Mismatch Negativity in Schizophrenia, Unaffected First-degree Relatives, and Healthy Controls.

BACKGROUND: Mismatch negativity (MMN) amplitude is attenuated in schizophrenia patients (SZ). However, variability in illness course among SZ samples and types of deviant stimuli used in MMN paradigms have contributed to inconsistent findings across studies. Though MMN is suggested to be impaired in schizotypy, the potential link between the two is yet to be systematically examined in unaffected first-degree relatives of schizophrenia patients (FDR). METHODS: The SZ sample had twenty-two drug-naïve or drug-free patients (dSZ) and thirty chronic/medicated patients (cSZ). dSZ and cSZ patients were compared with thirty-six unaffected FDR and thirty-two healthy controls (HC) using a two-tone passive auditory oddball MMN paradigm in an event-related potential experiment with two conditions (presented as separate blocks)-duration-deviant (duration-MMN) and frequency-deviant (frequency-MMN). Schizotypy scores and MMN indices were examined for correlation in FDR. RESULTS: Duration-MMN amplitude was significantly attenuated in both dSZ and cSZ compared to other groups. dSZ and cSZ did not differ on MMN indices. Psychopathology scores and features of illness (illness duration, medication dosage, etc.) did not correlate with MMN indices. In FDR, Schizotypal trait measures did not correlate with MMN indices. CONCLUSIONS: Duration-MMN emerged as a more robust indicator of prediction error signalling deficit in SZ. Frequency-MMN amplitude did not significantly differ among the groups, and MMN indices did not correlate with state and trait measures of schizophrenia-related psychopathology. These findings reiterates that auditory sensory processing captured by MMN is likely reflective of dynamic cognitive functions at the point of testing, and is unlikely to be an expression of enduring symptomatology.

Role of Ayurveda in the management of psychotic disorders: A systematic review of clinical evidence.

BACKGROUND: Despite advancements in the treatment of psychosis, many patients continue to experience persistent symptoms and relapses during antipsychotic treatment, particularly when they fail to adhere to prescribed medications. Ayurveda explains psychotic disorders as "Unmada" and describes various treatment protocols. Although these therapies and methods have been in practice for several years, systematic evidence has not been generated for the same. Thus, in the current review an attempt has been made to illustrate currently available clinical trials on Ayurveda management of psychosis. METHODS: We identified 23 studies by literature search in PubMed Central, Cochrane Library and AYUSH Research portal. Out of these, 21 were retrieved after systematic deduplication. After excluding nine studies, 12 studies were included for review. RESULTS: Total of 12 articles comprising 10 clinical trials and 2 case reports were reviewed. Most of the studies demonstrated significant improvement in psychopathology assessed through various symptom rating scales. DISCUSSION: The role of Ayurveda, in the treatment of psychosis is least explored. Currently available studies on the effect of Ayurveda treatment on psychosis are very less in number to draw a valuable conclusion. Hence there is a large scope for conducting neurobiologically informed clinical research in the management of psychotic disorders using Ayurvedic approaches.

Comparison of gut microbiome profile in patients with schizophrenia and healthy controls - A plausible non-invasive biomarker?

The human gut microbiome regulates brain function through the microbiome-gut-brain axis and is implicated in several neuropsychiatric disorders. However, the relationship between the gut microbiome and the pathogenesis of schizophrenia (SCZ) is poorly defined, and very few studies have examined the effect of antipsychotic treatment response. We aim to study the differences in the gut microbiota among drug-naïve (DN SCZ) and risperidone-treated SCZ patients (RISP SCZ), compared to healthy controls (HCs). We recruited a total of 60 participants, from the clinical services of a large neuropsychiatric hospital, which included DN SCZ, RISP SCZ and HCs (n = 20 each). Fecal samples were analyzed using 16s rRNA sequencing in this cross-sectional study. No significant differences were found in taxa richness (alpha diversity) but microbial composition differed between SCZ patients (both DN and RISP) and HCs (PERMANOVA, p = 0.02). Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest model identified the top six genera, which significantly differed in abundance between the study groups. A specific genus-level microbial panel of Ruminococcus, UCG005, Clostridium_sensu_stricto_1 and Bifidobacterium could discriminate SCZ patients from HCs with an area under the curve (AUC) of 0.79, HCs vs DN SCZ (AUC: 0.68), HCs vs RISP SCZ (AUC: 0.93) and DN SCZ vs RISP SCZ (AUC: 0.87). Our study identified distinct microbial signatures that could aid in the differentiation of DN SCZ, RISP SCZ, and HCs. Our findings contribute to a better understanding of the role of the gut microbiome in SCZ pathophysiology and suggest potential targeted interventions.

A Primer on Interoception and its Importance in Psychiatry.

Interoception is the perception of signals from inside the body. It plays a significant role in the nervous, cardiovascular, respiratory, gastrointestinal, genitourinary, and endocrine systems. It is also closely related to the autonomic nervous system and inflammatory pathways and plays a significant role in our optimal functioning. Recently, interoception has gained more attention in neuropsychiatric research. Anatomical and physiological aspects of interoception like relevant brain areas, the role of the vagus nerve, and the autonomic nervous system are gradually being understood. Different facets of interoception like interoceptive attention, detection, magnitude, discrimination, accuracy, awareness, and appraisal have been proposed and their assessments and importance are being evaluated. Further, interoception is often dysregulated or abnormal in psychiatric disorders. It has been implicated in the psychopathology, etiopathogenesis, clinical features and treatment of mood, anxiety, psychotic, personality and addiction-related disorders. This narrative review attempts to provide a nuanced understanding of the pathway(s), components, functions, assessments, and problems of interoception and will help us to detect its disturbances and evaluate its impact on psychiatric disorders, leading to a better perspective and management. This will also advance interoception-related research.

Resting-state functional connectivity correlates of antipsychotic treatment in unmedicated schizophrenia.

BACKGROUND: Antipsychotics may modulate the resting state functional connectivity(rsFC) to improve clinical symptoms in schizophrenia(Sz). Existing literature has potential confounders like past medication effects and evaluating preselected regions/networks. We aimed to evaluate connectivity pattern changes with antipsychotics in unmedicated Sz using Multivariate pattern analysis(MVPA), a data-driven technique for whole-brain connectome analysis. METHODS: Forty-seven unmedicated patients with Sz(DSM-IV-TR) underwent clinical evaluation and neuroimaging at baseline and after 3-months of antipsychotic treatment. Resting-state functional MRI was analysed using group-MVPA to derive 5-components. The brain region with significant connectivity pattern changes with antipsychotics was identified, and post-hoc seed-to-voxel analysis was performed to identify connectivity changes and their association with symptom changes. RESULTS: Connectome-MVPA analysis revealed the connectivity pattern of a cluster localised to left anterior cingulate and paracingulate gyri (ACC/PCG) (peak coordinates:x = -04,y = +30,z = +26;k = 12;cluster-pFWE=0.002) to differ significantly after antipsychotics. Specifically, its connections with clusters of precuneus/posterior cingulate cortex(PCC) and left inferior temporal gyrus(ITG) correlated with improvement in positive and negative symptoms scores, respectively. CONCLUSION: ACC/PCG, a hub of the default mode network, seems to mediate the antipsychotic effects in unmedicated Sz. Evaluating causality models with data from randomised controlled design using the MVPA approach would further enhance our understanding of therapeutic connectomics in Sz.

Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-Based Functional Magnetic Resonance Imaging Meta-analysis.

BACKGROUND: Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia. Functional magnetic resonance imaging studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular, decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the functional magnetic resonance imaging literature. METHODS: Functional magnetic resonance imaging studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy control subjects were identified. Frequentist and Bayesian voxelwise meta-analyses were performed separately, by implementing a random-effect model with unthresholded group-level T-maps from individual studies as input. RESULTS: In total, 17 studies with a cumulative total of 677 at-risk individuals and 805 healthy control subjects were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy control subjects. Similar results were observed with Bayesian analyses, which provided strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region. CONCLUSIONS: These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies instead focus on impaired functional connectivity as an alternative and promising endophenotype.

Altered Intestinal Permeability Biomarkers in Schizophrenia: A Possible Link with Subclinical Inflammation.

Background and Purpose: Emerging studies have shown that gut-derived endotoxins might play a role in intestinal and systemic inflammation. Although the significance of intestinal permeability in modulating the pathogenesis of Schizophrenia (SCZ) is recognized, not much data on the specific role of intestinal permeability biomarkers, viz., zonulin, lipopolysaccharide-binding protein (LBP), and intestinal alkaline phosphatase (IAP) in SCZ is available. Therefore, we measured the plasma levels of zonulin, LBP, and IAP and its correlation with neutrophil-to-lymphocyte ratio (NLR); a marker of systemic inflammation in patients with SCZ. Methods: We recruited 60 individuals, patients with SCZ (n = 40) and healthy controls (n = 20), from a large tertiary neuropsychiatry center. Plasma levels of zonulin, IAP, and LBP were quantified by enzyme-linked immunosorbent assay. Results: Plasma levels of both LBP and zonulin were significantly increased (P <0.05), whereas the IAP levels (P <0.05) were significantly decreased in patients with SCZ compared to healthy controls. Pearson correlation analysis revealed that zonulin and LBP had a significant positive correlation with NLR, and IAP negatively correlated with NLR. Individuals with SCZ had higher independent odds of zonulin [odds ratio (OR): 10.32, 95% CI: 1.85-57.12], LBP [OR: 1.039, 95% CI: 1.02-1.07], and IAP [OR: 0.643, 95% CI: 0.471-0.879], even after adjusting for potential confounders. Conclusion: Our study demonstrates an association of zonulin, LBP, and IAP in Asian Indian SCZ patients and correlates with NLR. Our results indicate that low-grade inflammation induced by metabolic endotoxemia might be implicated in the pathoetiology of SCZ.

Yoga and Integrative Healthcare: Lessons from the National Institute of Mental Health and Neurosciences (NIMHANS) in India.

Background: There is growing evidence and increasing interest for systemic integration of medicine (synergistic and evidence-based combination of different systems along with conventional biomedicine). The National Institute of Mental Health and Neurosciences (NIMHANS), an Institute of National Importance and a tertiary mental and neurological healthcare hospital situated in Bengaluru, India, has established one such integrative model. The present manuscript traces the history and describes the important steps followed in this integrative approach. Methodology: The NIMHANS model followed a stage-wise two-step approach: (1) First stage - Starting with Integration of Yoga: The process began more than a decade ago, with integrating yoga into a clinical department (rather than an exclusive research-based approach) of the institute which had relatively high clinical service load (For example, Department of Psychiatry in NIMHANS). Yoga was gradually formalized into academic and clinical activities (outpatient and inpatient services) by appointing a Yoga faculty with a medical background with an MD/PhD in Yoga. The research was primarily directed by the clinical observations of patients receiving yoga therapy. (2) Second stage: Adding an appropriate and compatible discipline from Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH) system (Ayurveda in this case): The center for yoga gradually evolved into the Department of Integrative Medicine with the appointment of faculty from the Ayurveda stream. In this model, specialists from each discipline provide clinical inputs after simultaneous consultation with the patient through systemic integration in clinical, academic, and research domains rather than mere co-location of AYUSH services with mainstream medicine. Conclusion: The NIMHANS model of integration suggests the application of yoga into mainstream clinical service as the first step toward integration. Yoga should be added as a formalized clinical discipline with systemic integration. Gradually, other feasible systems of traditional medicine from AYUSH can be integrated at a later stage in a step-by-step manner based on clinical practice and evidence.

Neurohemodynamic correlates of BDNF gene expression in schizophrenia patients with working memory deficits: A functional MRI study.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) is involved in neuroplasticity underlying cognitive deficits, including working memory deficits (WMD), in schizophrenia. Methodological challenges and inconsistencies are reported with peripheral BDNF levels. Left dorsolateral prefrontal cortex (DLPFC) is proposed to underlie WMD, though inconsistently. We aimed to explore the correlations between brain activation during working memory task-based functional Magnetic Resonance Imaging (fMRI) and BDNF gene expression in schizophrenia patients with WMD. METHODS: 26 patients with schizophrenia with established WMD were recruited for the study. Blood samples were collected to study lymphocyte BDNF gene expression. Patients underwent task-based fMRI to examine the working memory performance and related brain activation. Whole-brain analysis was performed with 2-back > 0-back and 2-back > rest contrast. The peak intensity values of the activation were used for correlation analysis. RESULTS: Whole brain analysis with 2-back > rest contrast revealed maximum activation in left DLPFC, Brodmann area 9 (t = 10.54, FWE corrected p < 0.05). The baseline BDNF gene expression correlated positively with the peak intensity of brain activation in left DLPFC (r = 0.365, p = 0.033). Negative symptom score negatively correlated with BDNF gene expression (r = -0.499, p = 0.005) and left DLPFC fMRI activation (r = -0.393, p = 0.023) respectively. CONCLUSION: We found a significant positive association between BDNF gene expression and the activation of the DLPFC during the working memory task. This novel observation needs further systematic evaluation to establish the potential role of peripheral BDNF expression in WMD in schizophrenia.

Superior temporal gyrus functional connectivity predicts transcranial direct current stimulation response in Schizophrenia: A machine learning study.

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.

Effect of Intranasal Oxytocin on Resting-state Effective Connectivity in Schizophrenia.

OBJECTIVES: Evidence from several lines of research suggests the critical role of neuropeptide oxytocin in social cognition and social behavior. Though a few studies have examined the effect of oxytocin on clinical symptoms of schizophrenia, the underlying neurobiological changes are underexamined. Hence, in this study, we examined the effect of oxytocin on the brain's effective connectivity in schizophrenia. METHODS: 31 male patients with schizophrenia (SCZ) and 21 healthy male volunteers (HV) underwent resting functional magnetic resonance imaging scans with intra-nasal oxytocin (24 IU) and placebo administered in counterbalanced order. We conducted a whole-brain effective connectivity analysis using a multivariate vector autoregressive granger causality model. We performed a conjunction analysis to control for spurious changes and canonical correlation analysis between changes in connectivity and clinical and demographic variables. RESULTS: Three connections, sourced from the left caudate survived the FDR correction threshold with the conjunction analysis; connections to the left supplementary motor area, left precentral gyrus, and left frontal inferior triangular gyrus. At baseline, SCZ patients had significantly weaker connectivity from caudate to these three regions. Oxytocin, but not placebo, significantly increased the strength of connectivity in these connections. Better cognitive insight and lower negative symptoms were associated with a greater increase in connectivity with oxytocin. CONCLUSIONS: These findings provide a preliminary mechanistic understanding of the effect of oxytocin on brain connectivity in schizophrenia. The study findings provide the rationale to examine the potential utility of oxytocin for social cognitive deficits in schizophrenia.

Functional near-infrared spectroscopy in schizophrenia patients with auditory verbal hallucinations: Preliminary observations.

Auditory Signal Detection (ASD) theory postulates that auditory verbal hallucinations (AVH) result from an aberrant association of meaningful connection to abstract noises. In this study, schizophrenia (SZ) patients with persistent AVH (N = 17) and matched controls (N = 25) performed an ASD task with concurrent functional near-infrared spectroscopy recording targetting the left dorsolateral prefrontal cortex (L-DLPFC) and left temporoparietal junction (L-TPJ). During the task, discriminability index had a significant negative correlation, and early deoxyhemoglobin (HbR) latency at L-TPJ positively correlated with AVH scores. Also, patients had significantly lower discriminability, early HbR latency at L-TPJ, and delayed latency at L-DLPFC. This finding suggests the presence of ASD abnormalities and impaired auditory processing in SZ patients with AVH supporting ASD-based pathogenesis.

Variants of Th17 pathway-related genes influence brain morphometric changes and the risk of schizophrenia through epistatic interactions.

OBJECTIVE: T helper 17 (Th17) pathway has been reported to be abnormal in schizophrenia; however, it is not known whether variation within genes of this pathway has any impact on schizophrenia. Herein, the impact of genetic variations and gene-gene interactions of Th17 pathway-related genes on the risk, psychopathology, and brain volume was examined in schizophrenia patients. METHODS: Functional polymorphisms within interleukin 6 ( IL6 )(rs1800795 and rs1800797), IL10 (rs1800872 and rs1800896), IL17A (rs2275913 and rs8193036), IL22 (rs2227484 and rs2227485), IL23R (rs1884444), and IL27 (rs153109 and rs181206) genes were studied in 224 schizophrenia patients and 226 healthy controls. These variants were correlated with the brain morphometry, analyzed using MRI in a subset of patients ( n = 117) and controls ( n = 137). RESULTS: Patients carrying CC genotype of rs2227484 of IL22 gene had significantly higher apathy total score [ F (1,183) = 5.60; P = 0.019; partial ɳ 2 = 0.030]. Significant epistatic interactions between IL6 (rs1800797) and IL17A (rs2275913) genes were observed in schizophrenia patients. GG genotype of rs2275913 of IL17A gene was associated with reduced right middle occipital gyrus volume in schizophrenia patients ( T = 4.56; P < 0.001). CONCLUSION: Interactions between genes of Th17 pathway impact the risk for schizophrenia. The variants of Th17 pathway-related genes seem to have a determining effect on psychopathology and brain morphometric changes in schizophrenia.

Prediction of Obsessive-Compulsive Disorder: Importance of Neurobiology-Aided Feature Design and Cross-Diagnosis Transfer Learning.

BACKGROUND: Machine learning applications using neuroimaging provide a multidimensional, data-driven approach that captures the level of complexity necessary for objectively aiding diagnosis and prognosis in psychiatry. However, models learned from small training samples often have limited generalizability, which continues to be a problem with automated diagnosis of mental illnesses such as obsessive-compulsive disorder (OCD). Earlier studies have shown that features incorporating prior neurobiological knowledge of brain function and combining brain parcellations from various sources can potentially improve the overall prediction. However, it is unknown whether such knowledge-driven methods can provide a performance that is comparable to state-of-the-art approaches based on neural networks. METHODS: In this study, we apply a transparent and explainable multiparcellation ensemble learning framework EMPaSchiz (Ensemble algorithm with Multiple Parcellations for Schizophrenia prediction) to the task of predicting OCD, based on a resting-state functional magnetic resonance imaging dataset of 350 subjects. Furthermore, we apply transfer learning using the features found effective for schizophrenia to OCD to leverage the commonality in brain alterations across these psychiatric diagnoses. RESULTS: We show that our knowledge-based approach leads to a prediction performance of 80.3% accuracy for OCD diagnosis that is better than domain-agnostic and automated feature design using neural networks. Furthermore, we show that a selection of reduced feature sets can be transferred from schizophrenia to the OCD prediction model without significant loss in prediction performance. CONCLUSIONS: This study presents a machine learning framework for OCD prediction with neurobiology-aided feature design using resting-state functional magnetic resonance imaging that is generalizable and reasonably interpretable.

Pars Triangularis Volume Asymmetry and Schneiderian First Rank Symptoms in Antipsychotic-naïve Schizophrenia.

OBJECTIVE: Schizophrenia is a disorder of language and self, with first-rank symptoms (FRS) as one of the predominant features in a subset of patients. Abnormal language lateralization is hypothesized to underlie the neurobiology of FRS in schizophrenia. The role of Broca's area with its right-hemispheric counterpart, consisting of pars triangularis (PTr) and pars opercularis (POp) of the inferior frontal gyrus in FRS is undetermined. We compared the volumes and asymmetries of PTr & POp in anti-psychotic-naive schizophrenia patients with FRS (FRS[＋]) with those without FRS (FRS[-]) and healthy-controls (HC) using three dimensional, interactive, semi-automated volumetric morphometry. METHODS: Antipsychotic naïve FRS(＋) (n = 27), FRS(-) (n = 24) and HC (n = 51) were carefully assessed with structured and semi-structured clinical tools. T1-weighted images were acquired in a 3T scanner. Volumes of regions of interest were measured independently for both sides using slicer-3D software, and asymmetry indices were calculated. RESULTS: FRS(＋) but not FRS(-) had a significant volume deficit in right PTr after controlling for the potential confounding effects of age, sex, and intracranial volume (p = 0.029). There was a significant leftward asymmetry of PTr in patients with FRS (i.e., leftward asymmetry in patients) (p = 0.026). No significant volume/asymmetry abnormalities were observed in POp. CONCLUSION: Study findings suggest reduced right PTr volume with leftward asymmetry to be associated with FRS in schizophrenia. This is consistent with the loss of Yakovlevian torque in schizophrenia. Role of PTr in the neurobiology of schizophrenia as a disorder of self, speech, and social cognition needs further systematic evaluation in future research.

Plasma IL-6 levels in unmedicated, comorbidity free obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is increasingly being evaluated for a neuro-immune basis. Interleukin-6 (IL-6) is the most widely studied cytokine with a potential role in altering neurotransmission. The evidence for plasma IL-6 alterations in OCD has yielded mixed results. Psychotropic medications are known to modulate inflammatory processes and cytokine levels. METHODS: In this study, we recruited unmedicated, co-morbidity-free adult OCD patients (n = 49) and sex-matched healthy controls HC (n = 47) and compared their plasma IL-6 levels and their correlation with age at onset, duration of illness, and severity. RESULTS: IL-6 plasma level (ng/ml) in unmedicated OCD patients (1.31 ± 0.67) was significantly greater compared to HC (1.03 ± 0.47) [t = 2.33 (p = 0.02)]. The group differences persisted even after controlling for age and sex [F(1, 91) = 4.57, p = 0.035, η2 = 0.05]. Plasma IL-6 did not correlate significantly with any clinical variables. CONCLUSIONS: This study adds to the existing literature on immune alterations in OCD. Alterations in plasma IL-6 might have implications in the neurotransmitter alterations and stress-response in OCD. The current study results in unmedicated and comorbidity-free OCD patients give us a better understanding of the immune alterations in OCD. Future studies in such a population will probably help in reducing the heterogeneity of findings.