Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many ...aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities. Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia.
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.
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.
From neurophenomenological perspectives, schizophrenia has been conceptualized as "a disorder with heterogeneous manifestations that can be integrally understood to involve fundamental perturbations ...in consciousness". While these theoretical constructs based on consciousness facilitate understanding the 'gestalt' of schizophrenia, systematic research to unravel translational implications of these models is warranted. To address this, one needs to begin with exploration of plausible biological underpinnings of "perturbed consciousness" in schizophrenia. In this context, an attractive proposition to understand the biology of consciousness is "the orchestrated object reduction (Orch-OR) theory" which invokes quantum processes in the microtubules of neurons. The Orch-OR model is particularly important for understanding schizophrenia especially due to the shared 'scaffold' of microtubules. The initial sections of this review focus on the compelling evidence to support the view that "schizophrenia is a disorder of consciousness" through critical summary of the studies that have demonstrated self-abnormalities, aberrant time perception as well as dysfunctional intentional binding in this disorder. Subsequently, these findings are linked with 'Orch-OR theory' through the research evidence for aberrant neural oscillations as well as microtubule abnormalities observed in schizophrenia. Further sections emphasize the applicability and translational implications of Orch-OR theory in the context of schizophrenia and elucidate the relevance of quantum biology to understand the origins of this puzzling disorder as "fundamental disturbances in consciousness".
Mounting evidence indicates that immune activation and/or immuno-inflammatory reactions during neurodevelopment apparently contribute to the pathogenesis and progression of schizophrenia. One of the ...important environmental factors that is known to trigger immune activation/inflammatory responses during early pregnancy is prenatal infection. Recent understanding from animal studies suggests that prenatal infection induced maternal immune activation (MIA)/inflammation in congruence with oxidative/nitrosative stress can lead to neurodevelopmental damage and behavioral abnormalities in the offspring.
Although the underlying precise mechanistic processes of MIA/inflammation are yet to be completely elucidated, it is being increasingly recognized that Toll-like receptors (TLRs) that form the first line of defense against invading microorganisms could participate in the prenatal infection induced immune insults. Interestingly, some of the TLRs, especially TLR3 and TLR4 that modulate neurodevelopment, neuronal survival and neuronal plasticity by regulating the neuro-immune cross-talk in the developing and adult brain could also be affected by prenatal infection. Importantly, sustained activation of TLR3/TLR4 due to environmental factors including infection and stress has been found to generate excessive reactive oxygen species (ROS)/reactive nitrogen species (RNS) as well as pro-inflammatory mediators during embryogenesis, which result into neuronal damage by necrosis/apoptosis.
In recent times, ROS/RNS and immuno-inflammatory mediators are being increasingly linked to progressive brain changes in schizophrenia. Although a significant role of TLR3/TLR4 in neurodegeneration is gaining certainty, their importance in establishing a causal link between prenatal infection and immuno-inflammatory, oxidative and nitrosative stress (IO&NS) responses and influence on adult presentation of schizophrenia is yet to be ascertained. We review here the current knowledge generated from the animal and human studies on the role of TLRs in schizophrenia and finally propose the “TRIPS Hypothesis” (Toll-like receptors in immuno-inflammatory pathogenesis) to elucidate the underlying mechanism(s) of TLR-mediated risk of schizophrenia. Considering the established role of TLR3 and TLR4 in antiviral and antibacterial responses respectively, we believe that in some cases of schizophrenia where IO&NS responses are evident, prenatal infection might lead to neuroprogressive changes in a TLR3/TLR4-dependent way.
•TLRs regulate immunity and core functions of the brain.•Microglial TLR3/TLR4 activation might affect schizophrenia through IO&NS pathways.•TLR3/TLR4 might increase schizophrenia risk via progressive neurodegeneration.
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.
Aim
Evidence suggests microvascular dysfunction (wider retinal venules and narrower arterioles) in schizophrenia (SCZ) and bipolar disorder (BD). The vascular development is synchronous with neuronal ...development in the retina and brain. The retinal vessel trajectory is related to retinal nerve fiber layer thinning and cerebrovascular abnormalities in SCZ and BD and has not yet been examined. Hence, in this study we examined the retinal vascular trajectory in SCZ and BD in comparison with healthy volunteers (HV).
Methods
Retinal images were acquired from 100 HV, SCZ patients, and BD patients, respectively, with a non‐mydriatic fundus camera. Images were quantified to obtain the retinal arterial and venous trajectories using a validated, semiautomated algorithm. Analysis of covariance and regression analyses were conducted to examine group differences. A supervised machine‐learning ensemble of bagged‐trees method was used for automated classification of trajectory values.
Results
There was a significant difference among groups in both the retinal venous trajectory (HV: 0.17 ± 0.08; SCZ: 0.25 ± 0.17; BD: 0.27 ± 0.20; P < 0.001) and the arterial trajectory (HV: 0.34 ± 0.15; SCZ: 0.29 ± 0.10; BD: 0.29 ± 0.11; P = 0.003) even after adjusting for age and sex (P < 0.001). On post‐hoc analysis, the SCZ and BD groups differed from the HV on retinal venous and arterial trajectories, but there was no difference between SCZ and BD patients. The machine learning showed an accuracy of 86% and 73% for classifying HV versus SCZ and BD, respectively.
Conclusion
Smaller trajectories of retinal arteries indicate wider and flatter curves in SCZ and BD. Considering the relation between retinal/cerebral vasculatures and retinal nerve fiber layer thinness, the retinal vascular trajectory is a potential marker for SCZ and BD. As a relatively affordable investigation, retinal fundus photography should be further explored in SCZ and BD as a potential screening measure.
Aim
Immunopathogenesis remains a widely appreciated etiopathological model of schizophrenia. Persistent efforts have aimed to identify schizophrenia biomarkers indexing immune system abnormalities ...and also immuno‐dampening effects of antipsychotic medications. Although data arising from published reports are encouraging, such studies are limited to a few immune parameters and not focused on a specific pathway. Th17 cells‐mediated immuno‐inflammatory responses have emerged as a potential mechanism in various neuropsychiatric conditions, including schizophrenia. The Th17 pathway is distinctly regulated through a coordinated action of multiple cytokines and transcription factors. In this study, we explored whether antipsychotic medication has any effect on the cytokines and transcription factors of the Th17 pathway.
Methods
A total of 27 drug‐naive schizophrenia patients were recruited and followed up for 3 months after initiation of antipsychotic medication. Lymphocyte gene expression levels of two transcription factors (STAT3 and RORC) and one of their upstream regulators, IL6, were quantified before and after treatment. Plasma levels of cytokines, such as interleukin (IL)‐1β, IL‐6, IL‐17A, IL‐23, and IL‐33, were also analyzed before and after treatment.
Results
Treatment with antipsychotic medication for 3 months resulted in significant downregulation of STAT3 gene expression as well as reduction in plasma levels of IL‐1β, IL‐6, and IL‐17A. Significant reduction in total scores for the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms was also observed in schizophrenia patients after 3 months of antipsychotic treatment.
Conclusion
Our findings suggest possible immuno‐modulatory effects of antipsychotic medication on the critical regulators, such as IL‐6 and STAT3, of the Th17 pathway in schizophrenia patients. The IL‐6/STAT3 signaling axis involved in the transcriptional regulation of Th17 cells might appear as an important target of antipsychotic treatment in schizophrenia patients. Alternatively, irrespective of the effect of antipsychotic drugs, the IL‐6/STAT3 signaling axis might be crucially involved in ameliorating psychotic symptoms.
Dengue is an arboviral infection endemic in tropical countries. Neurological sequelae to dengue infection are not uncommon, and psychiatric manifestations are increasingly reported. This narrative ...review aims to present the varied manifestations, postulated mechanisms, and the available treatment options for psychiatric morbidity associated with dengue. The evidence available from eight observational studies is summarized in this review. Depression and anxiety are noted to be prevalent during both the acute and convalescent stages of the infection. The presence of encephalopathy and other neurological conditions is not a prerequisite for developing psychiatric disorders. However, treatment options to manage such psychiatric manifestations were not specified in the observational studies. Anecdotal evidence from case reports is outlined. Special attention is paid to the role of epigenetic modifications following dengue infections and the role of histone deacetylase inhibitors in the management. DNA methylation inhibitors such as valproic acid play a significant role in reversing stress-, viral-, or drug-induced epigenetic modifications.
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