray (PAG) and basal ganglia (Putamen). Second, we found that activity within the overlapping areas is positively correlated with, and therefore likely contributing to, both

Urban-area extraction from polarimetric SAR image using combination of target decomposition and orientation angle

NASA Astrophysics Data System (ADS)

Zou, Bin; Lu, Da; Wu, Zhilu; Qiao, Zhijun G.

2016-05-01

The results of model-based target decomposition are the main features used to discriminate urban and non-urban area in polarimetric synthetic aperture radar (PolSAR) application. Traditional urban-area extraction methods based on modelbased target decomposition usually misclassified ground-trunk structure as urban-area or misclassified rotated urbanarea as forest. This paper introduces another feature named orientation angle to improve urban-area extraction scheme for the accurate mapping in urban by PolSAR image. The proposed method takes randomness of orientation angle into account for restriction of urban area first and, subsequently, implements rotation angle to improve results that oriented urban areas are recognized as double-bounce objects from volume scattering. ESAR L-band PolSAR data of the Oberpfaffenhofen Test Site Area was used to validate the proposed algorithm.

Common and distinct neural targets of treatment: changing brain function in substance addiction

PubMed Central

Konova, Anna B.; Moeller, Scott J.; Goldstein, Rita Z.

2013-01-01

Neuroimaging offers an opportunity to examine the neurobiological effects of therapeutic interventions for human drug addiction. Using activation likelihood estimation, the aim of the current meta-analysis was to quantitatively summarize functional neuroimaging studies of pharmacological and cognitive-based interventions for drug addiction, with an emphasis on their common and distinct neural targets. More exploratory analyses also contrasted subgroups of studies based on specific study and sample characteristics. The ventral striatum, a region implicated in reward, motivation, and craving, and the inferior frontal gyrus and orbitofrontal cortex, regions involved in inhibitory control goal-directed behavior, were identified as common targets of pharmacological and cognitive-based interventions; these regions were observed when the analysis was limited to only studies that used established or efficacious interventions, and across imaging paradigms and types of addictions. Consistent with theoretical models, cognitive-based interventions were additionally more likely to activate the anterior cingulate cortex, middle frontal gyrus, and precuneus, implicated in self-referential processing, cognitive control, and attention. These results suggest that therapeutic interventions for addiction may target the brain structures that are altered across addictions and identify potential neurobiological mechanisms by which the tandem use of pharmacological and cognitive-based interventions may yield synergistic or complementary effects. These findings could inform the selection of novel functional targets in future treatment development for this difficult-to-treat disorder. PMID:24140399

Deep Brain Stimulation: A Paradigm Shifting Approach to Treat Parkinson's Disease.

PubMed

Hickey, Patrick; Stacy, Mark

2016-01-01

Parkinson disease (PD) is a chronic and progressive movement disorder classically characterized by slowed voluntary movements, resting tremor, muscle rigidity, and impaired gait and balance. Medical treatment is highly successful early on, though the majority of people experience significant complications in later stages. In advanced PD, when medications no longer adequately control motor symptoms, deep brain stimulation (DBS) offers a powerful therapeutic alternative. DBS involves the surgical implantation of one or more electrodes into specific areas of the brain, which modulate or disrupt abnormal patterns of neural signaling within the targeted region. Outcomes are often dramatic following DBS, with improvements in motor function and reductions motor complications having been repeatedly demonstrated. Given such robust responses, emerging indications for DBS are being investigated. In parallel with expansions of therapeutic scope, advancements within the areas of neurosurgical technique and the precision of stimulation delivery have recently broadened as well. This review focuses on the revolutionary addition of DBS to the therapeutic armamentarium for PD, and summarizes the technological advancements in the areas of neuroimaging and biomedical engineering intended to improve targeting, programming, and overall management.

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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effective Connectivity Analysis of the Brain Network in Drivers during Actual Driving Using Near-Infrared Spectroscopy

PubMed Central

Liu, Zhian; Zhang, Ming; Xu, Gongcheng; Huo, Congcong; Tan, Qitao; Li, Zengyong; Yuan, Quan

2017-01-01

Driving a vehicle is a complex activity that requires high-level brain functions. This study aimed to assess the change in effective connectivity (EC) between the prefrontal cortex (PFC), motor-related areas (MA) and vision-related areas (VA) in the brain network among the resting, simple-driving and car-following states. Twelve young male right-handed adults were recruited to participate in an actual driving experiment. The brain delta [HbO2] signals were continuously recorded using functional near infrared spectroscopy (fNIRS) instruments. The conditional Granger causality (GC) analysis, which is a data-driven method that can explore the causal interactions among different brain areas, was performed to evaluate the EC. The results demonstrated that the hemodynamic activity level of the brain increased with an increase in the cognitive workload. The connection strength among PFC, MA and VA increased from the resting state to the simple-driving state, whereas the connection strength relatively decreased during the car-following task. The PFC in EC appeared as the causal target, while the MA and VA appeared as the causal sources. However, l-MA turned into causal targets with the subtask of car-following. These findings indicate that the hemodynamic activity level of the cerebral cortex increases linearly with increasing cognitive workload. The EC of the brain network can be strengthened by a cognitive workload, but also can be weakened by a superfluous cognitive workload such as driving with subtasks. PMID:29163083

[Alterations of glial fibrillary acidic protein in rat brain after gamma knife irradiation].

PubMed

Ma, Z M; Jiang, B; Ma, J R

2001-08-28

To study glial fibrillary acidic protein (GFAP) immunoreactivity in different time and water content of the rat brain treated with gamma knife radiotherapy and to understand the alteration course of the brain lesion after a single high dose radiosurgical treatment. In the brains of the normal rats were irradiated by gamma knife with 160 Gy-high dose. The irradiated rats were then killed on the 1st day, 7th day, 14th day, and 28th day after radiotherapy, respectively. The positive cells of GFAP in brain tissue were detected by immunostaining; the water content of the brain tissue was measured by microgravimetry. The histological study of the irradiated brain tissue was performed with H.E. and examined under light microscope. The numbers of GFAP-positive astrocytes began to increase on the 1st day after gamma knife irradiation. It was enlarged markedly in the number and size of GFAP-stained astrocytes over the irradiated areas. Up to the 28th day, circumscribed necrosis foci (4 mm in diameter) was seen in the central area of the target. In the brain tissue around the necrosis, GFAP-positive astrocytes significantly increased (P < 0.01, compared with the control group). The swelling of cells in irradiated region was observed on the 1st day; after irradiation endothelial cells degenerated and red blood cells escaped from blood vessel on the 7th day; leakage of Evans blue dye was observed in the target region on the 14th day. There was a significant decrease of specific gravity in the irradiated brain tissue the 14th and 28th day after irradiation. The results suggest that GFAP can be used as a marker for the radiation-induced brain injury. The brain edema and disruption of brain-blood barrier can be occurred during the acute stage after irradiation.

7 CFR 3402.4 - Food and agricultural sciences areas targeted for National Needs Graduate and Postdoctoral...

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 15 2014-01-01 2014-01-01 false Food and agricultural sciences areas targeted for... AGRICULTURE FOOD AND AGRICULTURAL SCIENCES NATIONAL NEEDS GRADUATE AND POSTGRADUATE FELLOWSHIP GRANTS PROGRAM Program Description § 3402.4 Food and agricultural sciences areas targeted for National Needs Graduate and...

7 CFR 3402.4 - Food and agricultural sciences areas targeted for National Needs Graduate and Postdoctoral...

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 15 2013-01-01 2013-01-01 false Food and agricultural sciences areas targeted for... AGRICULTURE FOOD AND AGRICULTURAL SCIENCES NATIONAL NEEDS GRADUATE AND POSTGRADUATE FELLOWSHIP GRANTS PROGRAM Program Description § 3402.4 Food and agricultural sciences areas targeted for National Needs Graduate and...

7 CFR 3402.4 - Food and agricultural sciences areas targeted for National Needs Graduate and Postdoctoral...

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 15 2011-01-01 2011-01-01 false Food and agricultural sciences areas targeted for... AGRICULTURE FOOD AND AGRICULTURAL SCIENCES NATIONAL NEEDS GRADUATE AND POSTGRADUATE FELLOWSHIP GRANTS PROGRAM Program Description § 3402.4 Food and agricultural sciences areas targeted for National Needs Graduate and...

7 CFR 3402.4 - Food and agricultural sciences areas targeted for National Needs Graduate and Postdoctoral...

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 15 2012-01-01 2012-01-01 false Food and agricultural sciences areas targeted for... AGRICULTURE FOOD AND AGRICULTURAL SCIENCES NATIONAL NEEDS GRADUATE AND POSTGRADUATE FELLOWSHIP GRANTS PROGRAM Program Description § 3402.4 Food and agricultural sciences areas targeted for National Needs Graduate and...

Brain Distribution of a Novel MEK Inhibitor E6201: Implications in the Treatment of Melanoma Brain Metastases.

PubMed

Gampa, Gautham; Kim, Minjee; Cook-Rostie, Nicholas; Laramy, Janice K; Sarkaria, Jann N; Paradiso, Linda; DePalatis, Louis; Elmquist, William F

2018-05-01

Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and mitogen-activated protein/extracellular signal-regulated kinase (MEK) has been identified to be an important target. E6201 is a potent synthetic small-molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the blood-brain barrier on the central nervous system (CNS) exposure of E6201. In vitro studies utilizing transfected Madin-Darby canine kidney II (MDCKII) cells indicate that E6201 is not a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). In vivo studies also suggest a minimal involvement of P-gp and Bcrp in E6201's brain distribution. The total concentrations in brain were higher than in plasma, resulting in a brain-to-plasma AUC ratio (Kp) of 2.66 in wild-type mice. The brain distribution was modestly enhanced in Mdr1a/b -/- , Bcrp1 -/- , and Mdr1a/b -/- Bcrp1 -/- knockout mice. The nonspecific binding of E6201 was higher in brain compared with plasma. However, free-drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro half-maximal inhibitory concentration (IC 50 ) values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The brain distribution characteristics of E6201 make it an attractive targeted agent for clinical testing in MBM, glioblastoma, and other CNS tumors that may be effectively targeted with inhibition of MEK signaling. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Immunotherapy targeting immune check-point(s) in brain metastases.

PubMed

Di Giacomo, Anna Maria; Valente, Monica; Covre, Alessia; Danielli, Riccardo; Maio, Michele

2017-08-01

Immunotherapy with monoclonal antibodies (mAb) directed to different immune check-point(s) is showing a significant clinical impact in a growing number of human tumors of different histotype, both in terms of disease response and long-term survival patients. In this rapidly changing scenario, treatment of brain metastases remains an high unmeet medical need, and the efficacy of immunotherapy in these highly dismal clinical setting remains to be largely demonstrated. Nevertheless, up-coming observations are beginning to suggest a clinical potential of cancer immunotherapy also in brain metastases, regardless the underlying tumor histotype. These observations remain to be validated in larger clinical trials eventually designed also to address the efficacy of therapeutic mAb to immune check-point(s) within multimodality therapies for brain metastases. Noteworthy, the initial proofs of efficacy on immunotherapy in central nervous system metastases are already fostering clinical trials investigating its therapeutic potential also in primary brain tumors. We here review ongoing immunotherapeutic approaches to brain metastases and primary brain tumors, and the foreseeable strategies to overcome their main biologic hurdles and clinical challenges. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Controlling feeding behavior by chemical or gene-directed targeting in the brain: what's so spatial about our methods?

PubMed Central

Khan, Arshad M.

2013-01-01

Intracranial chemical injection (ICI) methods have been used to identify the locations in the brain where feeding behavior can be controlled acutely. Scientists conducting ICI studies often document their injection site locations, thereby leaving kernels of valuable location data for others to use to further characterize feeding control circuits. Unfortunately, this rich dataset has not yet been formally contextualized with other published neuroanatomical data. In particular, axonal tracing studies have delineated several neural circuits originating in the same areas where ICI injection feeding-control sites have been documented, but it remains unclear whether these circuits participate in feeding control. Comparing injection sites with other types of location data would require careful anatomical registration between the datasets. Here, a conceptual framework is presented for how such anatomical registration efforts can be performed. For example, by using a simple atlas alignment tool, a hypothalamic locus sensitive to the orexigenic effects of neuropeptide Y (NPY) can be aligned accurately with the locations of neurons labeled by anterograde tracers or those known to express NPY receptors or feeding-related peptides. This approach can also be applied to those intracranial “gene-directed” injection (IGI) methods (e.g., site-specific recombinase methods, RNA expression or interference, optogenetics, and pharmacosynthetics) that involve viral injections to targeted neuronal populations. Spatial alignment efforts can be accelerated if location data from ICI/IGI methods are mapped to stereotaxic brain atlases to allow powerful neuroinformatics tools to overlay different types of data in the same reference space. Atlas-based mapping will be critical for community-based sharing of location data for feeding control circuits, and will accelerate our understanding of structure-function relationships in the brain for mammalian models of obesity and metabolic disorders

Mapping the areas sensitive to long-term endotoxin tolerance in the rat brain: a c-fos mRNA study.

PubMed

Vallès, Astrid; Martí, Octavi; Armario, Antonio

2005-06-01

We have recently found that a single endotoxin administration to rats reduced the hypothalamic-pituitary-adrenal response to another endotoxin administration 4 weeks later, which may be an example of the well-known phenomenon of endotoxin tolerance. However, the time elapsed between the two doses of endotoxin was long enough to consider the above results as an example of late tolerance, whose mechanisms are poorly characterized. To know if the brain plays a role in this phenomenon and to characterize the putative areas involved, we compared the c-fos mRNA response after a final dose of endotoxin in animals given vehicle or endotoxin 4 weeks before. Endotoxin caused a widespread induction of c-fos mRNA in the brain, similar to that previously reported by other laboratories. Whereas most of the brain areas were not sensitive to the previous experience with endotoxin, a few showed a reduced response in endotoxin-pretreated rats: the parvocellular and magnocellular regions of the paraventricular hypothalamic nucleus, the central amygdala, the lateral division of the bed nucleus and the locus coeruleus. We hypothesize that late tolerance to endotoxin may involve plastic changes in the brain, likely to be located in the central amygdala. The reduced activation of the central amygdala in rats previously treated with endotoxin may, in turn, reduce the activation of other brain areas, including the hypothalamic paraventicular nucleus.

Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies.

PubMed

Vosoughi, Elham; Lee, Jee Min; Miller, James R; Nosrati, Mehdi; Minor, David R; Abendroth, Roy; Lee, John W; Andrews, Brian T; Leng, Lewis Z; Wu, Max; Leong, Stanley P; Kashani-Sabet, Mohammed; Kim, Kevin B

2018-04-27

Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.

Maintaining older brain functionality: A targeted review.

PubMed

Ballesteros, Soledad; Kraft, Eduard; Santana, Silvina; Tziraki, Chariklia

2015-08-01

The unprecedented growth in the number of older adults in our society is accompanied by the exponential increase in the number of elderly people who will suffer cognitive decline and dementia in the next decades. This will create an enormous cost for governments, families and individuals. Brain plasticity and its role in brain adaptation to the process of aging is influenced by other changes as a result of co-morbidities, environmental factors, personality traits (psychosocial variables) and genetic and epigenetic factors. This review summarizes recent findings obtained mostly from interventional studies that aim to prevent and/or delay age-related cognitive decline in healthy adults. There are a multitude of such studies. In this paper, we focused our review on physical activity, computerized cognitive training and social enhancement interventions on improving cognition, physical health, independent living and wellbeing of older adults. The methodological limitations of some of these studies, and the need for new multi-domain synergistic interventions, based on current advances in neuroscience and social-brain theories, are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome.

PubMed

Guerra, Daniel A P; Paiva, Ana E; Sena, Isadora F G; Azevedo, Patrick O; Silva, Walison N; Mintz, Akiva; Birbrair, Alexander

2018-05-14

Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.

Development and characterization of niosomal formulations of doxorubicin aimed at brain targeting.

PubMed

Bragagni, Marco; Mennini, Natascia; Ghelardini, Carla; Mura, Paola

2012-01-01

The aim of the present work was the development and characterization of a niosomal formulation functionalized with the glucose-derivative N-palmitoylglucosamine (NPG) to obtain a potential brain targeted delivery system for the anticancer agent doxorubicin. Five different methods have been examined for vesicle preparation. Light scattering and transmission electron microscopy were used for vesicle characterization, in terms of mean size, homogeneity and Zeta potential, and selection of the best composition and preparation conditions for developing NPG-functionalized niosomes. Drug entrapment efficiency was determined after separation of loaded from unloaded drug by size exclusion chromatography or dialysis. Preliminary in vivo studies were performed on rats, injected i.v. with 12 mg/kg of doxorubicin as commercial solution (Ebewe, 2 mg/mL) or NPG-niosomal formulation. Drug amounts in the blood and in the major organs of the animals, sacrificed 60 min post injection, were determined by HPLC. The selected formulation consisted in Span:cholesterol:Solulan:NPG (50:40:10:10 mol ratio) vesicles obtained by thin-layer evaporation, leading to homogeneous vesicles of less than 200 nm diameter. This formulation was used for preparation of NPG-niosomes loaded with doxorubicin (mean size 161±4 nm, encapsulation efficacy 57.8±1.8%). No significant changes (P>0.05) in vesicle dimensions, Zeta potential or entrapment efficiency were observed after six months storage at room temperature, indicative of good stability. I.v. administration to rats of the NPG-niosomal formulation allowed for reducing drug accumulation in the heart and keeping it longer in the blood circulation with respect to the commercial formulation. Moreover, a doxorubicin brain concentration of 2.9±0.4 μg/g was achieved after 60 min, while the commercial solution yielded undetectable drug brain concentrations (<0.1 μg/g). The developed NPG-niosomal formulation gave rise to stable, nano-sized vesicles, able

Selective targeting of a TNFR decoy receptor pharmaceutical to the primate brain as a receptor-specific IgG fusion protein.

PubMed

Boado, Ruben J; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang; Zhou, Qing-Hui; Pardridge, William M

2010-03-01

Decoy receptors, such as the human tumor necrosis factor receptor (TNFR), are potential new therapies for brain disorders. However, decoy receptors are large molecule drugs that are not transported across the blood-brain barrier (BBB). To enable BBB transport of a TNFR decoy receptor, the human TNFR-II extracellular domain was re-engineered as a fusion protein with a chimeric monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the TNFR therapeutic decoy receptor across the BBB. The HIRMAb-TNFR fusion protein was expressed in stably transfected CHO cells, and was analyzed with electrophoresis, Western blotting, size exclusion chromatography, and binding assays for the HIR and TNFalpha. The HIRMAb-TNFR fusion protein was radio-labeled by trititation, in parallel with the radio-iodination of recombinant TNFR:Fc fusion protein, and the proteins were co-injected in the adult Rhesus monkey. The TNFR:Fc fusion protein did not cross the primate BBB in vivo, but the uptake of the HIRMAb-TNFR fusion protein was high and 3% of the injected dose was taken up by the primate brain. The TNFR was selectively targeted to brain, relative to peripheral organs, following fusion to the HIRMAb. This study demonstrates that decoy receptors may be re-engineered as IgG fusion proteins with a BBB molecular Trojan horse that selectively targets the brain, and enables penetration of the BBB in vivo. IgG-decoy receptor fusion proteins represent a new class of human neurotherapeutics. Copyright 2010 Elsevier B.V. All rights reserved.

Evaluation of a modified Fitts law brain-computer interface target acquisition task in able and motor disabled individuals

NASA Astrophysics Data System (ADS)

Felton, E. A.; Radwin, R. G.; Wilson, J. A.; Williams, J. C.

2009-10-01

A brain-computer interface (BCI) is a communication system that takes recorded brain signals and translates them into real-time actions, in this case movement of a cursor on a computer screen. This work applied Fitts' law to the evaluation of performance on a target acquisition task during sensorimotor rhythm-based BCI training. Fitts' law, which has been used as a predictor of movement time in studies of human movement, was used here to determine the information transfer rate, which was based on target acquisition time and target difficulty. The information transfer rate was used to make comparisons between control modalities and subject groups on the same task. Data were analyzed from eight able-bodied and five motor disabled participants who wore an electrode cap that recorded and translated their electroencephalogram (EEG) signals into computer cursor movements. Direct comparisons were made between able-bodied and disabled subjects, and between EEG and joystick cursor control in able-bodied subjects. Fitts' law aptly described the relationship between movement time and index of difficulty for each task movement direction when evaluated separately and averaged together. This study showed that Fitts' law can be successfully applied to computer cursor movement controlled by neural signals.

33 CFR 334.60 - Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Harbor, Mass.; naval aircraft bombing target area. 334.60 Section 334.60 Navigation and Navigable Waters... REGULATIONS § 334.60 Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area. (a... bombing target hulk James Longstreet in Cape Cod Bay at latitude 41°49′46″, longitude 70°02′54″. (b) The...

33 CFR 334.60 - Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Harbor, Mass.; naval aircraft bombing target area. 334.60 Section 334.60 Navigation and Navigable Waters... REGULATIONS § 334.60 Cape Cod Bay south of Wellfleet Harbor, Mass.; naval aircraft bombing target area. (a... bombing target hulk James Longstreet in Cape Cod Bay at latitude 41°49′46″, longitude 70°02′54″. (b) The...

Mesophotic depths as refuge areas for fishery-targeted species on coral reefs

NASA Astrophysics Data System (ADS)

Lindfield, Steven J.; Harvey, Euan S.; Halford, Andrew R.; McIlwain, Jennifer L.

2016-03-01

Coral reefs are subjected to unprecedented levels of disturbance with population growth and climate change combining to reduce standing coral cover and stocks of reef fishes. Most of the damage is concentrated in shallow waters (<30 m deep) where humans can comfortably operate and where physical disturbances are most disruptive to marine organisms. Yet coral reefs can extend to depths exceeding 100 m, potentially offering refuge from the threats facing shallower reefs. We deployed baited remote underwater stereo-video systems (stereo-BRUVs) at depths of 10-90 m around the southern Mariana Islands to investigate whether fish species targeted by fishing in the shallows may be accruing benefits from being at depth. We show that biomass, abundance and species richness of fishery-targeted species increased from shallow reef areas to a depth of 60 m, whereas at greater depths, a lack of live coral habitat corresponded to lower numbers of fish. The majority of targeted species were found to have distributions that ranged from shallow depths (10 m) to depths of at least 70 m, emphasising that habitat, not depth, is the limiting factor in their vertical distribution. While the gradient of abundance and biomass versus depth was steepest for predatory species, the first species usually targeted by fishing, we also found that fishery-targeted herbivores prevailed in similar biomass and species richness to 60 m. Compared to shallow marine protected areas, there was clearly greater biomass of fishery-targeted species accrued in mesophotic depths. Particularly some species typically harvested by depth-limited fishing methods (e.g., spearfishing), such as the endangered humphead wrasse Cheilinus undulatus, were found in greater abundance on deeper reefs. We conclude that mesophotic depths provide essential fish habitat and refuge for fishery-targeted species, representing crucial zones for fishery management and research into the resilience of disturbed coral reef ecosystems.

Ground target geolocation based on digital elevation model for airborne wide-area reconnaissance system

NASA Astrophysics Data System (ADS)

Qiao, Chuan; Ding, Yalin; Xu, Yongsen; Xiu, Jihong

2018-01-01

To obtain the geographical position of the ground target accurately, a geolocation algorithm based on the digital elevation model (DEM) is developed for an airborne wide-area reconnaissance system. According to the platform position and attitude information measured by the airborne position and orientation system and the gimbal angles information from the encoder, the line-of-sight pointing vector in the Earth-centered Earth-fixed coordinate frame is solved by the homogeneous coordinate transformation. The target longitude and latitude can be solved with the elliptical Earth model and the global DEM. The influences of the systematic error and measurement error on ground target geolocation calculation accuracy are analyzed by the Monte Carlo method. The simulation results show that this algorithm can improve the geolocation accuracy of ground target in rough terrain area obviously. The geolocation accuracy of moving ground target can be improved by moving average filtering (MAF). The validity of the geolocation algorithm is verified by the flight test in which the plane flies at a geodetic height of 15,000 m and the outer gimbal angle is <47°. The geolocation root mean square error of the target trajectory is <45 and <7 m after MAF.

Structural brain differences in emotional processing and regulation areas between male batterers and other criminals: A preliminary study.

PubMed

Verdejo-Román, Juan; Bueso-Izquierdo, Natalia; Daugherty, Julia C; Pérez-García, Miguel; Hidalgo-Ruzzante, Natalia

2018-05-31

Poor emotion processing is thought to influence violent behaviors among male batterers in abusive relationships. Nevertheless, little is known about the neural mechanisms of emotion processing in this population. With the objective of better understanding brain structure and its relation to emotion processing in male batterers, the present study compares the cortical grey matter thickness of male batterers to that of other criminals in brain areas related to emotion. Differences among these brain areas were also compared to an emotional perception task. An MRI study and an emotional perception assessment was conducted with 21 male batterers and 20 men convicted of crimes other than Intimate Partner Violence (IPV). Results demonstrated that batterers' had significantly thinner cortices in prefrontal (orbitofrontal), midline (anterior and posterior cingulate) and limbic (insula, parahipocampal) brain regions. The thickness of the dorsal posterior cingulate cortex in the batterer group correlated with scores on the emotional perception task. These findings shed light on a neuroscientific approach to analyzing violent behavior perpetrated by male batterers, leading to a better understanding of the underlying mechanisms involved in IPV.

33 CFR 334.1460 - Atlantic Ocean and Vieques Sound, in vicinity of Culebra Island; bombing and gunnery target area.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., in vicinity of Culebra Island; bombing and gunnery target area. 334.1460 Section 334.1460 Navigation...; bombing and gunnery target area. (a) The danger zone. From Punta Resaca on the north coast of Culebra at... danger zone is subject to use as a target area for bombing and gunnery practice. It will be open to...

33 CFR 334.1460 - Atlantic Ocean and Vieques Sound, in vicinity of Culebra Island; bombing and gunnery target area.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., in vicinity of Culebra Island; bombing and gunnery target area. 334.1460 Section 334.1460 Navigation...; bombing and gunnery target area. (a) The danger zone. From Punta Resaca on the north coast of Culebra at... danger zone is subject to use as a target area for bombing and gunnery practice. It will be open to...

A tri-modality image fusion method for target delineation of brain tumors in radiotherapy.

PubMed

Guo, Lu; Shen, Shuming; Harris, Eleanor; Wang, Zheng; Jiang, Wei; Guo, Yu; Feng, Yuanming

2014-01-01

To develop a tri-modality image fusion method for better target delineation in image-guided radiotherapy for patients with brain tumors. A new method of tri-modality image fusion was developed, which can fuse and display all image sets in one panel and one operation. And a feasibility study in gross tumor volume (GTV) delineation using data from three patients with brain tumors was conducted, which included images of simulation CT, MRI, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) examinations before radiotherapy. Tri-modality image fusion was implemented after image registrations of CT+PET and CT+MRI, and the transparency weight of each modality could be adjusted and set by users. Three radiation oncologists delineated GTVs for all patients using dual-modality (MRI/CT) and tri-modality (MRI/CT/PET) image fusion respectively. Inter-observer variation was assessed by the coefficient of variation (COV), the average distance between surface and centroid (ADSC), and the local standard deviation (SDlocal). Analysis of COV was also performed to evaluate intra-observer volume variation. The inter-observer variation analysis showed that, the mean COV was 0.14(± 0.09) and 0.07(± 0.01) for dual-modality and tri-modality respectively; the standard deviation of ADSC was significantly reduced (p<0.05) with tri-modality; SDlocal averaged over median GTV surface was reduced in patient 2 (from 0.57 cm to 0.39 cm) and patient 3 (from 0.42 cm to 0.36 cm) with the new method. The intra-observer volume variation was also significantly reduced (p = 0.00) with the tri-modality method as compared with using the dual-modality method. With the new tri-modality image fusion method smaller inter- and intra-observer variation in GTV definition for the brain tumors can be achieved, which improves the consistency and accuracy for target delineation in individualized radiotherapy.

Deep brain stimulation for the treatment of uncommon tremor syndromes

PubMed Central

Ramirez-Zamora, Adolfo; Okun, Michael S.

2016-01-01

ABSTRACT Introduction: Deep brain stimulation (DBS) has become a standard therapy for the treatment of select cases of medication refractory essential tremor and Parkinson’s disease however the effectiveness and long-term outcomes of DBS in other uncommon and complex tremor syndromes has not been well established. Traditionally, the ventralis intermedius nucleus (VIM) of the thalamus has been considered the main target for medically intractable tremors; however alternative brain regions and improvements in stereotactic techniques and hardware may soon change the horizon for treatment of complex tremors. Areas covered: In this article, we conducted a PubMed search using different combinations between the terms ‘Uncommon tremors’, ‘Dystonic tremor’, ‘Holmes tremor’ ‘Midbrain tremor’, ‘Rubral tremor’, ‘Cerebellar tremor’, ‘outflow tremor’, ‘Multiple Sclerosis tremor’, ‘Post-traumatic tremor’, ‘Neuropathic tremor’, and ‘Deep Brain Stimulation/DBS’. Additionally, we examined and summarized the current state of evolving interventions for treatment of complex tremor syndromes. Expert c ommentary: Recently reported interventions for rare tremors include stimulation of the posterior subthalamic area, globus pallidus internus, ventralis oralis anterior/posterior thalamic subnuclei, and the use of dual lead stimulation in one or more of these targets. Treatment should be individualized and dictated by tremor phenomenology and associated clinical features. PMID:27228280

Site-targeted complement inhibition by a complement receptor 2-conjugated inhibitor (mTT30) ameliorates post-injury neuropathology in mouse brains.

PubMed

Rich, Megan C; Keene, Chesleigh N; Neher, Miriam D; Johnson, Krista; Yu, Zhao-Xue; Ganivet, Antoine; Holers, V Michael; Stahel, Philip F

2016-03-23

Intracerebral complement activation after severe traumatic brain injury (TBI) leads to a cascade of neuroinflammatory pathological sequelae that propagate host-mediated secondary brain injury and adverse outcomes. There are currently no specific pharmacological agents on the market to prevent or mitigate the development of secondary cerebral insults after TBI. A novel chimeric CR2-fH compound (mTT30) provides targeted inhibition of the alternative complement pathway at the site of tissue injury. This experimental study was designed to test the neuroprotective effects of mTT30 in a mouse model of closed head injury. The administration of 500 μg mTT30 i.v. at 1 h, 4 h and 24 h after head injury attenuated complement C3 deposition in injured brains, reduced the extent of neuronal cell death, and decreased post-injury microglial activation, compared to vehicle-injected placebo controls. These data imply that site-targeted alternative pathway complement inhibition may represent a new promising therapeutic avenue for the future management of severe TBI. Copyright © 2016. Published by Elsevier Ireland Ltd.

Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders.

PubMed

Luan, Hemi; Wang, Xian; Cai, Zongwei

2017-11-12

Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the

33 CFR 334.10 - Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. 334.10 Section 334.10 Navigation and Navigable Waters CORPS... REGULATIONS § 334.10 Gulf of Maine off Seal Island, Maine; naval aircraft bombing target area. (a) The danger...