Darren Clark

Protection against Recurrent Stroke with Resveratrol: Endothelial Protection

Despite increased risk of a recurrent stroke following a minor stroke, information is minimal regarding the interaction between injurious mild cerebral ischemic episodes and the possible treatments which might be effective. The aim of the current study was to investigate recurrent ischemic stroke and whether resveratrol, a nutritive polyphenol with promising cardio- and neuro- protective properties, could ameliorate the associated brain damage. Experiments in adult rats demonstrated that a mild ischemic stroke followed by a second mild cerebral ischemia exacerbated brain damage, and, daily oral resveratrol treatment after the first ischemic insult reduced ischemic cell death with the recurrent insult (P<0.002). Further investigation demonstrated reduction of both inflammatory changes and markers of oxidative stress in resveratrol treated animals. The protection observed with resveratrol treatment could not be explained by systemic effects of resveratrol treatment including effects either on blood pressure or body temperature measured telemetrically. Investigation of resveratrol effects on the blood-brain barrier in vivo demonstrated that resveratrol treatment reduced blood-brain barrier disruption and edema following recurrent stroke without affecting regional cerebral blood flow. Investigation of the mechanism in primary cell culture studies demonstrated that resveratrol treatment significantly protected endothelial cells against an in vitro ‘ischemia’ resulting in improved viability against oxygen and glucose deprivation (39.6±6.6% and 81.3±9.5% in vehicle and resveratrol treated cells, respectively). An inhibition of nitric oxide synthesis did not prevent the improved cell viability following oxygen glucose deprivation but SIRT-1 inhibition with sirtinol partially blocked the protection (P<0.001) suggesting endothelial protection is to some extent SIRT-1 dependent. Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature.

Cellular correlates of longitudinal diffusion tensor imaging of axonal degeneration following hypoxic-ischemic cerebral infarction in neonatal rats

Ischemically damaged brain can be accompanied by secondary degeneration of associated axonal connections e.g. Wallerian degeneration. Diffusion tensor imaging (DTI) is widely used to investigate axonal injury but the cellular correlates of many of the degenerative changes remain speculative. We investigated the relationship of DTI of directly damaged cerebral cortex and secondary axonal degeneration in the cerebral peduncle with cellular alterations in pan-axonal neurofilament staining, myelination, reactive astrocytes, activation of microglia/macrophages and neuronal cell death. DTI measures (axial, radial and mean diffusivity, and fractional anisotropy (FA)) were acquired at hyperacute (3 h), acute (1 and 2 d) and chronic (1 and 4 week) times after transient cerebral hypoxia with unilateral ischemia in neonatal rats. The tissue pathology underlying ischemic and degenerative responses had a complex relationship with DTI parameters. DTI changes at hyperacute and subacute times were smaller in magnitude and tended to be transient and/or delayed in cerebral peduncle compared to cerebral cortex. In cerebral peduncle by 1 d post-insult, there were reductions in neurofilament staining corresponding with decreases in parallel diffusivity which were more sensitive than mean diffusivity in detecting axonal changes. Ipsilesional reductions in FA within cerebral peduncle were robust in detecting both early and chronic degenerative responses. At one or four weeks post-insult, radial diffusivity was increased ipsilaterally in the cerebral peduncle corresponding to pathological evidence of a lack of ontogenic myelination in this region. The detailed differences in progression and magnitude of DTI and histological changes reported provide a reference for identifying the potential contribution of various cellular responses to FA, and, parallel, radial, and mean diffusivity.

Cognitive insight is associated with cortical thickness in first-episode psychosis

Compared to non-clinical subjects, people with psychosis show poor cognitive insight as reflected in low Self-Reflectiveness and high Self-Certainty. Neuroimaging studies have reported that 1) low Self-Reflectiveness is associated with volumetric reductions in ventrolateral prefrontal cortex (VLPFC), 2) higher Self-Certainty is associated with volumetric reductions in hippocampus, and 3) higher Self-Certainty is associated with fractional anisotropy in the fornix, in people with psychosis. The aims of the current study were to expand on this research by 1) performing an exploratory whole-brain cortical thickness analysis of the neural correlates of cognitive insight, to reveal whether regions outside the VLPFC are important for cognitive insight, and 2) to evaluate associations between cognitive insight and subfields of the hippocampus, which are distinct, interacting, and have different functions. We also aimed to replicate previous research documenting associations between cognitive insight and 3) total hippocampal volumes and 4) fornix fractional anisotropy. Fifteen people with a first-episode psychosis completed the Beck Cognitive Insight Scale and provided magnetic resonance and diffusion tensor imaging scans. Cortical thickness and hippocampal volumes were analyzed in FreeSurfer, and fornixfractional anisotropy was analyzed in Diffusion Toolkit/TrackVis. Higher Self-Reflectiveness and lower Self-Certainty significantly associated with thickness and thinness in VLPFC, respectively, as well as thickness and thinness in widespread frontal, parietal and temporal cortices. No associations emerged between Self-Reflectiveness or Self-Certainty and hippocampal total or sub-field volumes, or fornix fractional anisotropy. Results suggest that the neural correlates of cognitive insight involve a network of frontal, temporal and parietal brain regions.

Amygdala responses to quetiapine XR and citalopram treatment in major depression: The role of 5-HTTLPR-S/Lg polymorphisms

Genotype and drug pharmacology may contribute to variations in brain response to antidepressants. We examined the impact of two antidepressants with differential actions on serotonin transporter and the 5‐HHTLPR‐S/Lg polymorphisms on amygdala responses in major depressive disorder (MDD).

Thalamocortical connectivity in major depressive disorder

BACKGROUND Major Depressive Disorder (MDD) is highly prevalent and potentially devastating, with widespread aberrations in brain activity. Thalamocortical networks are a potential candidate marker for psychopathology in MDD, but have not yet been thoroughly investigated. Here we examined functional connectivity between major cortical areas and thalamus. METHOD Resting-state fMRI from 54 MDD patients and 40 healthy controls were collected. The cortex was segmented into six regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and pre-central and post-central gyri. BOLD signal time courses were extracted from each ROI and correlated with voxels in thalamus, while removing signals from every other ROI. RESULTS Our main findings showed that MDD patients had predominantly increased connectivity between medial thalamus and temporal areas, and between medial thalamus and somatosensory areas. Furthermore, a positive correlation was found between thalamo-temporal connectivity and severity of symptoms. LIMITATIONS Most of the patients in this study were not medication naïve and therefore we cannot rule out possible long-term effects of antidepressant use on the findings. CONCLUSION The abnormal connectivity between thalamus and temporal, and thalamus and somatosensory regions may represent impaired cortico-thalamo-cortical modulation underlying emotional, and sensory disturbances in MDD. In the context of similar abnormalities in thalamocortical systems across major psychiatric disorders, thalamocortical dysconnectivity could be a reliable transdiagnostic marker.