Nagalingam Rajakumar

The hippocampus is implicated in numerous neurological disorders and the ability to detect subtle or focal hippocampal abnormalities earlier in disease progression could significantly improve the treatment of patients. Ex vivo studies with ultra-high field have revealed that diffusion MRI (dMRI) can reveal microstructural variations within the hippocampal subfields and lamina, and may also be sensitive to intra-hippocampal pathways. However, translation to lower resolution in vivo dMRI studies of the hippocampus is challenging due to its complicated geometry. One novel way to overcome some of these obstacles is by transforming the usual Cartesian coordinates in an MRI image to coordinates that are crafted to curve themselves according to the complicated geometry of the hippocampus. This procedure allows us to virtually unfold the hippocampus into a thin sheet. In this work, we introduce an algorithm to map diffusion MRI data to this sheet, allowing us to overcome the difficulties associated with the hippocampus’ complicated geometry. We demonstrate how our method can be readily integrated into existing implementations of traditional tractography methods and how it leads to enhancements in the resulting tracts. Further, our results on high quality in vivo dMRI acquisitions show that unfolding the hippocampus leads to a more anatomically plausible modelling of the connectivity of the hippocampus as probed by probabilistic tractography, revealing key elements of the polysynaptic pathway and anterior-posterior connectivity gradients.

BACKGROUND AND PURPOSE: The anterior cingulate cortex (ACC) is involved in several cognitive processes including executive function. Degenerative changes of ACC are consistently seen in Alzheimer's disease (AD). However, volumetric changes specific to the ACC in AD are not clear because of the difficulty in segmenting this region. The objectives of the current study were to develop a precise and high‐throughput approach for measuring ACC volumes and to correlate the relationship between ACC volume and cognitive function in AD.METHODS: Structural T₁‐weighted magnetic resonance images of AD patients (n = 47) and age‐matched controls (n = 47) at baseline and at 24 months were obtained from the Alzheimer's disease neuroimaging initiative (ADNI) database and studied using a custom‐designed semiautomated segmentation protocol.RESULTS: ACC volumes obtained using the semiautomated protocol were highly correlated to values obtained from manual segmentation (r = .98) and the semiautomated protocol was considerably faster. When comparing AD and control subjects, no significant differences were observed in baseline ACC volumes or in change in ACC volumes over 24 months using the two segmentation methods. However, a change in ACC volume over 24 months did not correlate with a change in mini‐mental state examination scores.CONCLUSIONS: Our results indicate that the proposed semiautomated segmentation protocol is reliable for determining ACC volume in neurodegenerative conditions including AD.

Background: The temporoparietal junction (TPJ) has been linked to lower-level attentional and higher-level social processing, both of which are affected in schizophrenia (SZ) and major depressive disorder (MDD). We examined resting functional connectivity of bilateral anterior and posterior TPJ in SZ and MDD to evaluate potential anomalies in each disorder and differences between disorders. Methods: Resting-state functional magnetic resonance imaging data were acquired from 24 patients with SZ, 24 patients with MDD, and 24 age-matched healthy controls. We performed seed-based functional connectivity analyses with seed regions in bilateral anterior and posterior TPJ, covarying for gender and smoking. Results: SZ had reduced connectivity versus controls between left anterior TPJ and dorsolateral prefrontal cortex (dlPFC) and posterior cingulate cortex (PCC); between left posterior TPJ and middle cingulate cortex, left dorsal PFC, and right lateral PFC; between right anterior TPJ and bilateral PCC; and between right posterior TPJ and middle cingulate cortex, left posterior insula, and right insula. MDD had reduced connectivity versus controls between left posterior TPJ and right dlPFC and between right posterior TPJ and PCC and dlPFC. SZ had reduced connectivity versus MDD between right posterior TPJ and left fusiform gyrus and right superior-posterior temporal cortex. Conclusion: Functional connectivity to the TPJ was demonstrated to be disrupted in both SZ and MDD. However, TPJ connectivity may differ in these disorders with reduced connectivity in SZ versus MDD between TPJ and posterior brain regions.

In the pursuit of further establishing a neurodevelopmental animal model to investigate the mechanisms underlying impaired executive function, a core and severely debilitating symptom of schizophrenia, we sought to characterize the deficits in behavioral flexibility in adult rats following neonatal infusions of nerve growth factor (NGF) into the medial part of the developing frontal cortex. Our previous studies using this neonatal frontal cortical lesion model have shown that it leads to adult-onset positive and negative symptom-like features, and several neuropathological abnormalities of schizophrenia. In the present study, we used operant conditioning-based paradigms to investigate set-shifting ability and reversal learning performance in adult rats that received infusions of NGF into the developing frontal cortex on post-natal day 1. NGF-infusion caused apoptosis of cells in the subplate layer. Adult rats that received neonatal infusions of NGF showed decreased grey matter thickness, and decreased levels of parvalbumin in prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC). NGF-treated rats had difficulty completing the set-shifting and reversal learning tasks due to increased perseverance (ie, a failure to disengage from the previously-learned strategy once the rule contingencies were changed) compared to the control group. Collectively, these results identify the crucial role of the frontal cortical subplate layer in the structural and functional development of the mPFC relevant to schizophrenia. Furthermore, the present findings substantially advance the face and construct validity of this putative preclinical model of schizophrenia based on developmental disruption of the frontal cortical subplate.

The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders. The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment. The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis.

Background: The mechanism of action of olanzapine in treating schizophrenia is not clear. This research reports the effects of a therapeutic equivalent treatment of olanzapine on DNA methylation in a rat model in vivo. Genome-wide DNA methylation was assessed using a MeDIP-chip analysis. All methylated DNA immunoprecipitation (MeDIP), sample labelling, hybridization and processing were performed by Arraystar Inc (Rockville, MD, USA). The identified gene promoters showing significant alterations to DNA methylation were then subjected to Ingenuity Pathway Analysis (Ingenuity System Inc, CA, USA). Results: The results show that olanzapine causes an increase in methylation in 1,140, 1,294 and 1,313 genes and a decrease in methylation in 633, 565 and 532 genes in the hippocampus, cerebellum and liver, respectively. Most genes affected are tissue specific. Only 41 affected genes (approximately 3%) showed an increase and no gene showed a decrease in methylation in all three tissues. Further, the two brain regions shared 123 affected genes (approximately 10%). The affected genes are enriched in pathways affecting dopamine signalling, molecular transport, nervous system development and functions in the hippocampus; ephrin receptor signalling and synaptic long-term potentiation in the cerebellum; and tissue morphology, cellular assembly and organization in the liver. Also, the affected genes included those previously implicated in psychosis. Conclusions: The known functions of affected genes suggest that the observed epigenetic changes may underlie the amelioration of symptoms as well as accounting for certain adverse effects including the metabolic syndrome. The results give insights into the mechanism of action of olanzapine, therapeutic effects and the side effects of antipsychotics.