Target Brain Regions Research Articles

Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex

Cocaine-cue extinction training combined with brief interventions of environmental enrichment (EE) was shown previously to facilitate extinction and attenuate reacquisition of cocaine self-administration in rats. It is unknown whether or not the usefulness of this approach would be undermined if extinction training took place in a novel rather than familiar context. Drawing on previous studies involving pharmacological interventions, we hypothesized that the facilitative effects of EE for cocaine relapse prevention would be independent of the context used for extinction training. Rats trained to self-administer cocaine underwent cocaine-cue extinction training in either the familiar self-administration context or a novel context, with or without EE. Rats then were tested for reacquisition of cocaine self-administration in the familiar context. Target brain regions were lysed and probed for memory-related changes in receptors for glutamate and BDNF by western blotting. Contrary to our hypothesis, the facilitative effects of EE for cocaine relapse prevention were dependent on the context used for extinction training. While EE facilitated extinction regardless of context used, it inhibited cocaine relapse only after extinction training in the familiar context. EE was associated with increased GluA2 in nucleus accumbens, TrkB in dorsal hippocampus and activated TrkB in ventromedial prefrontal cortex. Of these, the changes in dorsal hippocampus and ventromedial prefrontal cortex mirrored outcomes of the cocaine relapse tests in that these changes were specific to rats receiving EE plus extinction training in the familiar context. These findings support a role for hippocampal-prefrontal BDNF-TrkB signaling in extinction-based relapse prevention strategies involving EE.

Modulation of amygdala reactivity following rapidly acting interventions for major depression.

Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.

Design of a high-resolution light field miniscope for volumetric imaging in scattering tissue.

Integrating light field microscopy techniques with existing miniscope architectures has allowed for volumetric imaging of targeted brain regions in freely moving animals. However, the current design of light field miniscopes is limited by non-uniform resolution and long imaging path length. In an effort to overcome these limitations, this paper proposes an optimized Galilean-mode light field miniscope (Gali-MiniLFM), which achieves a more consistent resolution and a significantly shorter imaging path than its conventional counterparts. In addition, this paper provides a novel framework that incorporates the anticipated aberrations of the proposed Gali-MiniLFM into the point spread function (PSF) modeling. This more accurate PSF model can then be used in 3D reconstruction algorithms to further improve the resolution of the platform. Volumetric imaging in the brain necessitates the consideration of the effects of scattering. We conduct Monte Carlo simulations to demonstrate the robustness of the proposed Gali-MiniLFM for volumetric imaging in scattering tissue.

Protective role of functional food in cognitive deficit in young and senile rats.

Cognitive decline and neurodegenerative diseases pose a significant burden on healthcare resources both in developed and developing countries which is a major socio-economic and healthcare concern. Alzheimer's disease is the most common form of progressive neurodegenerative dementia of the aged brain. Aluminum is a constituent of antacids, deodorants, kitchenware and food additives which allows easy access into the body posing risk to development of senile dementia of Alzheimer's type. Virgin coconut oil was declared as a potential cognitive strengthener. Assessment of cognitive and memory-enhancing effects of virgin coconut oil in senile and young rats to gain vital insights into its effective use in the prevention of neurodegeneration in dementia/Alzheimer's disease-like manifestations and alleviate cognitive dysfunction and learning impairment with neuronal damage imparted by daily oral intake of aluminum. Alzheimer's disease-like symptoms and memory impairment were experimentally induced using oral anhydrous aluminum chloride given daily for five successive weeks in young and old age albino rats. Treatment groups received virgin coconut oil to assess protection during the experimental period. Behavioral test, Morris water maze was conducted before/after induction/treatment. At the end of the experimental period, cholinergic, dopaminergic, noradrenergic and serotonergic neurotransmission as well as brain-derived neurotrophic factor were being investigated, in addition to immunochemical and histopathological examination of targeted brain regions. Virgin coconut oil significantly improved cholinergic activity and monoaminergic neurotransmission. Moreover, immunochemical and histopathological examination revealed marked protection with virgin coconut oil against aluminum-induced Alzheimer's disease-like pathology and cognitive deficit.

Activity or connectivity? A randomized controlled feasibility study evaluating neurofeedback training in Huntington's disease.

Non-invasive methods, such as neurofeedback training, could support cognitive symptom management in Huntington’s disease by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of neurofeedback training in Huntington’s disease by examining two different methods, activity and connectivity real-time functional MRI neurofeedback training. Thirty-two Huntington’s disease gene-carriers completed 16 runs of neurofeedback training, using an optimized real-time functional MRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the supplementary motor area, and another receiving neurofeedback based on the correlation of supplementary motor area and left striatum activity (connectivity neurofeedback training), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during neurofeedback training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants’ ability to upregulate neurofeedback training target levels without feedback (near transfer), as well as by examining change in objective, a priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher neurofeedback training target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two neurofeedback training methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and learning success. We conclude that although there is evidence that neurofeedback training can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust.

Personality traits and negative affect mediate the relationship between cortical thickness of superior frontal cortex and aggressive behavior

Aggression reflects the psychological and physical behavior that perpetrator intends to harm victim. Initiation of aggression is influenced by the distal factors (e.g. personality) and proximate causes (e.g. affect) of perpetrator. However, few studies explored the brain structural basis of relationship between these traits and aggressive behavior. In this study, we first explored the association between cortical thickness and aggression in a large young adult sample from the Human Connectome Project. Results found aggressive behavior assessed by the Adult Self-Report was positively correlated with cortical thickness in left superior frontal gyrus (SFG), which was implicated in emotion regulation and executive function. Then, mediation analyses with distal and proximate factors separately showcased that the association between the left SFG thickness and aggressive behavior was partially mediated by negative affect (anger and sadness), and fully mediated by personality traits (agreeableness and neuroticism). Taken together, these experimental findings established dorsal prefrontal cortex as the key region in generating aggressive behavior, and gave a neutral explanation for why individuals with high negative affect and neuroticism exhibit more aggression. This study implicated the possible targeted brain region and behavioral intervention for such at-risk individuals initiating violence.

Brain Stimulation to Modulate Food Intake and Eating Behavior.

Appetitive behaviors are mediated through homeostatic and reward signaling of brain circuits. There has been increasing interest in the use of neuromodulation techniques aimed at targeting brain regions such as the lateral prefrontal and subcortical regions associated with dysregulation of eating behaviors. Invasive brain stimulation techniques have demonstrated promising results in treating severe and enduring anorexia nervosa and morbid obesity. In addition, non-invasive techniques have been shown to successfully reduce food craving, hunger ratings, and calorie intake as well as binge/purge symptoms in eating disorders. Brain stimulation offers promising results for treating symptoms associated with eating disorders and modifying appetitive behaviors including craving and caloric consumption. Future research should focus on identifying optimal frequency and duration of stimulation and employ longitudinal studies to assess long-term effectiveness on clinical outcomes such as eating disorder symptomatology, weight loss, and sustained improvements in eating behaviors over time.

TinyFSCV: FSCV for the Masses.

The ability to monitor neurochemical dynamics in target brain regions with a high degree of temporal resolution has assisted researchers in investigating the pathogenesis, and pathophysiology of a variety of neurological and psychiatric disorders. Current systems for neurochemical monitoring are bulky or expensive, limiting widespread exploration of this research field and preventing large-scale parallel experimentation. In this paper, we present a new miniaturized research platform, the TinyFSCV system, which can be used to monitor dynamic changes in neurochemicals through Fast-Scan Cyclic Voltammetry (FSCV). This system contains a precision voltage output circuit that can accurately output potentials between -0.55 to 2 V and scan a connected electrochemical cell at up to 400 V/s, the required speed to sense most neurochemicals with FSCV. In addition, the device includes precision current measurement circuity with a measurement range of -115 to [Formula: see text] capable of taking measurements at up to 56 KS/s. Four experiments are conducted to demonstrate the capability of the system. These consisted of: static bench tests, static ferrocene tests, and static and dynamic dopamine tests. These experiments demonstrate the ability of the miniaturized platform to accurately sense and measure neurochemicals. Ultimately, the TinyFSCV system is a platform that can enable large-scale, low-cost parallel experimentation to take place in the field of neurochemical monitoring. In addition, this device will increase the accessibility of neurochemical sensing, providing advanced tools and techniques to more researchers, and facilitating widespread exploration of the field of neurodynamics.

Brain Connectivity Based Prediction of Alzheimer's Disease in Patients With Mild Cognitive Impairment Based on Multi-Modal Images.

Structural and metabolic connectivity are advanced features that facilitate the diagnosis of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Connectivity from a single imaging modality, however, did not show evident discriminative value in predicting MCI-to-AD conversion, possibly because the inter-modal information was not considered when quantifying the relationship between brain regions. Here we introduce a novel approach that extracts connectivity based on both structural and metabolic information to improve AD early diagnosis. Principal component analysis was performed on each imaging modality to extract the key discriminative patterns of each brain region in an independent auxiliary domain composed of AD and normal control (NC) subjects, which were then used to project the two subtypes of MCI to the low-dimensional space. The connectivity between each target brain region and all other regions was quantified via a multi-task regression model using the projected data. The prediction performance was evaluated in 75 stable MCI (sMCI) patients and 51 progressive MCI (pMCI) patients who converted to AD within 3 years. We achieved 79.37% accuracy, with 74.51% sensitivity and 82.67% specificity, in predicting MCI-to-AD progression, superior to other existing algorithms using either structural and metabolic connectivities alone or a combination thereof. Our results demonstrate the effectiveness of multi-modal connectivity, serving as robust biomarker for early AD diagnosis.

Immediate brain plasticity after one hour of brain-computer interface (BCI).

Two groups of inexperienced brain-computer interface users underwent a purely mental EEG-BCI session that rapidly impacted on their brain. Modulations in structural and functional MRI were found after only 1h of BCI training. Two different types of BCI (based on motor imagery or visually evoked potentials) were employed and analyses showed that the brain plastic changes are spatially specific for the respective neurofeedback. This spatial specificity promises tailored therapeutic interventions (e.g. for stroke patients). A brain-computer-interface (BCI) allows humans to control computational devices using only neural signals. However, it is still an open question, whether performing BCI also impacts on the brain itself, i.e. whether brain plasticity is induced. Here, we show rapid and spatially specific signs of brain plasticity measured with functional and structural MRI after only 1h of purely mental BCI training in BCI-naive subjects. We employed two BCI approaches with neurofeedback based on (i) modulations of EEG rhythms by motor imagery (MI-BCI) or (ii) event-related potentials elicited by visually targeting flashing letters (ERP-BCI). Before and after the BCI session we performed structural and functional MRI. For both BCI approaches we found increased T1-weighted MR signal in the grey matter of the respective target brain regions, such as occipital/parietal areas after ERP-BCI and precuneus and sensorimotor regions after MI-BCI. The latter also showed increased functional connectivity and higher task-evoked BOLD activity in the same areas. Our results demonstrate for the first time that BCI by means of targeted neurofeedback rapidly impacts on MRI measures of brain structure and function. The spatial specificity of BCI-induced brain plasticity promises therapeutic interventions tailored to individual functional deficits, for example in patients after stroke.

An advanced focused ultrasound protocol improves the blood-brain barrier permeability and doxorubicin delivery into the rat brain

Despite the recent development of a focused ultrasound (FUS) technique for disrupting the blood-brain barrier (BBB) and enabling the delivery of drugs into the targeted brain region, different sonication protocols have not been fully explored. In this study, we suggest a simple and cost-effective protocol that improves the BBB permeability and drug delivery without damaging the tissue. In this protocol, called “FUS+BBBD protocol”, an additional FUS stimulation without microbubbles (“FUS protocol”; 0.5, 1.0, or 2.0MPa acoustic pressure, 10ms tone burst, 1Hz pulse repetition frequency, 120s total duration) is applied prior to the conventional BBB disruption with microbubbles (“BBBD protocol”; 0.6∼0.72MPa acoustic pressure, 10ms tone burst, 1Hz pulse repetition frequency, 120s total duration). With the “FUS+BBBD protocol”, the magnetic resonance signal intensity and doxorubicin delivery at the targeted brain region were increased by 1.59 and 1.75 times at an FUS intensity of 1.0MPa, respectively, compared to the conventional BBBD. Other conditions also increase the drug delivery, but the increase was smaller than that at 1.0MPa (1.15 times for 0.5MPa and 1.60 times for 2.0MPa). The H&E histopathological analysis of the sonicated brain region using the proposed “FUS+BBBD protocol” showed no significant brain tissue damage at a FUS intensity of 0.5 and 1.0MPa. However, region cavities due to the damage were observed after an FUS intensity of 2.0MPa. These results suggest that the 1.0MPa “FUS+BBBD protocol” increases the BBB permeability and enhances the drug delivery efficiency without noticeable brain tissue damage, compared with the conventional BBBD. Although further studies are needed to determine the underlying mechanism of this effect, drugs that have been reported to be effective in the treatment of brain disease but had limited use due to severe systemic side effects will benefit from the enhanced drug delivery of “FUS+BBBD protocol”. Furthermore, the suggested protocol may facilitate the development of new strategies in clinical trials to treat brain disorders with improved drug delivery and safety.

Recent advances in therapies for eating disorders.

Eating disorders are serious psychiatric illnesses with high rates of morbidity and mortality. Effective treatments have traditionally included behaviorally focused therapies as well as several medication strategies. Recent years have seen promising developments in these treatments, including additional support for family-based approaches for children and adolescents, new evidence for “third-wave” behavioral therapies, and new support for the use of lisdexamfetamine for binge eating disorder and olanzapine for anorexia nervosa. Case study and pilot data are beginning to show limited support for neuromodulatory interventions targeting brain regions thought to be involved in eating disorders. This review summarizes treatment developments over the last several years and points towards future directions for the field.

Fuzzy General Linear Modeling for Functional Magnetic Resonance Imaging Analysis

Functional magnetic resonance imaging (fMRI) is a key neuroimaging technique. The classic fMRI analysis pipeline is based on the assumption that the hemodynamic response (HR) is the same across brain regions, time, and subjects. Although convenient, there is ample evidence that this assumption does not hold, and that these differences result in inaccuracies in brain activity detection. This article presents a new fMRI processing pipeline that captures the intrinsic intra- and intersubject variability of the HR. At the core of this new pipeline is the definition of a fuzzy hemodynamic response function (HRF). The proposed pipeline includes a new fuzzy general linear model (GLM) able to handle the fuzzy HRF, including a practical realization based on the LR representation of fuzzy numbers. This article also describes how to obtain activation maps from the fuzzy GLM, and a methodology to compute the statistical power of the analysis. The method is evaluated in synthetic and real fMRI data and compared with other state-of-the-art techniques. The experiments based on synthetic data show that the fuzzy GLM approach is more robust under uncertainty regarding the true specific shape of the HR. The experiments based on the real data show an increased volume of the activated brain areas, suggesting that the proposed method is able to prevent false negative errors in the boundaries of target brain regions in which HR should be negligible.

Chemogenetic manipulation of parasympathetic neurons (DMV) regulates feeding behavior and energy metabolism

Parasympathetic nervous system (PNS) innervates with several peripheral organs such as liver, pancreas and regulates energy metabolism. However, the direct role of PNS on food intake has been poorly understood. In the present study, we investigated the role of parasympathetic nervous system in regulation of feeding by chemogenetic methods. Adeno associated virus carrying DREADD (designer receptors exclusively activated by designer drugs) infused into the target brain region by stereotaxic surgery. The stimulatory hM3Dq or inhibitory hM4Di DREADD was over-expressed in selective population of dorsal motor nucleus of the vagus (DMV) neurons by Cre-recombinase-dependent manners. Activation of parasympathetic neuron by intraperitoneal injection of the M3-muscarinic receptor ligand clozapine-N-oxide (CNO) (1 mg/kg) suppressed food intake and resulted in body weight loss in ChAT-Cre mice. Parasympathetic neurons activation resulted in improved glucose tolerance while inhibition of the neurons resulted in impaired glucose tolerance. Stimulation of parasympathetic nervous system by injection of CNO (1 mg/kg) increased oxygen consumption and energy expenditure. Within the hypothalamus, in the arcuate nucleus (ARC) changed AGRP/POMC neurons. These results suggest that direct activation of parasympathetic nervous system decreases food intake and body weight with improved glucose tolerance.

Alterations in NMDAR-mediated signaling within the laterodorsal tegmental nucleus are associated with prenatal nicotine exposure

Cigarette smoking during pregnancy has been clinically associated with a variety of poorbehavioral outcomes for the exposed individuals, including higher risks for drug abuse and development of attention/deficit-hyperactive disorder (ADHD). Experimental studies support the hypothesis that nicotine might contribute to these risks, since prenatal nicotine exposure (PNE) in rodents was associated with greater addiction liability, hyperactivity, social impairments and a wide range of emotional and cognitive deficits. Alterations of glutamate signaling within brain regions involved in behavioral circuits could contribute to these outcomes. The pontine laterodorsal tegmental nucleus (LDT) exerts cholinergic modulation within the ventral tegmental area, nucleus accumbens, and cortical-projecting thalamic centers and PNE-associated alterations in LDT glutamate signaling could impact cholinergic output to these LDT targets. We have previously demonstrated that PNE alters AMPA-mediated signaling within LDT neurons, and in the present investigation, we focused on changes of NMDA receptors (NMDARs) and presence of silent synapses as an indicator of metaplastic processes in LDT cells associated with PNE treatment. PNE was associated with a decreased functional presence of GluN2B NMDAR subunits in synapses of large, putatively cholinergic neurons, whereas an increased function of this subunit was detected in small, likely GABAergic cells. In addition, PNE was associated with functional alterations of extrasynaptic NMDARs in putative cholinergic neurons, suggestive of an increased presence of GluN3A-containing NMDARs. An increased number of silent synapses was exclusively seen in the small cells. When taken together, we hypothesize that NMDA-mediated signaling changes within LDT neurons following PNE treatment would result in reductions of excitatory cholinergic modulatory tone in target brain regions, which would be expected to contribute to the behavioral deficits found among these individuals.

Stimulation of the Posterior Cingulate Cortex Impairs Episodic Memory Encoding.

Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory processing, making it a potential target for responsive neuromodulation strategies outside of the hippocampal network. However, causal evidence for the role that PCC plays in memory encoding is lacking. In human female and male participants (N = 17) undergoing seizure mapping, we investigated functional properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography. We used a verbal free recall paradigm in which the PCC was stimulated during presentation of half of the study lists, whereas no stimulation was applied during presentation of the remaining lists. We investigated whether stimulation affected memory and modulated hippocampal activity. Results revealed four main findings. First, stimulation during episodic memory encoding impaired subsequent free recall, predominantly for items presented early in the study lists. Second, PCC stimulation increased hippocampal gamma-band power. Third, stimulation-induced hippocampal gamma power predicted the magnitude of memory impairment. Fourth, functional connectivity between the hippocampus and PCC predicted the strength of the stimulation effect on memory. Our findings offer causal evidence implicating the PCC in episodic memory encoding. Importantly, the results indicate that stimulation targeted outside of the temporal lobe can modulate hippocampal activity and impact behavior. Furthermore, measures of connectivity between brain regions within a functional network can be informative in predicting behavioral effects of stimulation. Our findings have significant implications for developing therapies to treat memory disorders and cognitive impairment using DBS.SIGNIFICANCE STATEMENT Cognitive impairment and memory loss are critical public health challenges. Deep brain stimulation (DBS) is a promising tool for developing strategies to ameliorate memory disorders by targeting brain regions involved in mnemonic processing. Using DBS, our study sheds light on the lesser-known role of the posterior cingulate cortex (PCC) in memory encoding. Stimulating the PCC during encoding impairs subsequent recall memory. The degree of impairment is predicted by stimulation-induced hippocampal gamma oscillations and functional connectivity between PCC and hippocampus. Our findings provide the first causal evidence implicating PCC in memory encoding and highlight the PCC as a favorable target for neuromodulation strategies using a priori connectivity measures to predict stimulation effects. This has significant implications for developing therapies for memory diseases.

Constrained maximum intensity optimized multi-electrode tDCS targeting of human somatosensory network.

Transcranial direct current stimulation (tDCS) is a noninvasive method that delivers current through the scalp to enhance or suppress brain activity. The standard way of applying tDCS is by the use of two large rectangular sponge electrodes on the scalp. The resulting currents often stimulate a broad region of the brain distributed over brain networks. In order to address this issue, recently, multi-electrode transcranial direct current stimulation with optimized montages has been used to stimulate brain regions of interest (ROI) with improved trade-off between focality and intensity of the electrical current at the target brain region. However, in many cases only the location of target region is considered and not the orientation. Here we emphasize the importance of calculating the individualized target location and orientation by combined electroencephalography and magnetoencephalography (EMEG) source analysis in individualized skull-conductivity calibrated finite element method (FEM) head models and stimulate the target region by four different tDCS montages. We have chosen the generator of the P20/N20 component, located at Brodmann area 3b and oriented mainly from posterior to anterior directions as our target for stimulation because it can be modeled as a single dipole source with a fixed position and orientation. The simulations will deliver optimized excitatory and inhibitory electrode montages that are in future investigations compared to standard and sham tDCS in a somatosensory experiment. We also present a new constrained maximum intensity (CMI) optimization approach that better distributes the currents over multiple electrodes, therefore should lead to less tingling and burning sensations at the skin, and thus allows an easier realization of the sham condition significantly reducing the current intensity parallel to the target.

Tracking Changes in Brain Network Connectivity under Transcranial Current Stimulation.

Noninvasive transcranial brain stimulation has been widely used in experimental and clinical applications to perturb the brain activity, aiming at promoting synaptic plasticity or enhancing functional connectivity within targeted brain regions. However, there are different types of neurostimulations and various choices of stimulation parameters; how these choices influence the intermediate neurophysiological effects and brain connectivity remain incompletely understood. We propose several quantitative methods to investigate the brain connectivity of an epileptic patient before and after transcranial alternating/direct current stimulation (tACS/tDCS). The neuro-feedback derived from our analyses may provide useful cues for the effectiveness of neurostimulation.

Optimization of surgical intervention outside the epileptogenic zone in the Virtual Epileptic Patient (VEP).

Studies to improve the efficacy of epilepsy surgery have focused on better refining the localization of the epileptogenic zone (EZ) with the aim of effectively resecting it. However, in a considerable number of patients, EZs are distributed across multiple brain regions and may involve eloquent areas that cannot be removed due to the risk of neurological complications. There is a clear need for developing alternative approaches to induce seizure relief, but minimal impact on normal brain functions. Here, we develop a personalized in-silico network approach, that suggests effective and safe surgical interventions for each patient. Based on the clinically identified EZ, we employ modularity analysis to identify target brain regions and fiber tracts involved in seizure propagation. We then construct and simulate a patient-specific brain network model comprising phenomenological neural mass models at the nodes, and patient-specific structural brain connectivity using the neuroinformatics platform The Virtual Brain (TVB), in order to evaluate effectiveness and safety of the target zones (TZs). In particular, we assess safety via electrical stimulation for pre- and post-surgical condition to quantify the impact on the signal transmission properties of the network. We demonstrate the existence of a large repertoire of efficient surgical interventions resulting in reduction of degree of seizure spread, but only a small subset of them proves safe. The identification of novel surgical interventions through modularity analysis and brain network simulations may provide exciting solutions to the treatment of inoperable epilepsies.

Characterization of Inflammation in Delayed Cortical Transplantation.

We previously reported that embryonic motor cortical neurons transplanted 1-week after lesion in the adult mouse motor cortex significantly enhances graft vascularization, survival, and proliferation of grafted cells, the density of projections developed by grafted neurons and improves functional repair and recovery. The purpose of the present study is to understand the extent to which post-traumatic inflammation following cortical lesion could influence the survival of grafted neurons and the development of their projections to target brain regions and conversely how transplanted cells can modulate host inflammation. For this, embryonic motor cortical tissue was grafted either immediately or with a 1-week delay into the lesioned motor cortex of adult mice. Immunohistochemistry (IHC) analysis was performed to determine the density and cell morphology of resident and peripheral infiltrating immune cells. Then, in situ hybridization (ISH) was performed to analyze the distribution and temporal mRNA expression pattern of pro-inflammatory or anti-inflammatory cytokines following cortical lesion. In parallel, we analyzed the protein expression of both M1- and M2-associated markers to study the M1/M2 balance switch. We have shown that 1-week after the lesion, the number of astrocytes, microglia, oligodendrocytes, and CD45+ cells were significantly increased along with characteristics of M2 microglia phenotype. Interestingly, the majority of microglia co-expressed transforming growth factor-β1 (TGF-β1), an anti-inflammatory cytokine, supporting the hypothesis that microglial activation is also neuroprotective. Our results suggest that the modulation of post-traumatic inflammation 1-week after cortical lesion might be implicated in the improvement of graft vascularization, survival, and density of projections developed by grafted neurons.