A comparative study of the dorsolateral prefrontal cortex targeting approaches for transcranial magnetic stimulation treatment: Insights from the healthy control data.

Repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) is an established treatment for medication-resistant depression. Several targeting methods for the left DLPFC have been proposed including identification with resting-state functional magnetic resonance imaging (rs-fMRI) neuronavigation, stimulus coordinates based on structural MRI, or electroencephalography (EEG) F3 site by Beam F3 method. To date, neuroanatomical and neurofunctional differences among those approaches have not been investigated on healthy subjects, which are structurally and functionally unaffected by psychiatric disorders. This study aimed to compare the mean location, its dispersion, and its functional connectivity with the subgenual cingulate cortex (SGC), which is known to be associated with the therapeutic outcome in depression, of various approaches to target the DLPFC in healthy subjects. Fifty-seven healthy subjects underwent MRI scans to identify the stimulation site based on their resting-state functional connectivity and were measured their head size for targeting with Beam F3 method. In addition, we included two fixed stimulus coordinates over the DLPFC in the analysis, as recommended in previous studies. From the results, the rs-fMRI method had, as expected, more dispersed target sites across subjects and the greatest anticorrelation with the SGC, reflecting the known fact that personalized neuronavigation yields the greatest antidepressant effect. In contrast, the targets located by the other methods were relatively close together with less dispersion, and did not differ in anticorrelation with the SGC, implying their limitation of the therapeutic efficacy and possible interchangeability of them.

Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia.

Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues' magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility-volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group's nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.

Decreased short-latency afferent inhibition in individuals with mild cognitive impairment: A TMS-EEG study.

TMS combined with EEG (TMS-EEG) is a tool to characterize the neurophysiological dynamics of the cortex. Among the TMS paradigms, short-latency afferent inhibition (SAI) allows the investigation of inhibitory effects mediated by the cholinergic system. The aim of this study was to compare cholinergic function in the DLPFC between individuals with mild cognitive impairment (MCI) and healthy controls (HC) using TMS-EEG with the SAI paradigm. In this study, 30 MCI and 30 HC subjects were included. The SAI paradigm consisted of 80 single pulse TMS and 80 SAI stimulations applied to the left DLPFC. N100 components, global mean field power (GMFP) and total power were calculated. As a result, individuals with MCI showed reduced inhibitory effects on N100 components and GMFP at approximately 100 ms post-stimulation and on ß-band activity at 200 ms post-stimulation compared to HC. Individuals with MCI showed reduced SAI, suggesting impaired cholinergic function in the DLPFC compared to the HC group. We conclude that these findings underscore the clinical applicability of the TMS-EEG method as a powerful tool for assessing cholinergic function in individuals with MCI.

Neuroplasticity of the left dorsolateral prefrontal cortex in patients with treatment-resistant depression as indexed with paired associative stimulation: a TMS-EEG study.

Major depressive disorder affects over 300 million people globally, with approximately 30% experiencing treatment-resistant depression (TRD). Given that impaired neuroplasticity underlies depression, the present study focused on neuroplasticity in the dorsolateral prefrontal cortex (DLPFC). Here, we aimed to investigate the differences in neuroplasticity between 60 individuals with TRD and 30 age- and sex-matched healthy controls (HCs). To induce neuroplasticity, participants underwent a paired associative stimulation (PAS) paradigm involving peripheral median nerve stimulation and transcranial magnetic stimulation (TMS) targeting the left DLPFC. Neuroplasticity was assessed by using measurements combining TMS with EEG before and after PAS. Both groups exhibited significant increases in the early component of TMS-evoked potentials (TEP) after PAS (P < 0.05, paired t-tests with the bootstrapping method). However, the HC group demonstrated a greater increase in TEPs than the TRD group (P = 0.045, paired t-tests). Additionally, event-related spectral perturbation analysis highlighted that the gamma power significantly increased after PAS in the HC group, whereas it was decreased in the TRD group (P < 0.05, paired t-tests with the bootstrapping method). This gamma power modulation revealed a significant group difference (P = 0.006, paired t-tests), indicating an inverse relationship for gamma power modulation. Our findings underscore the impaired neuroplasticity of the DLPFC in individuals with TRD.

Development of Artificial Intelligence for Determining Major Depressive Disorder Based on Resting-State EEG and Single-Pulse Transcranial Magnetic Stimulation-Evoked EEG Indices.

Depression is the disorder with the greatest socioeconomic burdens. Its diagnosis is still based on an operational diagnosis derived from symptoms, and no objective diagnostic indicators exist. Thus, the present study aimed to develop an artificial intelligence (AI) model to aid in the diagnosis of depression from electroencephalography (EEG) data by applying machine learning to resting-state EEG and transcranial magnetic stimulation (TMS)-evoked EEG acquired from patients with depression and healthy controls. Resting-state EEG and single-pulse TMS-EEG were acquired from 60 patients and 60 healthy controls. Power spectrum analysis, phase synchronization analysis, and phase-amplitude coupling analysis were conducted on EEG data to extract feature candidates to apply different types of machine learning algorithms. Furthermore, to address the limitation of the sample size, dimensionality reduction was performed in a manner to increase the quality of information by featuring robust neurophysiological metrics that showed significant differences between the two groups. Then, nine different machine learning models were applied to the data. For the EEG data, we created models combining four modalities, including (1) resting-state EEG, (2) pre-stimulus TMS-EEG, (3) post-stimulus TMS-EEG, and (4) differences between pre- and post-stimulus TMS-EEG, and evaluated their performance. We found that the best estimation performance (a mean area under the curve of 0.922) was obtained using receiver operating characteristic curve analysis when linear discriminant analysis (LDA) was applied to the combination of the four feature sets. This study showed that by using TMS-EEG neurophysiological indices as features, it is possible to develop a depression decision-support AI algorithm that exhibits high discrimination accuracy.

Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment. METHOD: Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis. RESULTS: A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs. CONCLUSION: This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia.

BACKGROUND: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. METHOD: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. RESULTS: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. CONCLUSION: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

Investigation of Spatiotemporal Profiles of Single-Pulse TMS-Evoked Potentials with Active Stimulation Compared with a Novel Sham Condition.

Identifying genuine cortical stimulation-elicited electroencephalography (EEG) is crucial for improving the validity and reliability of neurophysiology using transcranial magnetic stimulation (TMS) combined with EEG. In this study, we evaluated the spatiotemporal profiles of single-pulse TMS-elicited EEG response administered to the left dorsal prefrontal cortex (DLPFC) in 28 healthy participants, employing active and sham stimulation conditions. We hypothesized that the early component of TEP would be activated in active stimulation compared with sham stimulation. We specifically analyzed the (1) stimulus response, (2) frequency modulation, and (3) phase synchronization of TMS-EEG data at the sensor level and the source level. Compared with the sham condition, the active condition induced a significant increase in TMS-elicited EEG power in the 30-60 ms time interval in the stimulation area at the sensor level. Furthermore, in the source-based analysis, the active condition induced significant increases in TMS-elicited response in the 30-60 ms compared with the sham condition. Collectively, we found that the active condition could specifically activate the early component of TEP compared with the sham condition. Thus, the TMS-EEG method that was applied to the DLPFC could detect the genuine neurophysiological cortical responses by properly handling potential confounding factors such as indirect response noises.

Reduced signal propagation elicited by frontal transcranial magnetic stimulation is associated with oligodendrocyte abnormalities in treatment-resistant depression.

BACKGROUND: The efficacy of repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (dlPFC) has been established in patients with treatment-resistant depression (TRD), suggesting that alterations in signal propagation from the left dlPFC to other brain regions may be linked to the pathophysiology of TRD. Alterations at the cellular level, including dysfunction of oligodendrocytes, may contribute to these network abnormalities. The objectives of the present study were to compare signal propagation from the left dlPFC to other neural networks in patients with TRD and healthy controls. We used TMS combined with electroencephalography to explore links between cell-specific gene expression and signal propagation in TRD using a virtual-histology approach. METHODS: We examined source-level estimated signal propagation from the left dlPFC to the 7 neural networks in 60 patients with TRD and 30 healthy controls. We also calculated correlations between the interregional profiles of altered signal propagation and gene expression for 9 neural cell types derived from the Allen Human Brain Atlas data set. RESULTS: Signal propagation from the left dlPFC to the salience network was reduced in the θ and α bands in patients with TRD (p = 0.0055). Furthermore, this decreased signal propagation was correlated with cellspecific gene expression of oligodendrocytes (p < 0.000001). LIMITATIONS: These results show only part of the pathophysiology of TRD, because stimulation was limited to the left dlPFC. CONCLUSION: Reduced signal propagation from the left dlPFC to the salience network may represent a pathophysiological endophenotype of TRD; this finding may be associated with reduced expression of oligodendrocytes.

Impact of Sevoflurane and Thiopental Used Over the Course of Electroconvulsive Therapy: Propensity Score Matching Analysis.

Objective: Although anesthetics play an important role in electroconvulsive therapy (ECT), the clinical efficacy and seizure adequacy of sevoflurane in the course of ECT remain unclear. The purpose of this study was to examine the clinical efficacy and seizure adequacy of sevoflurane, compared with those of thiopental, in the course of ECT in patients with mood disorders. Methods: We conducted a retrospective chart review. Patients who underwent a course of ECT and received sevoflurane (n = 26) or thiopental (n = 26) were included. Factors associated with ECT and treatment outcomes were compared between the two groups using propensity score (PS) matching. Between-group differences were examined using an independent t-test for continuous variables and a χ2-test for categorical variables. Results: Patients who received sevoflurane needed more stimulations (sevoflurane: 13.2 ± 4 times, thiopental: 10.0 ± 2.5 times, df = 51, p = 0.001) and sessions (sevoflurane: 10.0 ± 2.1 times, thiopental: 8.4 ± 2.1 times, df = 51, p = 0.01) and had more inadequate seizures (sevoflurane: 5 ± 3.9 times, thiopental: 2.7 ± 2.7 times, df = 51, p = 0.015). Remission and response rates were similar in both groups. Conclusion: The present findings indicate that sevoflurane should be used with caution in ECT and only when the clinical rationale is clear.

Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment.

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

Thalamic and striato-pallidal volumes in schizophrenia patients and individuals at risk for psychosis: A multi-atlas segmentation study.

Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness.

Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies.

BACKGROUND: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. METHODS: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. RESULTS: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18-0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21-0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05-0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = -0.40; 95% CIs: -0.62 to -0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38-1.01; Glu: g = 0.63; 95% CIs: 0.31-0.94) while MCC Glu levels were decreased in the patient group except TRS (g = -0.17; 95% CIs: -0.33 to -0.01). CONCLUSIONS: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

Absence of multiple sleep-onset rapid eye movement periods (SOREMPs) is not a specific feature of patients with pathological sleep prolongation.

Purpose: Multiple sleep-onset rapid eye movement periods (SOREMPs) are involved in the pathophysiology of narcolepsy, but it is not clear whether the lack of multiple SOREMPs is associated with the pathophysiology of idiopathic hypersomnia or not. We examined the significance of multiple SOREMPs in patients with pathological sleep prolongation. Methods: Participants were consecutive patients complaining of unexplained sleepiness and agreed to a 3-day-sleep studies; 24 h polysomnography (PSG) followed by standard PSG and multiple sleep latency test (MSLT). Forty-one (26 females, 21.9 ± 8.1 years old, BMI 20.4 ± 2.3 kg/m2) of 54 eligible patients without other sleep pathologies showed pathological sleep prolongation. We subdivided them into those with and without multiple SOREMPs on MSLT and compared clinical and PSG variables between groups. Results: Six of 41 (14.6%) patients showed multiple SOREMPs on MSLT. There were almost no differences in sleep variables between those with and without multiple SOREMPs. We only found shorter mean sleep latency on MSLT and more REM cycles on 24 h PSG in those with multiple SOREMPs (adjusted p = 0.016 and 0.031). The frequencies of REM-related phenomena and clinical symptoms related to idiopathic hypersomnia were not different between groups. Conclusion: Our results indicated that patients with pathological sleep prolongation had the same clinical profiles regardless of the status of SOREMPs, suggesting the absence of multiple SOREMPs, prerequisite for the diagnosis of idiopathic hypersomnia, is not a specific feature of pathological sleep prolongation. Confirmation of sleep prolongation alone could be a diagnostic tool for idiopathic hypersomnia.

Insights of neurophysiology on unconscious state using combined transcranial magnetic stimulation and electroencephalography: A systematic review.

Unconscious state has been investigated in numerous studies so far, but pathophysiology of this state is not fully understood. Recently, combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been developed to allow for non-invasive assessment of neurophysiology in the cerebral cortex. We conducted a systematic literature search for TMS-EEG studies on human unconscious state using PubMed with cross-reference and manual searches. The initial search yielded 137 articles, and 19 of them were identified as relevant, including one article found by manual search. This review included 10 studies for unresponsive wakefulness syndrome (UWS), 9 for minimally conscious states (MCS), 5 for medication-induced unconscious states, and 6 for natural non-rapid eye movement states. These studies analyzed TMS-evoked potential to calculate perturbational complexity index (PCI) and OFF-periods. In particular, PCI was found to be a potentially useful marker to differentiate between UWS and MCS. This review demonstrated that TMS-EEG could represent a promising neuroscientific tool to investigate various unconscious states. Further TMS-EEG research may help elucidate the neural basis of unconscious state.

Photobiological Neuromodulation of Resting-State EEG and Steady-State Visual-Evoked Potentials by 40 Hz Violet Light Optical Stimulation in Healthy Individuals.

Photobiological neuromodulation and its clinical application has been investigated in recent years. The response of the gamma-oscillation to human visual stimuli is known to be both burst and resonant in nature, and the coupling between alpha and gamma oscillations may play a functional role in visual processing. To date, there is no study that examined the effects of gamma-frequency violet light (VL) stimulation on human electroencephalography (EEG). In this study, we investigated the neurophysiological changes induced by light stimulation using EEG. The purpose of this study was to evaluate the specific effects of 40 Hz gamma-frequency VL stimulation on EEG activity by comparing the effects of white light (WL) with the same condition. Twenty healthy participants (10 females: 37.5 ± 14.3 years; 10 males: 38.0 ± 13.3 years) participated in this study and the following results were observed. First, when compared with the power spectrum density (PSD) of baseline EEG, 40 Hz-WL induced significant increase of PSD in theta band. Second, compared the PSDs between EEG with 40 Hz-VL and EEG with 40 Hz-WL, 40 Hz-VL induced significantly lower enhancement in delta and theta bands than 40 Hz-WL. Third, when focused on the occipital area, negative peak of VEP with 40 Hz-VL was smaller than that of 40 Hz-WL. Fourth, 40 Hz-VL induced an increase of alpha-gamma coupling during the VEP at the F5 electrode site as well as post-EEG at the C4 electrode site, compared with baseline EEG. Thus, the present study suggested that 40 Hz-VL stimulation may induce unique photobiological neuromodulations on human EEG activity.

TMS-EEG Research to Elucidate the Pathophysiological Neural Bases in Patients with Schizophrenia: A Systematic Review.

Schizophrenia (SCZ) is a serious mental disorder, and its pathogenesis is complex. Recently, the glutamate hypothesis and the excitatory/inhibitory (E/I) imbalance hypothesis have been proposed as new pathological hypotheses for SCZ. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a non-invasive novel method that enables us to investigate the cortical activity in humans, and this modality is a suitable approach to evaluate these hypotheses. In this study, we systematically reviewed TMS-EEG studies that investigated the cortical dysfunction of SCZ to examine the emerging hypotheses for SCZ. The following search terms were set in this systematic review: (TMS or 'transcranial magnetic stimulation') and (EEG or electroencephalog*) and (schizophrenia). We inspected the articles written in English that examined humans and were published by March 2020 via MEDLINE, Embase, PsycINFO, and PubMed. The initial search generated 379 studies, and 14 articles were finally identified. The current review noted that patients with SCZ demonstrated the E/I deficits in the prefrontal cortex, whose dysfunctions were also associated with cognitive impairment and clinical severity. Moreover, TMS-induced gamma activity in the prefrontal cortex was related to positive symptoms, while theta/delta band activities were associated with negative symptoms in SCZ. Thus, this systematic review discusses aspects of the pathophysiological neural basis of SCZ that are not explained by the traditional dopamine hypothesis exclusively, based on the findings of previous TMS-EEG research, mainly in terms of the E/I imbalance hypothesis. In conclusion, TMS-EEG neurophysiology can be applied to establish objective biomarkers for better diagnosis as well as to develop new therapeutic strategies for patients with SCZ.

A comparison of cost-effectiveness between offering antidepressant-CBT combinations first or second, for moderate to severe depression in Japan.

BACKGROUND: It is not clear which method is more cost-effective: To initially provide all depressed patients with combination therapy (COMB; i.e. cognitive behavioural therapy plus pharmacotherapy), followed by antidepressant treatment (AD) for those still in depression; or, to first provide AD for all patients, followed by COMB for non-remission patients. The aim is to investigate whether a COMB-first strategy would be more cost-effective than an AD-first strategy, in treating depression. METHODS: A Markov model was developed to perform the analysis. The primary outcome was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) at 104 weeks. Probabilistic sensitivity analysis and scenario analysis were performed, to investigate the uncertainty associated with the clinical parameters and the impact of CBT's cost on the results, respectively. RESULTS: The ICER per QALY at 104 week, was JPY 591,822 (USD 5,725) for moderate depression and JPY 499,487 (USD 4,832) for severe one. The scenario analysis revealed the ICER became JPY 1,147,518 (USD 11,101) for moderate and JPY 968,484 (USD 9,369) for severe when the CBT cost was set as JPY 14,400 (USD 139)(i.e. GBP 96: the unit cost of CBT in UK), which is well below the threshold recommended by NICE (i.e. GBP 20,000-30,000). LIMITATIONS: This is a model-based analysis which was conducted from the health insurance perspective. Then, the analysis from the societal perspective would generate different results. CONCLUSIONS: The results suggest that a COMB-first strategy would be more cost effective than an AD-first strategy.

Polygenic risk scores for major psychiatric and neurodevelopmental disorders contribute to sleep disturbance in childhood: Adolescent Brain Cognitive Development (ABCD) Study.

Sleep disturbance is a common symptom of psychiatric and neurodevelopmental disorders and, especially in childhood, can be a precursor to various mental disorders. However, the genetic etiology of mental illness that contributes to sleep disturbance during childhood is poorly understood. We investigated whether the polygenic features of psychiatric and neurodevelopmental disorders are associated with sleep disturbance during childhood. We conducted polygenic risk score (PRS) analyses by utilizing large-scale genome-wide association studies (GWASs) (n = 46,350-500,199) of five major psychiatric and neurodevelopmental disorders (autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and bipolar disorder) and, additionally, anxiety disorders as base datasets. We used the data of 9- to 10-year-olds from the Adolescent Brain Cognitive Development study (n = 9683) as a target dataset. Sleep disturbance was assessed based on the Sleep Disturbance Scale for Children (SDSC) scores. The effects of PRSs for these psychiatric and neurodevelopmental disorders on the total scores and six subscale scores of the SDSC were investigated. Of the PRSs for the five psychiatric and neurodevelopmental disorders, the PRSs for ADHD and MDD positively correlated with sleep disturbance in children (ADHD: R2 = 0.0033, p = 6.19 × 10-5, MDD: R2 = 0.0042, p = 5.69 × 10-6). Regarding the six subscale scores of the SDSC, the PRSs for ADHD positively correlated with both disorders of initiating and maintaining sleep (R2 = 0.0028, p = 2.31 × 10-4) and excessive somnolence (R2 = 0.0023, p = 8.44 × 10-4). Furthermore, the PRSs for MDD primarily positively correlated with disorders of initiating and maintaining sleep (R2 = 0.0048, p = 1.26 × 10-6), followed by excessive somnolence (R2 = 0.0023, p = 7.74 × 10-4) and sleep hyperhidrosis (R2 = 0.0014, p = 9.55 × 10-3). Despite high genetic overlap between MDD and anxiety disorders, PRSs for anxiety disorders correlated with different types of sleep disturbances such as disorders of arousal or nightmares (R2 = 0.0013, p = 0.011). These findings suggest that greater genetic susceptibility to specific psychiatric and neurodevelopmental disorders, as represented by ADHD, MDD, and anxiety disorders, may contribute to greater sleep problems among children.