Investigational applications of transcranial magnetic stimulation (TMS) in Mood Disorders: Studies from a tertiary care center in India.

The investigational potential of TMS in psychiatry is largely underutilized. In the current article, we present the results of five studies with similar TMS protocols that looked at the investigative applications of TMS via measuring cortical reactivity as potential biomarkers in mood disorders. The first two studies, evaluate potential of TMS parameters and Motor neuron system (MNS) as state or trait markers of BD. Third and fourth studies evaluate these as endophenotypic markers of BD. The fifth study which is an RCT evaluating add-on yoga in UD, evaluates if markers of CI can index the therapeutic response of yoga. In study one MT1 was significantly greater in the SM (symptomatic-mania) group compared to HC (healthy-control) (P=0.032). The cortical inhibition measures SICI was reduced in SM(P=0.021) and BD (remitted Bipolar) (P=0.023) groups compared to HC. LICI was increased in the SM(0.021) and BD(P=0.06) groups compared to HC. In study two, a significant group x time interaction effect was observed indicating higher putative MNS-activity mediation in patients compared to HC on SlCl(P=0.024), LlCl(P=0.033). There were no significant group differences noted in the endophenotype studies. The fifth study showed a significant time X group interaction for CSP, favoring improvement in YG (yoga-group) (p<0.01).No significant change was observed for LICI(p=0.2), SICI(p=0.5). Limitations of these studies notwithstanding, we conclude that cortical reactivity measured using TMS is a potential biomarker across the course of mood disorders, starting from state and trait markers to understanding the therapeutic mechanism of a particular treatment modality in these disorders.

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.

Microstructural Mapping of Neural Pathways in Alzheimer's Disease using Macrostructure-Informed Normative Tractometry.

INTRODUCTION: Diffusion MRI is sensitive to the microstructural properties of brain tissues and shows great promise in detecting the effects of degenerative diseases. However, many approaches analyze single measures averaged over regions of interest, without considering the underlying fiber geometry. METHODS: Here, we propose a novel Macrostructure-Informed Normative Tractometry (MINT) framework, to investigate how white matter microstructure and macrostructure are jointly altered in mild cognitive impairment (MCI) and dementia. We compare MINT-derived metrics with univariate metrics from diffusion tensor imaging (DTI), to examine how fiber geometry may impact interpretation of microstructure. RESULTS: In two multi-site cohorts from North America and India, we find consistent patterns of microstructural and macrostructural anomalies implicated in MCI and dementia; we also rank diffusion metrics' sensitivity to dementia. DISCUSSION: We show that MINT, by jointly modeling tract shape and microstructure, has potential to disentangle and better interpret the effects of degenerative disease on the brain's neural pathways.

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.

Deep Normative Tractometry for Identifying Joint White Matter Macro- and Micro-structural Abnormalities in Alzheimer's Disease.

This study introduces the Deep Normative Tractometry (DNT) framework, that encodes the joint distribution of both macrostructural and microstructural profiles of the brain white matter tracts through a variational autoencoder (VAE). By training on data from healthy controls, DNT learns the normative distribution of tract data, and can delineate along-tract micro-and macro-structural abnormalities. Leveraging a large sample size via generative pre-training, we assess DNT's generalizability using transfer learning on data from an independent cohort acquired in India. Our findings demonstrate DNT's capacity to detect widespread diffusivity abnormalities along tracts in mild cognitive impairment and Alzheimer's disease, aligning closely with results from the Bundle Analytics (BUAN) tractometry pipeline. By incorporating tract geometry information, DNT may be able to distinguish disease-related abnormalities in anisotropy from tract macrostructure, and shows promise in enhancing fine-scale mapping and detection of white matter alterations in neurodegenerative conditions.

Posterior Cerebellar Resting-State Functional Hypoconnectivity: A Neural Marker of Schizophrenia Across Different Stages of Treatment Response.

BACKGROUND: Identifying stable and consistent resting-state functional connectivity patterns across illness trajectories has the potential to be considered fundamental to the pathophysiology of schizophrenia. We aimed to identify consistent resting-state functional connectivity patterns across heterogeneous schizophrenia groups defined based on treatment response. METHODS: In phase 1, we used a cross-sectional case-control design to characterize and compare stable independent component networks from resting-state functional magnetic resonance imaging scans of antipsychotic-naïve participants with first-episode schizophrenia (n = 54) and healthy participants (n = 43); we also examined associations with symptoms, cognition, and disability. In phase 2, we examined the stability (and replicability) of our phase 1 results in 4 groups (N = 105) representing a cross-sequential gradation of schizophrenia based on treatment response: risperidone responders, clozapine responders, clozapine nonresponders, and clozapine nonresponders following electroconvulsive therapy. Hypothesis-free whole-brain within- and between-network connectivity were examined. RESULTS: Phase 1 identified posterior and anterior cerebellar hypoconnectivity and limbic hyperconnectivity in schizophrenia at a familywise error rate-corrected cluster significance threshold of p < .01. These network aberrations had unique associations with positive symptoms, cognition, and disability. During phase 2, we replicated the phase 1 results while comparing each of the 4 schizophrenia groups to the healthy participants. The participants in 2 longitudinal subdatasets did not demonstrate a significant change in these network aberrations following risperidone or electroconvulsive therapy. Posterior cerebellar hypoconnectivity (with thalamus and cingulate) emerged as the most consistent finding; it was replicated across different stages of treatment response (Cohen's d range -0.95 to -1.44), reproduced using different preprocessing techniques, and not confounded by educational attainment. CONCLUSIONS: Posterior cerebellar-thalamo-cingulate hypoconnectivity is a consistent and stable state-independent neural marker of schizophrenia.

Association between urban upbringing and functional brain connectivity in schizophrenia.

Background: Environmental factors considerably influence the development of the human cortex during the perinatal period, early childhood, and adolescence. Urban upbringing in the first 15 years of life is a known risk factor for schizophrenia (SCZ). Though the risk of urban birth and upbringing is well-examined from an epidemiological perspective, the biological mechanisms underlying urban upbringing remain unknown. The effect of urban birth and upbringing on functional brain connectivity in SCZ patients is not yet examined. Methods: This is a secondary data analysis of three studies that included 87 patients with SCZ and 70 healthy volunteers (HV) aged 18 to 50 years. We calculated the developmental urbanicity index using a validated method in earlier studies. Following standard pre-processing of resting functional magnetic resonance imaging (fMRI) scans, seed-return on investment (ROI) functional connectivity analysis was performed. Results: The results showed a significant association between urban birth and upbringing on functional connectivity in SCZ patients and HV (P < 0.05). In SCZ patients, connections from the right caudate, anterior cingulate cortex, left and right intracalcarine cortices, left and right lingual gyri, left posterior parahippocampal cortex to the cerebellum, fusiform gyri, lateral occipital cortex, and amygdala were significantly associated with the urbanicity index (P < 0.05). Conclusions: These study findings suggest a significant association between urban birth and upbringing on functional brain connectivity in regions involved in reward processing and social cognition in SCZ. Assessment of social cognition could have implications in developing an in-depth understanding of this impairment in persons with SCZ.

Brain Age Analysis and Dementia Classification using Convolutional Neural Networks trained on Diffusion MRI: Tests in Indian and North American Cohorts.

Deep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimer's disease or infer dementia severity from T1-weighted brain MRI scans. Here, we examine the value of adding diffusion-weighted MRI (dMRI) as an input to these models. Much research in this area focuses on specific datasets such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), which assesses people of North American, largely European ancestry, so we examine how models trained on ADNI, generalize to a new population dataset from India (the NIMHANS cohort). We first benchmark our models by predicting 'brain age' - the task of predicting a person's chronological age from their MRI scan and proceed to AD classification. We also evaluate the benefit of using a 3D CycleGAN approach to harmonize the imaging datasets before training the CNN models. Our experiments show that classification performance improves after harmonization in most cases, as well as better performance for dMRI as input.

Age of onset of obsessive-compulsive disorder differentially affects white matter microstructure.

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation -particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)-and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD.

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.

BundleCleaner: Unsupervised Denoising and Subsampling of Diffusion MRI-Derived Tractography Data.

We present BundleCleaner, an unsupervised multi-step framework that can filter, denoise and subsample bundles derived from diffusion MRI-based whole-brain tractography. Our approach considers both the global bundle structure and local streamline-wise features. We apply BundleCleaner to bundles generated from single-shell diffusion MRI data in an independent clinical sample of older adults from India using probabilistic tractography and the resulting 'cleaned' bundles can better align with the atlas bundles with reduced overreach. In a downstream tractometry analysis, we show that the cleaned bundles, represented with less than 20% of the original set of points, can robustly localize along-tract microstructural differences between 32 healthy controls and 34 participants with Alzheimer's disease ranging in age from 55 to 84 years old. Our approach can help reduce memory burden and improving computational efficiency when working with tractography data, and shows promise for large-scale multi-site tractometry.

Clinical improvement in schizophrenia during antipsychotic treatment in relation to changes in glucose parameters: A systematic review.

Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) spectrum disorders. Previous research suggests that there may be a positive association between AP-induced weight gain and/or dyslipidemia and improvement in psychiatric symptoms, often referred to as a "metabolic threshold". To determine whether a similar relationship exists for glucose parameters, we conducted a systematic search in six databases from inception to June 2022 for all longitudinal studies that directly examined the relationship between changes in glucose-related outcomes and changes in psychopathology among patients with SCZ treated with APs. We identified 10 relevant studies and one additional study that considered cognition. In most cases, we found that increased levels of fasting glucose and insulin following treatment were associated with clinical improvement. These findings contribute to existing literature that could suggest a common mechanism between AP action and metabolic side effects and support a need for additional work aimed at exploring the validity of a glucose-psychopathology relation in SCZ.

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.

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.