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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.

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.

Transcranial direct current stimulation (tDCS) is a novel brain stimulation technique which has kindled hope in alleviating motor, language as well as cognitive deficits in neuronal injury. Current case report describes application of tDCS in two phases using two different protocols in a patient with hypoxic injury. In the first phase anodal stimulation of dorsolateral prefrontal cortex improved the language fluency. Subsequently, after 6 months second phase application of anodal stimulation over posterior parietal region targeted arithmetic and working memory deficits. Individualising the treatment protocols of brain stimulation, based on the lesion and the functional deficits, for neuro-rehabilitation is emphasised.

ObjectiveNo diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Magnetic resonance imaging (MRI) studies have provided evidence for structural abnormalities in distinct brain regions, but effect sizes are small and have limited clinical relevance. To investigate whether individual patients can be distinguished from healthy controls, we performed multivariate analysis of structural neuroimaging data from the ENIGMA-OCD consortium.MethodWe included 46 data sets with neuroimaging and clinical data from adult (≥18 years) and pediatric (1images from 2,304 OCD patients and 2,068 healthy controls were analyzed using standardized processing to extract regional measures of cortical thickness, surface area and subcortical volume. Machine learning classification performance was tested using cross-validation, and possible effects of clinical variables were investigated by stratification.ResultsClassification performance for OCD versus controls using the complete sample with different classifiers and cross-validation strategies was poor (AUC—0.57 (standard deviation (SD)=0.02;Pcorr=0.19) to 0.62 (SD=0.03;Pcorrcorr>.99) to 0.54 (SD=0.08;Pcorr>.99)). In contrast, good classification performance (>0.8 AUC) was achieved within subgroups of patients split according to their medication status.ConclusionsParcellated structural MRI data do not enable good distinction between patients with OCD and controls. However, classifying subgroups of patients based on medication status enables good identification at the individual subject level. This underlines the need for longitudinal studies on the short- and long-term effects of medication on brain structure.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

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.

Over the recent years, there has been an increasing application of noninvasive brain stimulation techniques such as transcranial direct-current stimulation (tDCS) to modify eating behaviors in healthy population and persons with eating disorders. tDCS is a noninvasive, neuromodulatory intervention which is well-tolerated and safe. In this case report, we describe the successful application of add-on tDCS in a patient with schizophrenia to reduce the craving for food that in turn, helped in reversing the weight gain.

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.

Abnormalities in resting and event-related brain oscillations are known to be associated with cognitive deficits in schizophrenia. Transcranial alternating current stimulation (tACS) modulates these rhythms across the neuronal circuits and could have a potential therapeutic role in psychiatric disorders. In this report, we describe, for the first time, application of online tACS in a schizophrenia patient with working memory deficits. This case report supports the feasibility and potential utility of online tACS in schizophrenia, which needs further systematic research.

Objective: structural brain imaging studies in obsessive compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta and mega-analyses of data from OCD sites worldwide. Method: T-1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results: the meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen's d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. Conclusions: the results indicate different patterns of sub cortical abnormalities in pediatric and adult OCD patients. The patlidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Background Auditory verbal hallucinations (AH), one of the hallmark symptoms, are present in 60–80% of schizophrenia (SZ) patients. 25% of patients suffering from AH in schizophrenia fail to respond to any psychotropic medication. Non-invasive brain stimulation techniques like transcranial direct current stimulation (tDCS), with cathodal electrode placement on the left temporoparietal junction (TPJ) is known to alleviate such symptoms in SZ. In this study, we describe the effects of booster tDCS after relapse of AH in patients. The pattern and effectiveness of booster treatment cycles for alleviation of AH in a naturalistic clinical setting are explored in this study. Methods Patients with persistent AH (n=15) received an initial course (cycle) of add-on tDCS with cathode at left TPJ and anode over left dorsolateral prefrontal cortex (L-DLPFC) with 2mA current, twice-daily 20-minute sessions for 5 days with intersession interval of 3-hours. Clinical global impression- improvement scale (CGI-I) was rated at the end of the course for every patient. All the patients who were found to show response (“much improved” and “very much improved”) received repeat cycles of add-on booster tDCS after a varying duration ranging from 1–32 months from initial treatment course, due to relapse/persistence of AH. Thirteen out of fifteen patients received one booster cycle while one patient received 3 booster cycles and another received 12 booster cycles. We conducted a spearman’s rank correlation test to determine the correlation between CGI-I score rating at the end of add-on tDCS, and the duration of maintenance of improvement before relapse/ worsening of AH. Results Six of the fifteen patients (40%) had responded “very much improved” and nine (60%) patients had responded “much improved” to tDCS in the initial cycle. It was found that 50% of the initial “very much improved” responders (n=3) had a comparable response to tDCS after booster sessions for relapse of symptoms while 50% of patients showed “much improved” (n=2) and “minimally improved” (n=1) response in the booster sessions. Among the nine patients who showed “much improved” response from the initial cycle, one patient showed better response than initial cycle (“very much improved”) to booster session. Five patients showed “minimally changed” response in the second cycle in the booster sessions while three patients had comparable responses. The average duration of symptom free interval/ maintenance of improvement with initial cycle of tDCS was found to be 10.46± 9.23 months. The CGI improvement from the initial add-on tDCS course and the duration of the maintenance of improvement/symptom-free interval before the booster session was not found to be significantly correlated (r=0.332, p=0.226) Discussion A reduction in hallucinations was noted with booster tDCS in patients who had responded to the initial course of add-on tDCS. Booster tDCS is a feasible option and given its cost-effectiveness and ease of administration, booster sessions of tDCS can be considered for resurgence of symptoms. Future studies are recommended in systematically exploring maintenance tDCS as an add-on treatment for persistent/recurring AVH in 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 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.

Transcranial Direct Current Stimulation (tDCS) involves application of weak direct electric currents (up to 2mA) using scalp electrodes with resultant neuroplasticity modulation by altering the cortical excitability. Though the side effect profile of tDCS is benign and less severe, the utility and safety of tDCS in dermatological conditions remains a concern. In this context, we report the safe administration of tDCS in a subject with substance induced psychosis and co-morbid psoriasis.

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.