Sri Mahavir Agarwal

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.

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.

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.

Rapid improvement of auditory verbal hallucinations in schizophrenia after add-on treatment with transcranial direct-current stimulation.

Abstract Treatment of nonresponsive auditory hallucinations in schizophrenia have been reported to improve with transcranial direct-current stimulation. This case description illustrates the use of add-on transcranial direct-current stimulation for rapid amelioration of auditory hallucinations in schizophrenia during the acute phase. Because transcranial direct-current stimulation is safe, largely well tolerated, and relatively inexpensive, this add-on treatment option is worth exploring through further rigorous studies.

Revisiting Geschwind's hypothesis on brain lateralisation: A functional MRI study of digit ratio (2D:4D) and sex interaction effects on spatial working memory

The Geschwind-Behan-Galaburda (GBG) hypothesis links cerebral lateralisation with prenatal testosterone exposure. Digit ratio measures in adults have been established as potential markers of foetal sex hormonal milieu. The aim of the study was to evaluate the sex-dependent interaction of digit ratio measures and cerebral lateralization as well as their neurohemodynamic correlates using functional MRI (fMRI). Digit ratio measures—ratio of index finger (2D) length to ring finger (4D) length (2D:4D) and difference between 2D:4D of two hands, i.e., right minus left (DR–L)—were calculated using high resolution digital images in 70 right-handed participants (42 men) based on reliable and valid method. fMRI was acquired during the performance of a spatial working memory task in a subset of 25 individuals (14 men), and analysed using Statistical Parametric Mapping 8 (SPM8) and the Laterality Index toolbox for SPM8. Men had significantly less bilateral 2D:4D than women. There was a significant negative correlation between right 2D:4D and 2-Back task accuracy (2BACC) in women. A significant sex-by-right 2D:4D interaction was observed in left parahippocampal gyrus activation. Additionally, sex-by-DR–L interaction was observed in left IPL activation. DR–L showed a significant positive correlation with the whole brain Laterality Index (LI), and LI, in turn, demonstrated a significant negative correlation with 2BACC. Our study observations suggest several novel sex-differential relationships between 2D:4D measures and fMRI activation during spatial working memory task performance. Given the pre-existing background data supporting digit ratio measures as putative indicator of prenatal sex hormonal milieu, our study findings add support to the Geschwind-Behan-Galaburda (GBG) hypothesis.

Impact of antipsychotic medication on transcranial direct current stimulation (tDCS) effects in schizophrenia patients

Transcranial direct current stimulation (tDCS) has generated interest as a treatment modality for schizophrenia. Dopamine, a critical pathogenetic link in schizophrenia, is also known to influence tDCS effects. We evaluated the influence of antipsychotic drug type (as defined by dopamine D2 receptor affinity) on the impact of tDCS in schizophrenia. DSM-IV-TR-diagnosed schizophrenia patients [N=36] with persistent auditory hallucinations despite adequate antipsychotic treatment were administered add-on tDCS. Patients were divided into three groups based on the antipsychotics affinity to D2 receptors. An auditory hallucinations score (AHS) was measured using the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS). Add-on tDCS resulted in a significant reduction inAHS. Antipsychotic drug type had a significant effect on AHS reduction. Patients treated with high affinity antipsychotics showed significantly lesser improvement compared to patients on low affinity antipsychotics or a mixture of the two. Furthermore, a significant sex-by-group interaction occurred; type of medication had an impact on tDCS effects only in women. Improvement differences could be due to the larger availability of the dopamine receptor system in patients taking antipsychotics with low D2 affinity. Sex-specific differences suggest potential estrogen-mediated effects. This study reports a first-time observation on the clinical utility of antipsychotic drug type in predicting tDCS effects in schizophrenia.

Sustained improvement of negative symptoms in schizophrenia with add-on tDCS: a case report.

To the Editor: Clozapine is an atypical antipsychotic with a wide range of adverse effects. It is important for clinicians to be aware of these side effects because many of these are life threatening. Even though myocarditis is a well-known serious cardiac adverse condition, pericarditis associated with clozapine use is also gaining attention (1-3). Here we report a case of clozapine-induced pericardial effusion and paracardiac pleural effusion. Case Report: Ms. L, a 45-year-old woman, presented with a chronic schizophrenic illness characterized by delusion of persecution, reference and third person discussing type of auditory hallucinations of eleven years duration. She was on treatment with tablet chlorpromazine up to 400 mg for almost five years and risperidone 6 mg for the next one year. She had not improved with these two trials of antipsychotics. Ms. L had developed severe tardive dyskinesia (TD), which involved the oro-bucco-lingual region resulting in severe impairment in speech. The Abnormal Involuntary Movements Scale (AIMS) rating was 24. Her speech was almost incomprehensible, and she had to use gestures while communicating to others due to the TD. In view of the failure of two antipsychotics and due to the presence of debilitating TD, she was started on clozapine and the dose was escalated gradually up to 300 mg per day. It was ensured that the dose escalation was slow, starting from 12.5 mg per day as per Maudsley Prescribing Guidelines (4). The baseline and follow-up blood counts were normal, and the baseline ECG was within normal limits. On the third week after starting clozapine, she developed fever (102° F), cough, chest pain of constricting type and dyspnea. The blood picture was that of neutrophilic leucocytosis without eosinophilia. The liver function test, renal function test and electrolytes were within normal limits. She did not respond to an antibiotic course of tablet levofloxacin 500 mg twice daily for three days. Subsequently, an emergency medical opinion was sought. The chest x-ray revealed paracardiac pleural effusion and echocardiogram revealed the presence of pericarditis and pericardial effusion. Other causes of pericarditis were ruled out by the cardiologist who managed her conservatively with discontinuation of clozapine. The cardiac troponins were in normal range. The symptoms resolved in four days and, by the tenth day, chest x-ray and echocardiogram were normal. The patient was subsequently started on tablet olanzapine up to 20 mg per day. There was 30% reduction in her symptoms with a six-week trial of olanzapine. She reported that the fearfulness and “voices” had come down to some extent and she was seen interacting better with others. However, on mental state examination, she still had the delusions which she had previously reported. She was also initiated on benzodiazepines (clonazepam 1 mg twice daily) for the treatment of TD, taking into consideration some preliminary evidence for this group of medications in TD (5). Discussion: The cardiac side effects of clozapine are potentially life threatening. Pericarditis and related pericardial effusion have been noted in some of the previous reports (6, 7). This report—which adds to the previous literature—raises concern about the risk of acute cardiac side effects in patients treated with clozapine (3, 8). The Naranjo Adverse Drug Reaction Probability Scale suggested a probable relationship between clozapine use and this adverse event (9). As reported previously in some papers, the patient in this report was managed conservatively with stoppage of clozapine (1, 3, 6). Some of the patients in the previous reports on this adverse event had developed serious associated concerns like cardiac tamponade and required pericardiocentesis (2). There was no evidence for associated polyserositis in our case in contrast to some other earlier reports (10, 11). The blood picture in our patient was devoid of eosinophilia even though, previously, eosinophilia as an indicator of clozapine-induced pericarditis has been reported (12). Even though pericarditis is unpredictable and relatively uncommon, it merits attention and early intervention when the pertinent clinical symptoms occur. It is important for clinicians to be aware of this adverse event. Note: Author JCN is supported by the INSPIRE faculty scheme of Department of Science and Technology, Government of India.

Enhancing Putative Mirror Neuron Activity with Magnetic Stimulation: A Single-Case Functional Neuroimaging Study

M irror neuron-driven embodied simulation, based on the neural exploitation hypothesis has been proposed as a physiological basis of social cognitive abilities in humans (1). Experimental evidence points to a relationship between social cognition and putative mirror neuron activity in neuropsychiatric disorders like schizophrenia (2) and autism (3). Experiments to explore strategies to modulate mirror neuron activity (MNA) are rare (4). We are unaware of any previous report that applied targeted brain stimulation to improve functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) activation during action observation paradigms, an indirect method of measuring MNA. Transcranial magnetic stimulation (TMS) is a safe, noninvasive method of administering targeted brain stimulation (5) to enhance focal brain activity. In this letter, we describe the first report of a single session of high-frequency repetitive TMS (HF-rTMS) delivered at the left inferior frontal gyrus (IFG) enhancing putative MNA as ascertained by functional magnetic resonance imaging (MRI).

Cerebellar volume deficits in medication-naïve obsessive compulsive disorder

Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD.

Visual Image-induced Craving for Ethanol (VICE): Development, validation, and a pilot fmri study

Background: Craving induction in a controlled environment is helpful in the research of craving mechanism and its role in development of alcohol dependence (AD). We describe a novel tool Visual Image-induced Craving for Ethanol (VICE) and its effects on brain activation with pilot functional magnetic resonance imaging (fMRI). Materials and Methods: Alcohol-related visual cues (ARCs) in 5 scenarios were photographed, which included pictures of bars, alcoholic beverage bottles, pouring of alcohol into glasses, glasses filled with alcohol, and scenes of people sipping alcohol, counterbalanced with neutral pictures (involving water, milk etc.,). Craving scores were obtained from 15 hospitalized patients with AD to validate this tool. In the pilot fMRI (3-Tesla) study, 5 patients were examined using VICE in a symptom provocation model. Group level-fixed effect analysis of brain activation differences was done using SPM8. Results: VICE showed a high internal consistency with Cronbachs α coefficient of 0.86, which confirmed its reliability. Concurrent validity of VICE was demonstrated via its convergence with the Penn Alcohol Craving Scale. ARCs had significantly greater mean craving scores than neutral cues in all the 5 scenarios (intentional validity). In the pilot fMRI, patients were found to have greater activation while viewing ARCs compared to the neutral cues in right insular cortex and deficient activation in right orbitofrontal cortex. Conclusions: The VICE is a reliable and valid measure of alcohol craving with promising clinical and translational research implications. Preliminary fMRI findings indicate it can be used as a symptom provocation tool for fMRI experiments.