Harsha N. Halahalli

Complexity analysis of EEG in patients with schizophrenia using fractal dimension

We computed Higuchis fractal dimension (FD) of resting, eyes closed EEG recorded from 30 scalp locations in 18 male neuroleptic-naïve, recent-onset schizophrenia (NRS) subjects and 15 male healthy control (HC) subjects, who were group-matched for age. Schizophrenia patients showed a diffuse reduction of FD except in the bilateral temporal and occipital regions, with the reduction being most prominent bifrontally. The positive symptom (PS) schizophrenia subjects showed FD values similar to or even higher than HC in the bilateral temporo-occipital regions, along with a co-existent bifrontal FD reduction as noted in the overall sample of NRS. In contrast, this increase in FD values in the bilateral temporo-occipital region was absent in the negative symptom (NS) subgroup. The regional differences in complexity suggested by these findings may reflect the aberrant brain dynamics underlying the pathophysiology of schizophrenia and its symptom dimensions. Higuchis method of measuring FD directly in the time domain provides an alternative for the more computationally intensive nonlinear methods of estimating EEG complexity.

Transplantation of Hippocampal Cell Lines Restore Spatial Learning in Rats With Ventral Subicular Lesions

We have demonstrated in our previous studies that ventral subicular lesion induces neurodegeneration of the hippocampus and produces cognitive impairment in rats. In the present study, the efficacy of transplanted green fluorescent protein (GFP)-labeled hippocampal cell line (H3-GFP) cells in establishing functional recovery in ventral subicular lesioned rats has been evaluated. The survival of H3-GFP transplants and their ability to express trophic factors in vivo were also investigated. Adult male Wistar rats were subjected to selective lesioning of ventral subiculum and were transplanted with H3-GFP cells into the cornu ammonis 1 (CA1) hippocampus. The transplants settled mainly in the dentate gyrus and expressed neurotrophic factors, brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF). The ventral subicular lesioned (VSL) rats with H3-GFP transplants showed enhanced expression of BDNF in the hippocampus and performed well in eight-arm radial maze and Morris water maze tasks. The VSL rats without hippocampal transplants continued to show cognitive impairment in task learning. The present study demonstrated the H3-GFP transplants mediated recovery of cognitive functions in VSL rats. Our study supports the notion of graft meditated host regeneration and functional recovery through trophic support, although these mechanisms require further investigation.

Single-Trial EEG Classification Using Logistic Regression Based on Ensemble Synchronization

In this paper, we propose an ensemble synchronization measure across all EEG channel pairs of a cluster based on Frobenius norm of the phase synchronization matrix, in a 0-1 scale enabling a direct comparison between clusters with different number of channels. Using this metric, we studied the intrahemispheric EEG synchronization in the lower gamma band (30-40 Hz) during 1229 single trials of an audio-visual integration cross modal task (CMT) recorded from five patients with schizophrenia and five healthy control subjects. Using ensemble synchronization measure and response latency of single trials recorded during the CMT as features for logistic regression, we could classify each single trial of EEG as belonging to a patient with schizophrenia or a healthy control subject with 73% accuracy, with an area under receiver operating characteristics curve of 0.83. We also propose a likelihood rating to denote the possibility of a subject belonging to the schizophrenia group.

Differential relationship of frontal pole and whole brain volumetric measures with age in neuroleptic-naive schizophrenia and healthy subjects

Brodmanns area (BA) 10, which occupies the frontal pole (FP) of the human brain, has been proven to play a central role in the executive control of cognitive operations. Previous in vivo morphometric studies of the FP have been limited by the lack of an accepted boundary of its posterior limit. We studied the FP gray matter volume in 23 healthy subjects who were age-, sex-, and education-matched to 23 neuroleptic-naïve recent-onset schizophrenia subjects in the age span 20-40 years, using a cytoarchitectonically and functionally valid landmark-based definition of its posterior boundary that we proposed recently (John, J.P., Yashavantha, B.S., Gado, M., Veena, R., Jain, S., Ravishankar, S., Csernansky, J.G., 2007. A proposal for MRI-based parcellation of the frontal pole. Brain Struct. Funct. 212, 245-253. 2007). Additionally, we examined the relationship between FP volume and age in both healthy and schizophrenia subjects to examine evidence for a possible differential relationship between these variables across the samples. A major finding of the study was the absence of a group-level difference in frontal pole gray volumes between the healthy and schizophrenia participants. However, a more complex finding emerged in relation to age effects. The healthy participants showed an inverse relationship of FP gray volume with age, even after taking total brain volume differences into account. But this age effect was completely absent in the schizophrenia group. Moreover, all the volumetric measures in schizophrenia subjects showed substantially higher range, variance, skewness and kurtosis when compared to those of healthy subjects. These findings have implications in understanding the possible role of FP in the pathophysiology of schizophrenia.

An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India

Multiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N=38) and healthy subjects (N=37) from South India. Patients with schizophrenia showed trend-level (p<0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia.

Apolipoprotein E4 and brain white matter integrity in Alzheimer's disease: tract-based spatial statistics study under 3-Tesla MRI.

Introduction: Apolipoprotein E4 (ApoE ε4) polymorphism is a known genetic risk factor for Alzheimer’s disease (AD). Objectives: To evaluate the role of ApoE ε4 on white matter structural integrity in AD. Methods: Subjects were 32 patients with probable AD (ApoE ε4-positive: n = 15) and 18 matched controls (ApoE ε4-positive: n = 6). All subjects were right-handed, evaluated using standard scales and genotyped at the ApoE locus. Diffusion tensor imaging was performed with a 3-tesla MRI scanner and analyzed using the tract-based spatial statistics method. Results: AD patients had significantly lower fractional anisotropy (FA) in bilateral temporoparietal, limbic and parahippocampal regions in comparison to healthy comparison subjects. ApoE ε4 carriers among both AD and healthy comparison subjects showed lower FA in limbic and medial temporal regions. Conclusions: There is a modest association between ApoE ε4 carrier status and reduction in white matter tract integrity at medial temporal and limbic regions in both healthy and AD subjects.

Effect of Polymorphisms of Three Genes Mediating Monoamine Signalling on Brain Morphometry in Schizophrenia and Healthy Subjects

Objective We examined the effect of risk alleles of polymorphisms of three schizophrenia risk genes that mediate monoamine signalling in the brain on regional brain volumes of schizophrenia and healthy control subjects. The risk alleles and the gene polymorphisms studied were: Val allele of catechol o-methyltransferase (COMT) rs4680 polymorphism; short allele of 5-hydroxy tryptamine transporter linked polymorphic region (5HTTLPR) polymorphism; and T allele of 5-hydroxy tryptamine 2A (5HT2A) rs6314 polymorphism. Methods The study was carried out on patients with recent onset schizophrenia (n=41) recruited from the outpatient department of National Institute of Mental Health and Neurosciences, Bangalore, India and healthy control subjects (n=39), belonging to South Indian Dravidian ethnicity. Individual and additive effects of risk alleles of the above gene polymorphisms on brain morphometry were explored using voxel-based morphometry. Results Irrespective of phenotypes, individuals with the risk allele T of the rs6314 polymorphism of 5HT2A gene showed greater (at cluster-extent equivalent to family wise error-correction [FWEc] p<0.05) regional brain volumes in the left inferior temporal and left inferior occipital gyri. Those with the risk alleles of the other two polymorphisms showed a trend (at p<0.001, uncorrected) towards lower regional brain volumes. A trend (at p<0.001, uncorrected) towards additive effects of the above 3 risk alleles (subjects with 2 or 3 risk alleles vs. those with 1 or no risk alleles) on brain morphology was also noted. Conclusion The findings of the present study have implications in understanding the role of individual and additive effects of genetic variants in mediating regional brain morphometry in health and disease.

Erratum: Figure Correction

[This corrects the article on p. 124 in vol. 12, PMID: 25191502.].

Relationship of Clinical and Cognitive Variables with Brain Morphometric Abnormalities in Alzheimer’s Disease: a Voxel Based Morphometric Study Using 3-Tesla MRI

Alzheimers disease (AD) is associated with widespread structural and functional brain alterations. The current study examined the gray matter (GM) voxel based morphometric (VBM) correlates of cognitive and clinical severity scores in patients with AD. The study included 34 patients with AD according to NINCDS/ADRDA AD criteria and 28 matched elderly controls. All subjects were clinically evaluated using Hindi Mental Status Examination (HMSE), Everyday Abilities Scale for India (EASI) and the Clinical Dementia Rating (CDR) scale. The structural Magnetic Resonance Imaging (MRI) data were acquired using a 3 Tesla MRI scanner and VBM analysis was performed using VBM5.1 toolbox. The patients with AD had significantly lower GM volume, white matter volume and total brain volume as compared to controls. The HMSE scores were positively correlated (p=0.009) and EASI (p=0.04) & CDR (p=0.0004) were negatively correlated with the total GM volumes in patients with AD. The VBM analysis revealed diffuse GM atrophy in patients with AD. Frontal& temporal GM volumes were positively correlated with the HMSE scores. Thus the results of the study replicate the previous observations of generalized GM atrophy, in an Indian sample with AD. The cognitive decline, clinical dementia severity and impairment in activities of daily living were correlated whole brain GM and WM volumes as well as with specific brain regional atrophy in AD. However further studies with larger samples & with more detailed cognitive evaluation are required for confirmation & validation of the relationship between regional morphometric abnormalities and cognitive deficits in AD.

Functional connectivity patterns underlying the experience of auditory verbal hallucinations in patients with schizophrenia

Schizophrenia is characterized by functional connectivity aberrations between brain regions that mediate different cognitive processes. The characteristic symptoms of schizophrenia such as delusions, hallucinations, passivity experiences etc. are suggested to reflect a disordered self-awareness. In the present study, we used a novel fMRI paradigm, the ‘Hallucination Attentional Modulation Task (HAMT)”, to examine the functional connectivity patterns underlying the experience of auditory verbal hallucinations in contrast to the patterns associated with processing of visual stimuli. We found that there was substantial overlap amongst healthy (n=8) and schizophrenia (n=6) subjects with respect to the functional connectivity patterns during the ‘free attention’ and ‘visual attention’ conditions of the paradigm. In patients with schizophrenia having continuous auditory verbal hallucinations, the connectivity between the bilateral superior parietal lobules and bilateral thalami were stronger during the ‘hallucination attention’ condition. These results provide preliminary leads that link auditory verbal hallucinations to an underlying disorder of self-agency.