Sunil V. Kalmady

Transcranial direct current stimulation in schizophrenia.

Transcranial direct current stimulation (tDCS) is an upcoming treatment modality for patients with schizophrenia. A series of recent observations have demonstrated improvement in clinical status of schizophrenia patients with tDCS. This review summarizes the research work that has examined the effects of tDCS in schizophrenia patients with respect to symptom amelioration, cognitive enhancement and neuroplasticity evaluation. tDCS is emerging as a safe, rapid and effective treatment for various aspects of schizophrenia symptoms ranging from auditory hallucinations-for which the effect is most marked, to negative symptoms and cognitive symptoms as well. An interesting line of investigation involves using tDCS for altering and examining neuroplasticity in patients and healthy subjects and is likely to lead to new insights into the neurological aberrations and pathophysiology of schizophrenia. The mechanistic aspects of the technique are discussed in brief. Future work should focus on establishing the clinical efficacy of this novel technique and on evaluating this modality as an adjunct to cognitive enhancement protocols. Understanding the mechanism of action of tDCS as well as the determinants and neurobiological correlates of clinical response to tDCS remains an important goal, which will help us expand the clinical applications of tDCS for the treatment of patients with schizophrenia.

Neurohemodynamic correlates of 'OM' chanting: A pilot functional magnetic resonance imaging study.

Background: A sensation of vibration is experienced during audible ‘OM’ chanting. This has the potential for vagus nerve stimulation through its auricular branches and the effects on the brain thereof. The neurohemodynamic correlates of ‘OM’ chanting are yet to be explored. Materials and Methods: Using functional Magnetic Resonance Imaging (fMRI), the neurohemodynamic correlates of audible ‘OM’ chanting were examined in right-handed healthy volunteers (n=12; nine men). The ‘OM’ chanting condition was compared with pronunciation of “ssss” as well as a rest state. fMRI analysis was done using Statistical Parametric Mapping 5 (SPM5). Results: In this study, significant deactivation was observed bilaterally during ‘OM’ chanting in comparison to the resting brain state in bilateral orbitofrontal, anterior cingulate, parahippocampal gyri, thalami and hippocampi. The right amygdala too demonstrated significant deactivation. No significant activation was observed during ‘OM’ chanting. In contrast, neither activation nor deactivation occurred in these brain regions during the comparative task – namely the ‘ssss’ pronunciation condition. Conclusion: The neurohemodynamic correlates of ‘OM’ chanting indicate limbic deactivation. As similar observations have been recorded with vagus nerve stimulation treatment used in depression and epilepsy, the study findings argue for a potential role of this ‘OM’ chanting in clinical practice.

Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

Background Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. Methodology We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Results Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Conclusion Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a “differential susceptibility” effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin.

Insight facilitation with add-on tDCS in schizophrenia

Impaired insight in schizophrenia patients has been linked with prefrontal deficits. In this open-label study, we examined for potential insight facilitation effects of add-on tDCS (with anodal stimulation of left DLPFC and cathodal stimulation over left temporo-parietal junction) in schizophrenia patients (N=21) with persistent auditory hallucinations despite adequate antipsychotic treatment. Following tDCS, there was a significant improvement in insight with concurrent significant reduction in auditory hallucination severity. Improvement in insight correlated significantly with improvement in severity of auditory hallucinations. These findings suggest improvement of insight with add-on tDCS in schizophrenia with persistent auditory hallucinations.

Neural basis of tDCS effects on auditory verbal hallucinations in schizophrenia: a case report evidence for cortical neuroplasticity modulation.

Transcranial direct current stimulation (tDCS) has been reported to ameliorate auditory hallucinations that are nonresponsive/minimally responsive to antipsychotic treatment in schizophrenia. The neurobiological basis of the tDCS effects in ameliorating auditory hallucinations is yet to be explored. In this case report, for the first time, using the novel method for noninvasive assessment of cortical plasticity, we demonstrate potential neuroplasticity effect of tDCS in improving treatment-resistant auditory hallucinations in a schizophrenic patient.

Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive–compulsive disorder

Growing evidence in the last decade suggest significant role of immune alterations in the pathogenesis of obsessive-compulsive disorder (OCD). Cytokines, mediators of inflammation, alter the neurotransmitter concentration and result in a hyposerotonergic and hyperglutamatergic state implicated in pathogenesis of OCD. However, only few studies have examined cytokine abnormalities in OCD with inconsistent results possibly due to confounding effects of medications and comorbid anxiety-depression. We examined 20 comorbidity free, drug free OCD patients and 20 age and sex matched healthy controls. Clinical severity was assessed using Yale Brown Obsessive Compulsive Scale, Hamilton anxiety rating scale, Hamilton depression rating scale and Clinical Global Impression. Levels of different cytokines, Interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor (TNF)-α and Interferon (IFN)-γ were assessed using Cytometric Bead Array. OCD patients had significantly greater plasma levels of IL-2, IL-4, IL-6, IL-10 and TNF-α levels than controls but not IFN-γ. Reanalysis of data with only drug naïve patients (excluding 4 drug free patients) did not alter the results. Presence of these abnormalities in drug-naïve patients suggests the possible role of cytokines in the pathogenesis of OCD. Study findings have potential clinical utility in development of novel therapeutic options targeting cytokine aberrations in OCD.

Evidence for positive selection on Protocadherin Y gene in Homo sapiens: implications for schizophrenia.

Schizophrenia has been conceptualized as ‘the price that Homo sapiens pays for language’ — an elegant hypothesis that explains the paradoxical persistence of this disorder despite adverse fecundity (Crow, 2008). The origin of language and cerebral asymmetry have been linked to Protocadherin X and Y (PCDH11X/Y) genes — the uniquely human gene-pair created by duplicative translocation that occurred close to chimpanzee–human bifurcation 6 million years ago; this genetic event has been hypothesized as ‘the big bang’ which might have led to the origin of cerebral asymmetry and language (adaptive traits) as well as schizophrenia (maladaptive trait) (Crow, 2008). It has been proposed that due to its influence on these adaptive traits, this gene (and hence schizophrenia) persists (Crow, 2008). Hence, evidence for positive selection of PCDH11X/Y genes in Homo sapiens would further strengthen its hypothesized role as an answer to the ‘central paradox’. While Protocadherin Y (PCDH11Y) had been shown to have an accelerated rate of protein evolution in human lineage (Williams et al., 2006), definitive evidence for positive selection on PCDH11X/Y gene is yet to be established. In this letter, we present evidence for positive selection on Protocadherin Y gene in Homo sapiens. Eighteen orthologous mammalian gene sequences for human PCDH11X/Y genes (i.e. totally 20 homologous gene sequences including human PCDH11X and PCDH11Y) were analyzed in this study (Fig. 1; Supplementary-Table-1). The reading frames of these gene sequences were checked, corrected and aligned for further comparative genomic analyses using Phylogenetic Analysis by Maximum Likelihood (PAML) and Hypothesis testing using Phylogenies (HyPhy) software (for comprehensive methodology details please refer to Supplementary-Data-1). In comparative genomic analyses, a fundamental measure of the relative importance of selection and genetic drift in causing amino-acid substitutions is the dN/dS ratio or ω. dN is a measure of the degree to which two homologous coding DNA sequences differ at nonsynonymous sites. dS is a measure of the degree to which two homologous coding sequences differ with respect to silent nucleotide substitutions. Analyzing dN and dS are among the most direct ways to obtain evidence for positive selection on a

Yoga increases the volume of the hippocampus in elderly subjects

Context: The neurobiological effect of yoga on the cortical structures in the elderly is as yet unknown. Materials and Methods: Seven healthy elderly subjects received yoga intervention as an add-on life-style practice. Magnetic resonance imaging scans were obtained before and 6 months later. Voxel-based-morphometric analyses compared the brains before and after the yoga. Results: Yoga group was found to have increases in hippocampal, but not in occipital gray matter. Conclusion: Yoga has potential to reduce neuro-senescence. Small sample size and absence of the control group prevent generalization of the findings limiting its translational value.

Clinical correlates of thalamus volume deficits in anti-psychotic-naïve schizophrenia patients: A 3-Tesla MRI study

Background: Thalamus, the sensory and motor gateway to the cortex, plays an important role in cognitive and perceptual disturbances in schizophrenia. Studies examining the volume of the thalamus in schizophrenia have reported conflicting findings due to the presence of potential confounding factors such as low-resolution imaging and anti-psychotics. The thalamus volume in anti-psychotic-naïve patients determined using high-resolution 3-Tesla magnetic resonance imaging (MRI) has not yet been examined. Materials and Methods: Using 3-Tesla MRI, this study for the first time examined anti-psychotic-naïve schizophrenia patients (n=18; M:F:11:7) in comparison with healthy controls (n=19;M:F:9:10) group-matched for age, sex, handedness, education, and socioeconomic status. The volume of the thalamus was measured using a three-dimensional, interactive, semi-automated analysis with good inter-rater and intra-rater reliability. Psychopathology was assessed using the Scale for Assessment of Negative Symptoms (SANS) and the Scale for Assessment of Positive Symptoms (SAPS). Results: Right, left, and total thalamus volumes of patients were significantly smaller than those of controls after controlling for the potential confounding effect of intracranial volume. Thalamus volumes had significant positive correlation with positive symptoms score (SAPS) and significant negative correlation with negative symptoms score (SANS). Conclusions: Thalamus volume deficits in anti-psychotic-naïve schizophrenia patients support a neurodevelopmental pathogenesis. The contrasting correlation of thalamus volume deficits with psychopathology scores suggests that contrasting pruning aberrations underlie symptom genesis in schizophrenia.

Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders

Background and Aim Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders. Method A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. Result Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials. Conclusion Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry.