Search

BackgroundMismatch negativity (MMN) is elicited upon detecting background irregularities in the sensory environment and subsequent updating of the sensory context. Auditory MMN amplitude is reliably attenuated in schizophrenia patients. However, due to diversity in MMN deviant types (duration, frequency, intensity, gap, etc.), considerable variability exists in MMN findings reported from the early course and chronic samples. MMN is sometimes reported to be impaired or associated with schizotypy, but MMN and schizotypy are yet to be well examined in unaffected first-degree relatives of schizophrenia patients.MethodsFifty-two schizophrenia patients (SZ) were compared with thirty-six unaffected first-degree relatives (FDR) of schizophrenia patients and thirty-two age and sex-matched healthy controls (HC) on MMN indices using a two-tone passive auditory oddball paradigm with two conditions – duration deviant (MMNd) and frequency deviant (MMNf) event-related potential experiment. SZ sample was further split into two sub-groups 1) early-course/drug-naïve or drug-free (dSZ), and 2) chronic/medicated (cSZ) to examine the effect of illness chronicity and medication on MMN indices. We also checked whether schizotypy scores associated with MMNd and MMNf amplitudes in the FDR group.ResultsAt baseline, SZ group had significantly diminished MMNd amplitude compared to both HC and FDR groups (pDiscussionDeficient MMNd in SZ patients adds further support to the prediction error estimation abnormalities in schizophrenia. MMNd is a more robust measure than MMNf in differentiating SZ from FDR and HC. MMNd amplitude could be more impaired in hallucinating SZ patients and associate with illness chronicity. Though unaffected FDRs have MMN comparable to healthy controls, higher schizotypy in FDR is associated with lower MMN amplitude. MMN and schizotypy are potentially linked and deserve a nuanced examination.

BackgroundPrediction error is the surprise that is elicited when the sensory expectations are first established and then violated. Positive symptoms of schizophrenia, like auditory hallucinations (AH), are thought to arise from dysregulated prediction error-signalling. Roving mismatch negativity (rMMN) is a unique event-related potential (ERP) based assessment that allows examination of repetition-dependent adaptation and deviance detection—complimentary processes that are integral to prediction-error signalling. In the rMMN paradigm, the deviant tone becomes the new standard with several repetitions. Also, the number of repetitions of the standard stimuli keeps changing throughout the experiment; longer repetitions yield a more positive ERP response; this phenomenon is Repetition Positivity (RP). Longer repetitions of standard stimuli elicit stronger deviance detection when interrupted, and this is called deviant negativity (DN). A difference waveform between RP and DN reflects the strength of prediction error signalling, the mismatch negativity (MMN).MethodsTwenty-three schizophrenia patients with auditory hallucinations (SZ-AH) and twenty-three healthy controls (HC) underwent rMMN assessment. Standard stimuli were repeated in sets of 3, 8 and 33. The first tone of the succeeding set became the deviant for the preceding set, yielding three components for RP (RP3, RP8, RP33), DN (DN3, DN8, DN33), and MMN (MMN3, MMN8, MMN33). Amplitudes and latencies of these components were compared between SZ-AH and HC. We also looked for potential associations between rMMN indices (amplitudes and latencies) and clinical scores in SZ-AVH. We examined the correlation between the RP-DN pair for all three repetition sets (3, 8, 33).ResultsSZ-AH had suppressed DN (DN3, DN8, DN33) and MMN33 amplitudes in comparison to HC. However, none of the RP amplitudes were diminished. Only MMN33 latency was significantly longer in SZ-AH than in HC. Amplitudes and latencies associated with repetition set of 8 showed a significant correlation with the frequency and loudness of AH. HC showed a strong positive correlation between RP-DN pairs; SZ-AH did not, except for the RP33-DN33 pair.DiscussionThe link between repetition-dependent sensory adaptation and deviance detection is compromised in SZ-AH patients. Though RP profile (RP3, RP8, RP33) is unimpaired in SZ-AVH, it is potentially due to AH interfering with auditory information processing and not because of intact short-term plasticity of the echoic memory trace.

There are limited options to treat psychotic symptoms during early recovery stage of neuroleptic malignant syndrome (NMS) and catatonic symptoms in adolescents because of restrictions on the use of electroconvulsive therapy (ECT). Add-on transcranial direct current stimulation (tDCS) treatment twice daily for five consecutive days showed improvement in auditory–visual hallucinations and cognitive and bio-social functioning during early recovery stages of NMS in an adolescent. The use of tDCS in another adolescent diagnosed with severe depressive episode with psychotic symptoms and catatonia showed improvement in staring, mutism, rigidity, and interaction with add-on tDCS. The improvement observed lasted for a short duration and tDCS treatment was well tolerated without any severe adverse effect.

Background: The significance of selection and accelerated perception of self-related sensory information is an established phenomenon termed the self-bias effect. Self-related motor information is utilised by self-other monitoring processes like implicit measures of a sense of agency. Intentional binding is one such process that focuses on the temporal shift between a voluntary action and the sensory consequence. Recently, it was discovered that self-related information from visual stimuli could also affect retrospective intentional binding. Considering the importance of the left temporoparietal junction (l-TPJ) in self-other monitoring, we explored its causal role by modulating its activity with high-definition transcranial direct current stimulation (HD-tDCS). We predicted increased self-associated saliency and intentional binding from anodal HD-tDCS to l-TPJ compared to baseline and cathodal stimulation conditions. Methods: Fifteen healthy right-handed participants performed two computerized tasks: sound-label matching and intentional binding tasks. Behavioural data were collected at baseline and following randomly ordered anodal and cathodal HD-tDCS of l-TPJ. Anodal and cathodal HD-tDCS were administered to all the participants in two different sessions and were separated by at least 72 hours.Results: Strong self-bias effect was observed in all conditions. We didn’t note a retrospective intentional binding effect between self-associated and other-associated sounds in any of the conditions. HD-tDCS indicates a dual and crucial role of l-TPJ in general mismatch detection and other-associated stimulus representation in the self-bias effect.Conclusion: The results suggest a diverse role of l-TPJ in self-reference networks and general mismatch detection.

Objectives: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been used as neuromodulators in neuropsychiatric conditions. This study is aimed to find the effects of a single session of priming cathodal tDCS with intermittent theta-burst stimulation (iTBS) over left dorsolateral prefrontal cortex on heart rate variability (HRV) and cortical excitability parameters before and after perturbation. Materials and Methods: The neuromodulatory techniques used in the study were Cathodal tDCS for 20 min followed by iTBS for 3 min on the left dorsolateral prefrontal cortex (DLPFC). HRV variables and TMS parameters were recorded before and after this intervention of combined neuromodulation in 31 healthy volunteers (20 males and 11 females; age range of 19–35 years with Mean ± SD = 24.2 ± 4.7 years). Results: The results showed an overall increase in cortical excitability and parasympathetic dominance in healthy volunteers. Other measures of cortical excitability and HRV did not change significantly following single session of combined neuromodulation. Conclusion: This study showed that there is an overall increase in cortical excitability and parasympathetic dominance in the cohort of healthy volunteers following a combination of neuromodulation involving cathodal tDCS followed by iTBS over left DLPFC. Future studies exploring the effects of other possible combinations with sham stimulation could be carried out to explore the utility of dual stimulation as add-on therapy in disorders.

Objectives Electric field modeling utilizes structural brain magnetic resonance images (MRI) to model the electric field induced by non-invasive transcranial direct current stimulation (tDCS) in a given individual. Electric field modeling is being integrated with clinical outcomes to improve understanding of inter-individual variability in tDCS effects and to optimize tDCS parameters, thereby enhancing the predictability of clinical effects. The successful integration of modeling in clinical use will primarily be driven by choice of tools and procedures implemented in computational modeling. Thus, the electric field predictions from different modeling pipelines need to be investigated to ensure the validity and reproducibility of tDCS modeling results across clinical or translational studies. Methods We used T1w structural MRI from 32 healthy volunteer subjects and modeled the electric field distribution for a fronto-temporal tDCS montage. For five different computational modeling pipelines, we quantitatively compared brain tissue segmentation and electric field predicted in whole-brain, brain tissues and target brain regions between the modeling pipelines. Results Our comparisons at various levels did not reveal any systematic trend with regards to similarity or dissimilarity of electric field predicted in brain tissues and target brain regions. The inconsistent trends in the predicted electric field indicate variation in the procedures, routines and algorithms used within and across the modeling pipelines. Conclusion Our results suggest that studies integrating electric field modeling and clinical outcomes of tDCS will highly depend upon the choice of the modeling pipelines and procedures. We propose that using these pipelines for further research and clinical applications should be subject to careful consideration, and indicate general recommendations.

Transcranial direct current stimulation (tDCS) is a promising adjuvant treatment for persistent auditory verbal hallucinations (AVH) in Schizophrenia (SZ). Nonetheless, there is considerable inter-patient variability in the treatment response of AVH to tDCS in SZ. Machine-learned models have the potential to predict clinical response to tDCS in SZ. This study aims to examine the feasibility of identifying SZ patients with persistent AVH (SZ-AVH) who will respond to tDCS based on resting-state functional connectivity (rs-FC). Thirty-four SZ-AVH patients underwent resting-state functional MRI at baseline followed by add-on, twice-daily, 20-min sessions with tDCS (conventional/high-definition) for 5 days. A machine learning model was developed to identify tDCS treatment responders based on the rs-FC pattern, using the left superior temporal gyrus (LSTG) as the seed region. Functional connectivity between LSTG and brain regions involved in auditory and sensorimotor processing emerged as the important predictors of the tDCS treatment response. L1-regularized logistic regression model had an overall accuracy of 72.5% in classifying responders vs. non-responders. This model outperformed the state-of-the-art convolutional neural networks (CNN) model—both without (59.41%) and with pre-training (68.82%). It also outperformed the L1-logistic regression model trained with baseline demographic features and clinical scores of SZ patients. This study reports the first evidence that rs-fMRI-derived brain connectivity pattern can predict the clinical response of persistent AVH to add-on tDCS in SZ patients with 72.5% accuracy.

Background A significant proportion of obsessive compulsive disorder (OCD) patients do not respond to specific serotonin reuptake inhibitors (SSRIs). There is a need to evaluate novel treatment options for OCD. Objective In this double blinded, randomized, sham controlled study, we investigated the efficacy of add-on transcranial direct current stimulation (tDCS) in reducing the symptoms in SSRI-resistant OCD patients by employing anodal pre-supplementary motor area (pre-SMA) stimulation. Method Twenty-five patients with DSM-IV OCD having persistent symptoms despite adequate and stable treatment with at least one SSRI were randomly allocated to receive 20 min of verum (active) 2-mA tDCS or sham stimulation twice daily on 5 consecutive days [anode over Pre-SMA; cathode over right supra-orbital area]. Response to treatment was defined as at least 35% reduction in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) total score along with a Clinical Global Impression – Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Results The response rate was significantly greater in the verum tDCS(4 out of 12) compared to sham-tDCS (0 out of 13) [Fisher's exact test, p = 0.04]. Repeated measures analysis of variance with tDCS type (verum vs. sham) as between subjects factor showed that there was a significant tDCS-type X time-point interaction with significantly greater reduction of YBOCS total score [F (1,22) = 4.95,p = 0.04,partial-η2 = 0.18] in verum-tDCS group. Conclusions The results of this RCT suggest that tDCS may be effective in treating SSRI-resistant OCD. Future studies should examine the efficacy in larger samples of OCD and explore other potential target regions using randomized sham-controlled designs, in addition to examining the sustainability of the beneficial effects. Trial registration Clinical Trials Registry India ( http://ctri.nic.in/Clinicaltrials/login.php ): Registration Number- CTRI/2016/04/006837).

Corollary discharge mechanism refers to the suppression of sensory consequences of self-generated actions; a process that serves to distinguish between self and non-self based on discrimination of origination of action. It explains, say for example, why we cannot tickle ourselves. This review discusses how corollary discharge model is an essential neural integration mechanism central to the motor functioning of animal kingdom. In this article, research conducted in the field of corollary discharge has been reviewed to understand the neuroanatomical and neurophysiological basis of corollary discharge and gain insight into the biochemical basis of its dysfunction. This review article also explores the role of corollary discharge and its dysfunction in the presentation of symptoms of schizophrenia, discussing the findings from corollary discharge studies on schizophrenia population. Lastly, the link between schizophrenia psychopathology and corollary discharge dysfunction has been highlighted, and an attempt has been made to establish a case for correction of corollary discharge deficit in schizophrenia through neuromodulation.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Conventional transcranial Direct Current Stimulation (tDCS) has been reported to alleviate persistent auditory hallucinations (AH) in schizophrenia as an add-on intervention. High-Definition tDCS (HD-tDCS), an optimized form of tDCS, has the potential for more focalized neuromodulation. In this study, add-on HD-tDCS (5 days twice daily session with 2-mA cathodal current on left temporo-parietal junction) using 4 × 1 ring montage significantly reduced persistent AH (t = 3.6;p

Transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique that uses low-intensity alternating current, has been postulated to be a potential therapeutic option in treating the cognitive deficits in schizophrenia. Transcranial alternating current stimulation synchronizes the neural oscillations to the applied stimulation frequency in the stimulated cortical regions. In this report, we have reviewed the literature pertinent to the clinical application of tACS in psychiatric disorders; in addition, we have described the clinical use of online theta tACS in a schizophrenia patient with cognitive deficits. Online theta tACS led to improvement in working memory, attention, processing speed, and emotional processing. The beneficial effect of tACS persisted during reassessment of the patient after 50 days. Transcranial alternating current stimulation, given its noninvasiveness, safety, and ease of administration, has the potential to ameliorate cognitive deficits in neuropsychiatric disorders like schizophrenia.

Some aspects of saccadic performance have been found to be abnormal in chronic schizophrenia. The majority of this research has, however, been performed on patients treated with long-term antipsychotic medication. Very few studies have examined saccadic performance in antipsychotic-naïve/free patients. There are also very few studies describing the relationship between saccadic performance and clinical symptoms, particularly in antipsychotic free patients. In this study, we compared pro and antisaccade performance in a large sample of antipsychotic-naïve/free schizophrenia patients (N = 45) with healthy controls (N = 57). Clinical symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Negative Symptoms (SANS). In the antisaccade task, patients made significantly more errors, and their correct antisaccades had smaller amplitudes in comparison to healthy controls. Higher error rates were associated with increased severity of hallucinations. In the prosaccade task, patients had less accurate final eye positions, and made saccades with slower latency and reduced amplitude compared to the healthy controls. These observations in schizophrenia patients without the potential confounds of antipsychotic treatment suggest intrinsic link between saccadic deficits and schizophrenia pathogenesis. The relationship between antisaccade errors and hallucination severity supports the potential link between hallucinations and deficits in inhibitory control.

Delusions are false, fixed beliefs which are held with incredible conviction, in spite of being substantiated to the contrary. These are present in a number of brain disorders, primarily representing one of the fundamental components of schizophrenia, presenting in about 70% of the patient population. Responsivity of delusions to antipsychotic medication, if present, is only partial, with absolutely no response in several other cases. Limited studies have engaged in exploring the neural substrates of delusion. The most extensive study conducted in this field has implicated the right dorsolateral prefrontal cortex (rDLPFC) disruption, to be clinically associated with the severity of delusions. Using a brain stimulation technique, high-definition transcranial direct current stimulation (HD-tDCS), targeting the rDLPFC, has a potential to induce neuroplasticity changes that are presumed to decrease the delusion score and severity. Using HD-tDCS, focalized neuromodulation of rDLPFC can be implemented. Alongside mainstream treatment such as antipsychotic medications and cognitive behavioral interventions, HD-tDCS to rDLPFC, holds the potential to be an effective treatment module for addressing refractory delusions in schizophrenia.

The research on the alterations in functional connectivity in schizophrenia has been facilitated by development of an array of functional neuroimaging techniques. Functional Near Infra Red Spectroscopy (fNIRS) is a novel diffuse optical neuromonitring method with its own advantages and limitations. The advantages of fNIRS have made it to be frequently used as a research tool by medical community in different settings. In fNIRS the property of haemoglobin to absorb near infrared light is used to measure brain activity. It provides the indirect measurement of the neuronal activity in the areas of interest. The advantage of fNIRS being less restrictive has made it to be used more commonly in the research of psychiatric disorders in general, schizophrenia in particular. The fNIRS studies on patients with schizophrenia have shown haemodynamic hypo activation primarily in the prefrontal cortex during various cognitive tasks. In this review, initially we have briefly explained the basic principles of fNIRS followed by detailed review of fNIRS findings in patients with schizophrenia.

Cognitive deficits in individuals diagnosed with schizophrenia are ubiquitous and, therefore, cognitive remediation is considered one of the prime targets of a comprehensive intervention program for schizophrenia. However, cognitive remediation is a resource consuming intervention and in lower and middle-income countries (LAMIC) such interventions are often neglected due to the resource constraints of the mental health services set-ups. Therefore, it is imperative to develop cognitive remediation programs that are less resource consuming for the mental health service delivery system. Keeping this in view, in the present pilot study, we tested the feasibility of a caregiver assisted home-based cognitive remediation program and compared its efficacy with a clinic-based cognitive remediation program. Findings show that it is feasible to conduct cognitive remediation program with the help of caregivers in patients’ home settings and that the home-based cognitive remediation is as effective as the clinic-based cognitive remediation. The results of the study have been further discussed in the light of the practical implications, limitations and future research.

Obsessive-Compulsive Disorder (OCD) is characterized by abnormalities in the cortico-striato-thalamo-cortical (CSTC) circuitry of the brain. Antisaccade eye movement tasks measure aspects of the voluntary control of behaviour that are sensitive to CSTC circuitry dysfunction.In this study, we examined antisaccade eye movement parameters of OCD patients in comparison with healthy controls (HC). In addition, we also examined the relationship between the antisaccade eye movement parameters and the severity of OCD. Antisaccade performance among right handed OCD patients (N = 65) was compared to matched right handed HC (N = 57). Eye tracking data during the task performance were collected using an Eye-Link eye-tracker at 1000-Hz sampling rate. OCD symptom severity was evaluated using Yale-Brown obsessive compulsive scale.The antisaccade error percentage was significantly greater in OCD patients than HC (p0.001). In addition, OCD patients had less accurate final eye position compared to HC (p0.001). There were no significant correlation between antisaccade parameters and OCD severity measures.Deficient performance in antisaccade task supports CSTC abnormality in OCD and this appears to be independent of the illness severity. Examining this in remitted participants with OCD and in unaffected first degree relatives could help ascertaining their endophenotype validity.

Multiple lines of evidence have suggested a potential role of Neuregulin-1 (NRG1) in the neurodevelopmental pathogenesis of schizophrenia. Interaction between genetic risk variants present within NRG1 locus and non-specific gestational putative insults can significantly impair crucial processes of brain development. Such genetic effects can be analyzed through the assessment of digit ratio and dermatoglyphic patterns. We examined the role of two well-replicated polymorphisms of NRG1 (SNP8NRG221533 and SNP8NRG243177) on schizophrenia risk and its probable impact on the digit ratio and dermatoglyphic measures in patients (N = 221) and healthy controls (N = 200). In schizophrenia patients, but not in healthy controls, a significant association between NRG1 SNP8NRG221533 C/C genotype with lower left 2D:4D ratio, as well as with higher FA_TbcRC and DA_TbcRC. The substantial effect of SNP8NRG221533 on both digit ratio and dermatoglyphic measures suggest a potential role for NRG1 gene variants on neurodevelopmental pathogenesis of schizophrenia.

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 D 2 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 antipsychotic's affinity to D 2 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 D 2 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.

Combining cognitive retraining with transcranial direct current stimulation (tDCS) has been hypothesized to improve cognitive deficits in schizophrenia. The effect of combining a neuropsychological/psychophysiological task with tDCS, called "online-tDCS" for cognitive enhancement in schizophrenia is not rigorously assessed. In this proof-of-concept study, we aimed at evaluating the effect of a single session online-tDCS on working memory(WM) and its transferability to other cognitive functions. Numerical n-back(NNB), digit symbol substitution test(DSST), emotional matching and labelling test(E-MALT), and anti-saccade eye movement beeforefore and after 20 min tDCS (anode: left dorsolateral prefrontal cortex and cathode: left temporoparietal junction) applied during Sternberg's task(WM-task) were assessed. Twenty-three schizophrenia patients with cognitive deficits were randomized to receive either online-tDCS or offline-tDCS (without simultaneous Sternberg's task) sessions. All patients received one session each of active and sham tDCS in a randomized counterbalanced double-blind cross-over design. RMANOVA revealed a significant interaction effect between tDCS type (Online/Offline) x activeness (active/sham) of tDCS; the reaction time during 2-back performance in the NNB test improved in online-sham (F = 5.23, p < 0.038) but not online-active tDCS session. No significant changes were noted in DSST, E-MALT, and anti-saccade performance. Improved performance after online-sham tDCS suggests that performing the Sternberg's task enhanced 2-back performance. The counterintuitive observation was noted with respect to the non-enhancement of WM performance on combining the task to tDCS. Aberrant plasticity in schizophrenia might attain a transitional ceiling that would have resulted in restriction of enhancement on combining the two plasticity modulators. The transferability of improvement to other cognitive domains could not be ascertained.

Transcranial direct current stimulation (tDCS), a non-invasive, neuromodulatory technique, is being increasingly applied to several psychiatric disorders. In this study, we describe the side-effect profile of repeated tDCS sessions (N = 2005) that were administered to 171 patients (156 adults and 15 adolescents) with different psychiatric disorders [schizophrenia [N = 109], obsessive-compulsive disorder [N = 28], alcohol dependence syndrome [N = 13], mild cognitive impairment [N = 10], depression [N = 6], dementia [N = 2] and other disorders [N = 3]]. tDCS was administered at a constant current strength of 2 mA with additional ramp-up and ramp-down phase of 20 s each at the beginning and end of the session, respectively. Other tDCS protocol parameters were: schizophrenia and obsessive-compulsive disorder: 5-days of twice-daily 20-min sessions with an inter-session interval of 3-h; Mild cognitive impairment/dementia and alcohol dependence syndrome: at least 5-days of once-daily 20-min session; Depression: 10-days of once-daily 30 min session. At the end of each tDCS session, any adverse event observed by the administrator and/or reported by the patient was systematically assessed using a comprehensive questionnaire. The commonly reported adverse events during tDCS included burning sensations (16.2%), skin redness (12.3%), scalp pain (10.1%), itching (6.7%), and tingling (6.3%). Most of the adverse events were noted to be mild, transient and well-tolerated. In summary, our observations suggest that tDCS is a safe mode for therapeutic non-invasive neuromodulation in psychiatric disorders in adults as well as the adolescent population.

ObjectiveRecent observations demonstrate a significant ameliorative effect of add-on transcranial direct current stimulation (tDCS) on auditory verbal hallucinations (AVHs) in schizophrenia. Of the many SNPs, NRG1 rs35753505 and catechol-o-methyl transferase (COMT) rs4680 polymorphisms have shown to have a strong association with neuroplasticity effect in schizophrenia.MethodsSchizophrenia patients (n=32) with treatment resistant auditory hallucinations were administered with an add-on tDCS. The COMT (rs4680) and NRG1 (rs35753505) genotypes were determined. The COMT genotypes were categorised into Val group (GG; n=15) and Met group (GG/AG; n=17) and NRG1 genotypes were categorised into AA group (n=12) and AG/GG group (n=20).ResultsThe reduction in auditory hallucination sub-scale score was significantly affected by COMT-GG genotype [Time×COMT interaction: F(1,28)=10.55, p=0.003, ɳ2=0.27]. Further, COMT-GG effect was epistatically influenced by the co-occurrence of NRG1-AA genotype [Time×COMT×NRG1 interaction: F(1,28)=8.09, p=0.008, ɳ2=0.22]. Irrespective of genotype, females showed better tDCS response than males [Time×Sex interaction: F(1,21)=4.67, p=0.04, ɳ2=0.18].ConclusionCOMT-GG and NRG1-AA genotypes aid the tDCS-induced improvement in AVHs in schizophrenia patients. Our preliminary observations need replication and further systematic research to understand the neuroplastic gene determinants that modulate the effect of tDCS.

Objective: Brain imaging studies of structural abnormalities in OCD have yielded inconsistent results, partly because of limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and mega-analyses comprising the largest study of cortical morphometry in OCD ever undertaken. Method: T1-weighted MRI scans of 1,905 OCD patients and 1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness and surface area. Effect sizes for differences between patients and controls, and associations with clinical characteristics, were calculated using linear regression models controlling for age, sex, site, and intracranial volume. Results: In adult OCD patients versus controls, we found a significantly lower surface area for the transverse temporal cortexand a thinner inferiorparietalcortex.Medicated adult OCD patients also showed thinner cortices throughout the brain. In pediatric OCD patients compared with controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed showedsignificant differences in surface area. However, medicated pediatric OCD patients had lower surface area in frontal regions. Cohen's d effect sizes varied from 20.10 to 20.33. Conclusions: The parietal cortex was consistently implicated in both adults and children with OCD. More widespread cortical thickness abnormalities were found in medicated adult OCD patients, and more pronounced surface area deficits (mainly in frontal regions) were found in medicated pediatric OCD patients. These cortical measures represent distinct morphological features and may be differentially affected during different stages of development and illness, and possibly moderated by disease profile and medication.

This chapter attempts to summarize the existing literature in the domain of genetic basis of auditory hallucinations in schizophrenia. The proposed theoretical bases for hallucinations and their relevant neural substrates in the context of specific genes are discussed—these include language pathways, source monitoring deficits, aberrant salience, and dysregulated emotional valence. The key genes that have been implicated include FOXP2, dystrobrevin-binding protein 1 (DTNBP1), dopamine system genes, cholecystokinin, serotonergic genes, as well as microdeletion of the long arm of 22q11.2 chromosome. Future research with more robust methodology should replicate the present genetic findings as many of the present studies are limited by small sample size. These studies should be aimed at uncovering links between neurobiological parameters of auditory hallucination and gene-gene/gene-environment interactions. The complexity of genetic interactions with respect to the pathophysiology of auditory hallucinations is in need of further discourse and scientific elucidation.

Background: Deficient prefrontal cortex inhibitory control is of particular interest with regard to the pathogenesis of auditory hallucinations (AHs) in schizophrenia. Antisaccade task performance is a sensitive index of prefrontal inhibitory function and has been consistently found to be abnormal in schizophrenia. Methods: This study investigated the effect of transcranial direct current stimulation (tDCS) on antisaccade performance in 13 schizophrenia patients. Results: The tDCS resulted in significant reduction in antisaccade error percentage ( t = 3.4; P = 0.005), final eye position gain ( t = 2.3; P = 0.042), and AHs severity ( t = 4.1; P = 0.003). Conclusion: Our results raise the possibility that improvement in antisaccade performance and severity of AH may be mechanistically related.

Background and AimTranscranial 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.MethodA 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.ResultSynthesis 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.ConclusionTaking 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.

Persistent auditory verbal hallucinations (AVH) that are refractory to antipsychotic medications are reported in about 20-30% of schizophrenia patients. Transcranial Direct Current Stimulation (tDCS), a non-invasive and safe neuromodulatory technique, has attracted significant interest as an add-on treatment for refractory AVH in schizophrenia. Studies examining the efficacy of tDCS for refractory AVH in schizophrenia have reported inconsistent findings. In this study, using a randomized, double-blind, sham-controlled design (RCT), we sought to examine the effect of add-on tDCS [anode corresponding to left dorsolateral prefrontal cortex and cathode to left temporo-parietal junction; 2-mA, twice-daily sessions for 5-days] to treat refractory AVH in schizophrenia patients (N=25); following this RCT phase, patients that had30% reduction in AVH severity were offered an open-label extension (OLE) active stimulation to evaluate the effect of cross-over to verum tDCS. In the RCT phase, repeated measures ANOVA with tDCS type [verum (N=12) vs. sham (N=13)] as between subjects factor demonstrated a significant tDCS-type X time-point interaction [F=21.5, p0.001, partial-η2=0.48] with significantly greater reduction of AVH score in verum tDCS group as compared to sham group. In the OLE phase, sham-to-verum crossed over patients (N=13) showed significantly greater reduction in AVH severity than their corresponding change during RCT phase (t=2.9; p=0.01). Together, these observations add further support to the beneficial effects of add-on tDCS to treat refractory AVH schizophrenia.

Hippocampal deficits are an established feature of schizophrenia and are complementary with recent evidences of marked allocentric processing deficits being reported in this disorder. By "Cognitive mapping" we intend to refer to the concepts from the seminal works of O′Keefe and Nadel (1978) that led to the development of cognitive map theory of hippocampal function. In this review, we summarize emerging evidences and issues that indicate that "Cognitive mapping deficits" form one of the important cognitive aberrations in schizophrenia. The importance has been placed upon hippocampally mediated allocentric processing deficits and their role in pathology of schizophrenia, for spatial/representational cognitive deficits and positive symptoms in particular. It is modestly summarized that emerging evidences point toward a web of spatial and cognitive representation errors concurrent with pronounced hippocampal dysfunction. In general, it can be stated that there are clear and consistent evidences that favor the cognitive mapping theory in explaining certain deficits of schizophrenia and for drawing out a possible and promising endophenotype/biomarkers. Further research in this regard demands attention.

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.

Objective Perspective-taking ability is an essential spatial faculty that is of much interest in both health and neuropsychiatric disorders. There is limited data on the neural correlates of perspective taking in the context of a realistic three-dimensional environment. We report the results of a pilot study exploring the same in eight healthy volunteers. Methods Subjects underwent two runs of an experiment in a 3 Tesla magnetic resonance imaging (MRI) involving alternate blocks of a first-person perspective based allocentric object location memory task (OLMT), a third-person perspective based egocentric visual perspective taking task (VPRT), and a table task (TT) that served as a control. Difference in blood oxygen level dependant response during task performance was analyzed using Statistical Parametric Mapping software, version 12. Activations were considered significant if they survived family-wise error correction at the cluster level using a height threshold of p＜0.001, uncorrected at the voxel level. Results A significant difference in accuracy and reaction time based on task type was found. Subjects had significantly lower accuracy in VPRT compared to TT. Accuracy in the two active tasks was not significantly different. Subjects took significantly longer in the VPRT in comparison to TT. Reaction time in the two active tasks was not significantly different. Functional MRI revealed significantly higher activation in the bilateral visual cortex and left temporoparietal junction (TPJ) in VPRT compared to OLMT. Conclusion The results underscore the importance of TPJ in egocentric manipulation in healthy controls in the context of reality-based spatial tasks.

Error monitoring and response inhibition is a key cognitive deficit in obsessive-compulsive disorder (OCD). Frontal midline regions such as the cingulate cortex and pre-supplementary motor area are considered critical brain substrates of this deficit. Electrophysiological equivalent of the above dysfunction is a fronto-central event related potential (ERP) which occurs after an error called the error related negativity (ERN). In this study, we sought to compare the ERN parameters between medication-naive, comorbidity-free subjects with OCD and healthy controls (HC). Age, sex and handedness matched subjects with medication-naive, comorbidity-free OCD (N = 16) and Healthy Controls (N = 17) performed a modified version of the flanker task while EEG was acquired for ERN. EEG signals were recorded from the electrodes FCz and Cz. Clinical severity of OCD was assessed using the Yale Brown Obsessive Compulsive Scale. The subjects with OCD had significantly greater ERN amplitude at Cz and FCz. There were no significant correlations between ERN measures and illness severity measures. Overactive performance monitoring as evidenced by enhanced ERN amplitude could be considered as a biomarker for OCD.

Background Corollary discharge (CD), ubiquitous throughout the animal kingdom, refers to suppression of sensory consequences arising from self-generated actions. Complex motor acts like covert/overt speech are associated with corollary discharge that helps in ascertaining agency. Auditory verbal hallucinations (AVH) are hypothesized to originate due to failure of corollary discharge in auditory processing system. Transcranial Direct Current Stimulation (tDCS), as an add-on treatment, has been reported to significantly reduce severity of persistent AVH in schizophrenia patients. In this study, we describe mediation analysis findings that strongly support a role for amelioration of corollary discharge deficits as a mechanistic basis for tDCS effects on AVH in schizophrenia. Methods 27 DSM-IV-TR Schizophrenia patients (SCZ) with persistent AVH despite adequate antipsychotic treatment and 27 healthy controls (HC) underwent neurophysiological assessment for CD. In an event-related potential task, N1 component that reflects cortical responsiveness of auditory cortex to sounds, was elicited and examined in two conditions – i) Talk (with online auricular feedback of self-spoken speech sounds) and ii) Listen (passive playback of recorded self-spoken speech sounds). Corollary discharge index (CDI) was calculated by subtracting Listen condition N1 amplitude from Talk condition N1 amplitude (at FCz). Among these 27 patients, 13 patients participated in a randomized, double-blind, sham-controlled study examining the effect of add-on tDCS on AVH and CDI [5 consecutive days, twice-daily, 20-minute sessions; 2mA; anode: left dorsolateral prefrontal cortex; cathode: left temporo-parietal junction]. Mediation analysis was modelled with tDCS type (Verum vs. Sham) as independent variable, percent change in auditory hallucination rating scale score (AHRS) as dependent variable and percent change in CDI as the mediator. As recommended for small samples, bootstrap estimation approach with 5000 samples was used to examine the indirect effect of independent variable on dependent variable through proposed mediator for significance. Results SCZ (Mean±SD: -0.67 ± 1.93) had significantly deficient CDI than HC (1.36 ± 2.18) (t=3.62; p=0.001). Verum tDCS (32.24 ± 16.48) resulted in greater percentage reduction in AHRS than sham (4.79 ± 8.84) (t=3.64, p=0.004). There was a significant increase in CDI (t=2.48; p=0.03) with verum (0.85 ± 1.08) but not sham (-0.55 ± 0.98) tDCS. Percent change in CDI positively correlated with percent change in AHRS from pre-RCT to post-RCT time-point for the entire sample (N=13; ρ=0.55, p=0.05). Regression analysis showed that tDCS type (verum/sham) was a significant predictor of percent change in AHRS (β=-27.46, p=0.003) as well as percent change in CDI (β=-1.40, p=0.033). Percent change in CDI was a significant predictor of percent change in AHRS (β=8.87, p=0.014). When controlled for percent change in CDI, tDCS type ceased to be a significant predictor of percent change in AHRS (β=-15.0, p=0.063). The predictors accounted for approximately 75% of the variance (R2=0.756, p

The ‘cognitive mapping' component of spatial cognition, namely – the allocentric/egocentric function and its relation to symptoms in schizophrenia is relatively unexplored. In this study, we compared schizophrenia patients ( N =44) to demographically-matched healthy controls ( N =43) using computer-administered visuospatial transformation tasks with egocentric and allocentric components and analyzed their correlation with symptoms. Significant diagnosis X task-type interaction effect was seen on task accuracy. Patients performed significantly worse than controls in the allocentric letter rotation task (LRT) but not in the egocentric people rotation task (PRT). Accuracy in the LRT was significantly lesser than in PRT among patients but not among controls. Patients were significantly slower as compared to controls in both tasks. Both groups took longer to perform PRT as compared to LRT. LRT accuracy showed significant negative correlation with total positive symptoms as well as negative symptoms scores. Angle of rotation, perspective (front-facing/back-facing), orientation (mirrored/normal), and stimulus type (letter/number) were found to significantly influence performance in both groups of subjects. The present data support the finding that there is a differential impairment of allocentric abilities in schizophrenia patients. Further systematic research in this area may facilitate better understanding of schizophrenia pathogenesis.

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.

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.