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.

Oculomotor Abnormalities and Aberrant Neuro-Developmental Markers: Composite Endophenotype for Bipolar I Disorder: Anomalies Oculomotrices et Marqueurs Neuro-Développementaux Aberrants : Endophénotype Composite du Trouble Bipolaire I.

BACKGROUND: Neurological soft signs (NSSs), minor physical anomalies (MPAs), and oculomotor abnormalities were plausible biomarkers in bipolar disorder (BD). However, specific impairments in these markers in patients after the first episode mania (FEM), in comparison with first-degree relatives (high risk [HR]) of BD and healthy subjects (health control [HC]) are sparse. AIM OF THE STUDY: This study aimed at examining NSSs, MPAs, and oculomotor abnormalities in remitted adult subjects following FEM and HR subjects in comparison with matched healthy controls. Investigated when taken together, could serve as composite endophenotype for BD. METHODS: NSSs, MPAs, and oculomotor abnormalities were evaluated in FEM (n = 31), HR (n = 31), and HC (n = 30) subjects, matched for age (years) (p = 0.44) and sex (p = 0.70) using neurological evaluation scale, Waldrop's physical anomaly scale and eye tracking (SPEM) and antisaccades (AS) paradigms, respectively. RESULTS: Significant differences were found between groups on NSSs, MPAs, and oculomotor parameters. Abnormalities are higher in FEM subjects compared to HR and HC subjects. Using linear discriminant analysis, all 3 markers combined accurately classified 72% of the original 82 subjects (79·2% BD, 56·70% HR, and 82·1% HC subjects). CONCLUSIONS: AS and SPEM could enhance the utility of NSSs, and MPAs as markers for BD. The presence of these abnormalities in FEM suggests their role in understanding the etiopathogenesis of BD in patients who are in the early course of illness. These have the potential to be composite endophenotypes and have further utility in early identification in BD.

Eye movement abnormalities and Atypical Neurodevelopmental markers as Composite Measurable components in the pathway between disease manifestation and genetics in Bipolar I DisorderPlain Language SummaryWhy was the study done?Neurological soft signs, Minor physical anomalies, and eye-movement abnormalities are known disease makers of Bipolar disorder but their utility in being intermediate markers between the disease manifestation and genetics has not been studied before. Hence we took up this study with the above aim.What did the researchers do?We compared the above-mentioned biomarkers between the patients diagnosed with first-episode mania (considered as early bipolar), the high-risk population (people with a family history of bipolar), and healthy subjects (without any self or family history of any psychiatric illnesses). Each group had 30 participants. We wanted to see if these markers taken together could predict the groups or classify the subjects into the three groups accurately.What did the researchers find?We found that in all the biomarkers there was a significant group difference between the the three groups. The abnormalities showed a pattern wherein they are higher in the first episode mania group compared to at-risk, and higher in at-risk compared to healthy subjects. When all these markers were combined and linear discriminant analysis was run, we noted they accurately classified 72% of the original participants (79·2% first episode bipolar 56·70% High risk, and 82·1% Healthy Subjects).What do the findings mean?The above findings indicate that the eye-movement or oculomotor abnormalities enhance the utility of neurodevelopmental markers as biomarkers of bipolar disorder. The presence of these abnormalities fairly early in the disease also means that they have a role in the etiopathogenesis of bipolar disorder. All the markers taken together can be composite measurable components in the pathway between disease manifestation and genetics in Bipolar I Disorder, and thus help in early identification.

Development, validation and clinical utility of short-term adverse-effects of electroconvulsive therapy (SAVE) checklist.

Electroconvulsive therapy (ECT) is one of the most effective treatments in psychiatry. However, it has many cognitive and non-cognitive adverse effects (AEs). There are lacunae in the literature on systematic assessment of non-cognitive AEs. There is a need for a standard, comprehensive and specific clinical tool to evaluate this. Hence, a checklist of short-term AEs of ECT (SAVE) with a 2-phase assessment was developed. Content validation was done using 15 experts' ratings and predefined content validity ratio and index (CVR and CVI) in a two-stage modified Delphi method. The checklist had a good CVR and CVI with a final tool of 39 items. The tool was sensitive and identified the non-cognitive AEs after ECT. Cardiovascular and musculoskeletal systems displayed the highest incidence. Many participants exhibited delayed recovery in orientation, gait, and stance, highlighting a necessity for meticulous monitoring. SAVE is the first standardised tool to assess short-term ECT-related AEs systematically. This checklist likely identifies clinically significant incidences of adverse effects. Its regular use may enhance the safety of ECT and patient comfort by supporting early identification and intervention for AEs. However, given the transient nature of AEs, further studies are needed to determine their predictive validity for long-term consequences.

Standards for medical devices: Electroconvulsive therapy machine.

The manuscript calls for establishing a standard for electroconvulsive devices by manufacturers for better regulation in India. This is most relevant in the context of two recent developments, (a) Notification of medical devices rules, 2017 with classification of ECT as Class C and (b) Recent change in classification of ECT devices by US-FDA in 2018. The establishment of standards would help in upregulating the standard of ECT devices as well as ECT practices.

Transcranial Alternating Current Stimulation (tACS) and Its Role in Schizophrenia: A Scoping Review.

Transcranial alternating current stimulation (tACS) may modulate neuronal oscillations by applying sinusoidal alternating current, thereby alleviating associated symptoms in schizophrenia. Considering its possible utility in schizophrenia, we reviewed the literature for tACS protocols administered in schizophrenia and their findings. A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline in databases and clinical trial registers. The search resulted in 59 publications. After excluding review articles unrelated to tACS, trials without published results or not involving patients with schizophrenia, 14 studies were included. Among the included studies/case reports only 5 were randomized controlled therapeutic trials. The studies investigated the utility of tACS for clinical and neurobiological outcomes. All studies reported good tolerability with only transient mild side effects. It was administered mostly during the working memory task (such as computerized n-back task, dual back task, and computerized digit symbol substitution task) for schizophrenia patients with cognitive deficits and during resting state while targeting positive symptoms. A possible reduction in hallucinations and delusions using alpha tACS, and improvement in negative and cognitive deficits with theta and gamma tACS were reported. Nevertheless, one of the randomized controlled trials targeting hallucinations was negative and rigorous large-sample studies are lacking for other domains. The current evidence for tACS in schizophrenia is preliminary though promising. In future, more sham controlled randomized trials assessing the effect of tACS on various domains are needed to substantiate these early findings.

Utility of Smartphone-Based Digital Phenotyping Biomarkers in Assessing Treatment Response to Transcranial Magnetic Stimulation in Depression: Proof-of-Concept Study.

BACKGROUND: Identifying biomarkers of response to transcranial magnetic stimulation (TMS) in treatment-resistant depression is a priority for personalizing care. Clinical and neurobiological determinants of treatment response to TMS, while promising, have limited scalability. Therefore, evaluating novel, technologically driven, and potentially scalable biomarkers, such as digital phenotyping, is necessary. OBJECTIVE: This study aimed to examine the potential of smartphone-based digital phenotyping and its feasibility as a predictive biomarker of treatment response to TMS in depression. METHODS: We assessed the feasibility of digital phenotyping by examining the adherence and retention rates. We used smartphone data from passive sensors as well as active symptom surveys to determine treatment response in a naturalistic course of TMS treatment for treatment-resistant depression. We applied a scikit-learn logistic regression model (l1 ratio=0.5; 2-fold cross-validation) using both active and passive data. We analyzed related variance metrics throughout the entire treatment duration and on a weekly basis to predict responders and nonresponders to TMS, defined as ≥50% reduction in clinician-rated symptom severity from baseline. RESULTS: The adherence rate was 89.47%, and the retention rate was 73%. The area under the curve for correct classification of TMS response ranged from 0.59 (passive data alone) to 0.911 (both passive and active data) for data collected throughout the treatment course. Importantly, a model using the average of all features (passive and active) for the first week had an area under the curve of 0.7375 in predicting responder status at the end of the treatment. CONCLUSIONS: The results of our study suggest that it is feasible to use digital phenotyping data to assess response to TMS in depression. Early changes in digital phenotyping biomarkers, such as predicting response from the first week of data, as shown in our results, may also help guide the treatment course.

Effect of left temporoparietal transcranial direct current stimulation on self-bias effect and retrospective intentional binding paradigm: A randomised, double-blind, controlled study.

BACKGROUND: Self-bias effect is expressed as a preferential selection and accelerated perception of self-related sensory information. Intentional binding (IB) is a related phenomenon where the sensory outcome from a voluntary action and the voluntary action itself are perceived to be closer to each other in time in both predictive (voluntary action predicting sensory consequence) and retrospective (sensory consequence features triggering self-related inference) contexts. Recent evidence indicates that self-related visual stimuli can affect retrospective intentional binding (rIB). We aimed to 1) replicate rIB in the auditory context, and 2) investigate the potential role of left temporoparietal junction (l-TPJ), a crucial node for the self-monitoring process, in self-bias effect and intentional binding effect by manipulating l-TPJ activity with neuromodulation [using High-Definition Transcranial Direct Current Stimulation (HD-tDCS)]. We anticipated self-bias and rIB effects to increase with anodal stimulation of l-TPJ in comparison to cathodal-stimulation of l-TPJ. METHODS: Fourteen, right-handed, healthy participants performed sound-label matching (matching tones to self-and-other labels) and rIB (estimating time interval between a button press and a self/other labelled tone) tasks. Each participant underwent both anodal and cathodal stimulation of l-TPJ in separate sessions (at least 72 h apart). Assignment of HD-tDCS type was random and counter-balanced across participants. Behavioural data was collected at three time points: once at baseline (no-stimulation), and twice after stimulation with HD-tDCS. RESULTS: Strong self-bias effect was observed across all experimental conditions. Neuromodulation of l-TPJ affected processing of other-labelled tone in the sound-label matching task. rIB was noted in baseline and anodal-HD-tDCS conditions where participants exhibited stronger binding for self-associated stimuli compared to other-associated stimuli. CONCLUSION: l-TPJ may potentially play a critical role in self-other distinction. This may have possible implications for disorders of self-disturbances like psychosis.

Paroxysmal dystonia and psychotic exacerbations in chronic psychosis: Diagnostic dilemmas and preliminary treatment approaches.

Patients with chronic psychosis on prolonged antipsychotic therapy may present with paroxysmal dystonia along with an exacerbation of their psychotic symptoms: paroxysmal dystonia and psychotic exacerbations (PDPE). The interindividual variability in the clinical presentations of PDPE can pose challenges in its diagnosis and treatment. The objectives of this work are to (i) discuss this rare phenomenon through a series of 10 patients and a relevant literature review, (ii) conceptualize its neurobiological underpinnings, and (iii) explore the preliminary treatment approaches for its management. Acute stress and/or a dysfunctional gamma-aminobutyric acid (GABA) ergic or dopaminergic system may be implicated in the pathogenesis of PDPE. The episodes respond acutely to parenteral benzodiazepines, while long-term management can be achieved by reducing antipsychotic doses, switching to clozapine or using central GABA enhancers. This article is the first attempt at conceptualizing and exploring treatment options for the rare condition PDPE and intends to guide future research in this regard.

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.

Feasibility of intermediate theta burst stimulation as sham control in therapeutic transcranial magnetic stimulation studies.

A major challenge in Transcranial Magnetic Stimulation trials is that of an inefficient sham protocol. This could potentially amplify the gap in behavioral outcomes following true and control treatments. Intermediate theta-burst stimulation (imTBS) is a promising sham alternative since it uses actual TMS pulses, thus mimicking the sensory effects of stimulation without producing physiological aftereffects. Here, we critically review controlled experiments that have examined physiological and behavioral aftereffects following imTBS with the intention to further investigate what appears to be a promising sham control modality for TBS studies.