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Abstract Background Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects. Objective We convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson’s disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction. Methods Experts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies. Results Although most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson’s disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy). Conclusion All recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs.

Our social world is an ever-changing milieu in which boundless verbal and nonverbal signals are generated by fellow humans. To ensure our survival, we must perceive certain regularities from the complexity that surrounds us. A failure to meet this daily challenge may prove costly for some; social encounters trigger several psychiatric symptoms, while social withdrawal reduces their intensity, at least temporarily. For example, disorganization (or formal thought disorder), one of the central features of schizophrenia, presents primarily as a disruption in cooperative communication that occurs in a social context. Though many technical advances now allow us to study \"socially\" interacting agents in the laboratory (for example, see Kingsbury and colleagues), psychiatric symptoms are rarely studied in the context of neural mechanisms of social encounters. One of the important pursuits of clinical neuroscience is to explain how computational failures of the brain result in symptoms and signs experienced by patients.

Schizophrenia is a complex neuropsychiatric disorder, influenced by a combined action of genes and environmental factors. The neurodevelopmental origin is one of the most widely recognized etiological models of this heterogeneous disorder. Environmental factors, especially infections during gestation, appear to be a major risk determinant of neurodevelopmental basis of schizophrenia. Prenatal infection may cause maternal immune activation (MIA) and enhance risk of schizophrenia in the offspring. However, the precise mechanistic basis through which MIA causes long-lasting schizophrenia-like behavioral deficits in offspring remains inadequately understood. Herein, we aimed to delineate whether prenatal infection-induced MIA causes schizophrenia-like behaviors through its long-lasting effects on immune-inflammatory and apoptotic pathways, oxidative stress toxicity, and antioxidant defenses in the brain of offspring. Sprague-Dawley rats were divided into three groups (n = 15/group) and were injected with poly (I:C), LPS, and saline at gestational day (GD)-12. Except IL-1β, plasma levels of IL-6, TNF-α, and IL-17A assessed after 24 h were significantly elevated in both the poly (I:C)- and LPS-treated pregnant rats, indicating MIA. The rats born to dams treated with poly (I:C) and LPS displayed increased anxiety-like behaviors and significant deficits in social behaviors. Furthermore, the hippocampus of the offspring rats of both the poly (I:C)- and LPS-treated groups showed increased signs of lipid peroxidation, diminished total antioxidant content, and differentially upregulated expression of inflammatory (TNFα, IL6, and IL1β), and apoptotic (Bax, Cas3, and Cas9) genes but decreased expression of neuroprotective (BDNF and Bcl2) genes. The results suggest long-standing effects of prenatal infections on schizophrenia-like behavioral deficits, which are mediated by immune-inflammatory and apoptotic pathways, increased oxidative stress toxicity, and lowered antioxidant and neuroprotective defenses. The findings suggest that prenatal infections may underpin neurodevelopmental aberrations and neuroprogression and subsequently schizophrenia-like symptoms.

The expressed emotion (EE) is considered to be an adverse family environment, which includes the quality of interaction patterns and nature of family relationships among the family caregivers and patients of schizophrenia and other psychiatric disorders. Influence of EE has been found to be one of the robust predictors of relapse in schizophrenia. This review article aims to provide a brief description of the origins and evolution of the EE as a construct from the available literature. The EE is modulated by multiple factors-some of which include certain personality profile, attribution factors by caregivers toward patient symptoms, and patient's vulnerability to stress. The psychosocial assessment and interventions specifically focused on family psychoeducation can potentially reduce high EE and relapse of symptoms as well. However, the theory surrounded with EE undermines the caregiver's positive attitudes toward the patients. Hence, it is important that the future studies should focus on both protective and vulnerable factors within the construct of EE in schizophrenia to facilitate comprehensive care.

Purpose of Review To review the efficacy of add-on yoga therapy in improving symptoms of schizophrenia and quality of life and examine the possible underlying biological mechanisms of yoga in schizophrenia. Recent Findings Quality of life, cognitive symptoms, and negative symptoms have been found to improve with add-on yoga therapy in schizophrenia (pooled mean effect size 0.8, 0.6, and 0.4, respectively). Yoga also seems to have a small effect on improving positive symptoms. Less explored areas include adverse effects of yoga itself as well as its effects on antipsychotic-induced complications. Preliminary findings suggest that the effects of yoga may be mediated by neurohormonal mechanisms and functional changes in brain activity. Summary Add-on yoga therapy is a potential treatment option for improving quality of life, cognitive symptoms, and negative symptoms in schizophrenia. Future studies should explore efficacy in multicentric trials as well as possible neurobiological changes underlying the effects.

Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a \"differential susceptibility\" effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin.

Background: Transcranial direct current stimulation (tDCS) aims to focalize the current reaching the target region-of-interest (ROI). The focality can be quantified by dose-target-determination-index (DTDI). Despite having a uniform tDCS setup, some individuals receive focal stimulation (high DTDI) while others show reduced focality (‘non-focal’). The volume of cerebrospinal fluid (CSF), grey matter (GM), and white matter (WM) underlying each ROI govern the tDCS current distribution, thereby regulating focality. Aim: To determine the regional-volume parameters that differentiate the focal and non-focal group. Method: T1-weighted brain images from 300 age-sex matched adults were divided into three equal groups- (a) Young (20 ≥ x ˂ 40 years), (b) Middle (40 ≥ x ˂ 60 years), and (c) Old (60 ≥ x ˂ 80 years). For each group, inter and intra-hemispheric montages with electrodes at (1) F3 and right supraorbital region (F3-RSO), and (2) CP5 and CZ (CP5-CZ) were simulated, targeting the left- Dorsolateral Prefrontal Cortex and -Inferior Parietal Lobule, respectively. Both montages were simulated for two current doses (1 and 2mA). For each individual head simulated for a tDCS configuration (montage and dose), the current density at each ROI and their DTDI were calculated. The individuals were categorized into two groups- (1) Focal (DTDI ≥ 0.75), and (2) Non-focal (DTDI ˂ 0.75). The regional-volume of CSF, GM, and WM of all the ROIs was determined. For each tDCS configuration and ROI, three 3-way analysis of variance was performed considering- (i) GM, (ii) WM, and (iii) CSF as the dependent variable. The age-group, sex, and focality-group were the between-subject factors. Result: Regional CSF was the principal determinant of focality. For interhemispheric F3-RSO montage, a significant interaction-effect of age and focality was observed at Left Caudate Nucleus with the focal group exhibiting higher CSF volume. For intrahemispheric CP5-CZ montage, a significant-main effect was observed at the left pre- and post-central gyrus with the focal group showing lower CSF volume. Conclusion: The CSF channels the flow of tDCS current between electrodes with focal ROIs acting like reservoirs of current. The position of focal ROI in the channel determines the stimulation intensity at the target ROI.

Background The two subtypes of primary progressive aphasia (PPA) associated with Frontotemporal Lobar Degeneration (FTLD)—non-fluent (nfvPPA) and semantic (svPPA)—have distinct structural and functional abnormalities. Transcranial direct current stimulation (tDCS) targets the language network to address deficits, yet a single, arbitrary montage is often applied despite pathophysiological differences. Since tDCS current distribution depends on brain structure and function, variant-specific montages are essential. This study presents a pathology-specific approach for tDCS montage selection, identifying the optimal montage for each PPA variant. Method T1-weighted and resting-state fMRI data from 38 healthy, 31 nfvPPA and 32 svPPA subjects were obtained. Grey matter volume and functional entropy were analysed across 116 brain regions. Patients and controls were compared to identify significant differences in atrophy and entropy. Electric-field modelling of three widely used dorsal, ventral, and frontal tDCS montages provided current intensity estimates in the language network. Canonical Correlation Analysis examined the relationship between current intensity, atrophy, and entropy. Results Structural and functional changes differed between the two PPA variants: nfvPPA showed left frontal atrophy and reduced entropy in the left parietal/cerebellar areas, while svPPA exhibited left temporal atrophy and reduced entropy in the left frontal and right temporal regions. Atrophy distribution primarily influenced tDCS current spread, determining montage suitability. In nfvPPA, the frontal montage showed a strong association between delivered current and grey mettwr volume of atrophied areas, whereas in svPPA, a similar pattern was observed for the ventral montage. Conclusion The study identifies the frontal montage as the most suitable for nfvPPA and the ventral montage for svPPA. This study highlights the importance of pathology-specific tDCS montage selection, emphasizing the need for variant-based modulation of the language network in PPA.

Restless legs syndrome (RLS) is a neuro-sensorimotor disorder affecting 2–4% of adults. It is characterized by intense urges to move the legs, associated with unpleasant sensory disturbances in the legs occurring at rest and manifests mostly in the evening and night, relieved by movement. Diagnosis is primarily based on clinical presentation and the consensus criteria for the diagnosis have been established. Antipsychotics, the dopamine antagonists, have been reported to induce RLS. Dopamine agonists, the effective first-line treatment of RLS, carry the risk of inducing or worsening psychosis. Many nondopaminergic agents including antiepileptic medications have also been used in the treatment of primary RLS. In this report we describe clozapine-induced RLS in two patients with schizophrenia and its successful treatment with gabapentin, a nondopaminergic agent. In addition, we have reviewed the available literature on clozapine-induced RLS and its management.