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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.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.Signal propagation from the left dlPFC to the salience network was reduced in the θ and α bands in patients with TRD (These results show only part of the pathophysiology of TRD, because stimulation was limited to the left dlPFC.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.

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.

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.

Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to the development of clinically useful biomarkers. In this cross-sectional study, we adopted data-driven machine-learning techniques to classify and stage the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. We included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging from 3 institutions. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into Z-scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning classification and staging. As a result, SuStaIn identified three different subtypes: 1) subcortical volume reduction (SC) type (73 patients, 47.4%), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, 2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients, 27.3%), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, 3) cortical thinning (pure CX) type (39 patients, 25.3%), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages of progression than treatment-responsive cases (p=0.001). The GP-CX type presented in earlier stages than the pure CX type (p=0.009). In conclusion, the brain morphological progressions in schizophrenia can be classified into three subtypes by SuStaIn algorithm. Treatment resistance was associated with more progressed stages of the disease, which may suggest a novel biomarker for schizophrenia.

Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia.This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels.We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose.Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study.This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.

Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder.

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.

Cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain. Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. Here, we conducted a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, we identified six articles. Five studies measured MEP, where four studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy and postmortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. In conclusion, reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Therefore, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.

Aim Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F1, 8 = 8.67, adjusted R2 = 0.46). Conclusions The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347-351.

Highlights • Different etiology is assumed in treatment-resistant and responsive schizophrenia. • Patients with treatment-resistant schizophrenia were classified from controls. • Patients with non-treatment-resistant schizophrenia were classified from controls. • Two classifications reached area under the curve as high as 0.69 and 0.85. • Area under the curve remained as high as 0.69 when two classifiers were swapped., Background One-third of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics (TRS), while the rest respond (NTRS). Examining whether TRS and NTRS represent different pathophysiologies is an important step toward precision medicine. Methods Focusing on cortical thickness (CT), we analyzed international multi-site cross-sectional datasets of magnetic resonance imaging comprising 110 patients with schizophrenia (NTRS = 46, TRS = 64) and 52 healthy controls (HCs). We utilized a logistic regression with L1-norm regularization to find brain regions related to either NTRS or TRS. We conducted nested 10-fold cross-validation and computed the accuracy and area under the curve (AUC). Then, we applied the NTRS classifier to patients with TRS, and vice versa. Results Patients with NTRS and TRS were classified from HCs with 65% and 78% accuracies and with the AUC of 0.69 and 0.85 (p = 0.014 and

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 (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 byOne-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).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.

Background Resilience is a crucial factor preventing the onset of mental illness and contributing to the well-being and healthy longevity, whose neural bases are not fully elucidated in older people. The present study aimed to identify the cortical thickness associating with resilience in older adults. Methods This is a part of the cross-sectional Arakawa geriatric cohort study for people aged 65 years or older, consisting of 1001 individuals. A Self-Reported Resilience Scale (RS), neuropsychological batteries, face-to-face interviews for diagnosis, and a three-dimensional T1-weighted magnetic resonance imaging were conducted. Cortical thickness was computed by the FreeSurfer. The relationships among cortical thickness, total RS score, and clinico-demographic data were investigated using univariate and multivariable regression analyses. Results The total RS score was correlated with age, education, and scores of the Mini-Mental State Examination (MMSE) and Geriatric Depression Scale (GDS) in univariate analyses. The total RS score was associated with cortical thicknesses in the left posterior cingulate (β [95 % CI of B] = 0.07 [0.16–14.84]) and the left temporal pole (β [95 % CI of B] = 0.08 [0.63–9.93]) after adjusting sex, age, imaging acquisition site, education, MMSE and GDS scores, hypertension, hyperlipidemia, diabetes mellitus, Barthel index, BMI, and living situation in multivariable regression analyses. Conclusion The present analyses suggest that the resilience capacity may be related to the cortical thickness in the posterior cingulate and temporal cortices in older adults. Our findings warrant further longitudinal studies to confirm the causal relationship between stress events, resilience, and brain structures.

Major depressive disorder (MDD) is a mental illness with high socio-economic burden, but its pathophysiology has not been fully elucidated. Recently, the cortical excitatory and inhibitory imbalance hypothesis and neuroplasticity hypothesis have been proposed for MDD. Although several studies have examined the neurophysiological profiles in MDD using transcranial magnetic stimulation (TMS), a meta-analysis of TMS neurophysiology has not been performed. The objective of this study was to compare TMS-electromyogram (TMS-EMG) findings between patients with MDD and healthy controls (HCs). To this end, we examined whether patients with MDD have lower short-interval cortical inhibition (SICI) which reflects gamma-aminobutyric acid (GABA)A receptor-mediated activity, lower cortical silent period (CSP) which represents GABAB receptor-mediated activity, higher intracortical facilitation (ICF) which reflects glutamate N-methyl-D-aspartate receptor-mediated activity, and the lower result of paired associative stimulation (PAS) paradigm which shows the level of neuroplasticity in comparison with HC. Further, we explored the effect of clinical and demographic factors that may influence TMS neurophysiological indices. We first searched and identified research articles that conducted single- or paired-pulse TMS-EMG on patients with MDD and HC. Subsequently, we extracted the data from the included studies and meta-analyzed the data with the comprehensive meta-analysis software. Patients with MDD were associated with lower SICI, lower CSP, potentially higher ICF, and lower PAS compared with HC. Our results confirmed the proposed hypotheses, suggesting the usefulness of TMS neurophysiology as potential diagnostic markers of MDD.

Background: The neural basis of treatment-resistant schizophrenia (TRS) remains unclear. Previous neuroimaging studies suggest that aberrant connectivity between the anterior cingulate cortex (ACC) and default mode network (DMN) may play a key role in the pathophysiology of TRS. Thus, we aimed to examine the connectivity between the ACC and posterior cingulate cortex (PCC), a hub of the DMN, computing isolated effective coherence (iCoh), which represents causal effective connectivity. Methods: Resting-state electroencephalogram with 19 channels was acquired from seventeen patients with TRS and thirty patients with non-TRS (nTRS). The iCoh values between the PCC and ACC were calculated using sLORETA software. We conducted four-way analyses of variance (ANOVAs) for iCoh values with group as a between-subject factor and frequency, directionality, and laterality as within-subject factors and post-hoc independent t-tests. Results: The ANOVA and post-hoc t-tests for the iCoh ratio of directionality from PCC to ACC showed significant findings in delta (t45 = 7.659, p = 0.008) and theta (t45 = 8.066, p = 0.007) bands in the left side (TRS &lt, nTRS). Conclusion: Left delta and theta PCC and ACC iCoh ratio may represent a neurophysiological basis of TRS. Given the preliminary nature of this study, these results warrant further study to confirm the importance of iCoh as a clinical indicator for treatment-resistance.

Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with AD, mild cognitive impairment (MCI), and healthy controls (HC). Our meta-analyses indicated that RMT, SAI, SICI, and LICI were significantly lower in patients with AD, while ICF did not show a difference in patients with AD compared with HC. In patients with MCI, RMT and SAI were significantly lower than in HC. In conclusion, motor cortical excitability was increased, while cholinergic function was decreased in AD and MCI in comparison with HC and patients with AD had decreased GABAergic and glutamatergic functions compared with HC. Our results warrant further studies to differentiate AD, MCI, and HC, employing multimodal TMS neurophysiology.

Neurodevelopmental disorders, including autism spectrum disorder, are common in children and adolescents, but treatment strategies remain limited. Although repetitive transcranial magnetic stimulation has been studied for neurodevelopmental disorders, there is no clear consensus on its therapeutic effects. This systematic review examined literature on repetitive transcranial magnetic stimulation for children and adolescents with neurodevelopmental disorders published up to 2018 using the PubMed database. The search identified 264 articles and 14 articles met eligibility criteria. Twelve of these studies used conventional repetitive transcranial magnetic stimulation and two studies used theta burst stimulation. No severe adverse effects were reported in these studies. In patients with autism spectrum disorder, low-frequency repetitive transcranial magnetic stimulation and intermittent theta burst stimulation applied to the dorsolateral prefrontal cortex may have therapeutic effects on social functioning and repetitive behaviors. In patients with attention deficit/hyperactivity disorder, low-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex and high-frequency repetitive transcranial magnetic stimulation applied to the right dorsolateral prefrontal cortex may target inattention, hyperactivity, and impulsivity. In patients with tic disorders, low-frequency repetitive transcranial magnetic stimulation applied to the bilateral supplementary motor area improved tic symptom severity. This systematic review suggests that repetitive transcranial magnetic stimulation may be a promising intervention for children and adolescents with neurodevelopmental disorders. The results warrant further large randomized controlled trials of repetitive transcranial magnetic stimulation in children with neurodevelopmental disorders.

Repetitive transcranial magnetic stimulation (rTMS) is an effective clinical intervention for various neuropsychiatric diseases. However, it is still unclear whether rTMS has an effect on cognitive functioning. In this review, we aimed to systematically evaluate the cognitive effects of rTMS in depression, schizophrenia, and Alzheimer's disease. We searched PubMed (1996–2018) under the set terms to review randomized controlled trials (RCT) to examine the effectiveness of rTMS administered to the dorsolateral prefrontal cortex (DLPFC) and evaluated cognitive functions in patients with depression, schizophrenia, and Alzheimer's disease. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 579 articles, 31 of which met inclusion and exclusion criteria. Among them, 15 were conducted in patients with depression, 11 in patients with schizophrenia, and 5 in patients with Alzheimer's disease. Specifically, 6 studies demonstrated a significant improvement of executive function across these diseases. Further, no evidence for cognitive adverse effects was found in these included rTMS studies. Although the heterogeneity between studies in terms of cognitive measures applied, stimulation parameters, and participants limits the ability to generalize conclusions, this review demonstrated that prefrontal rTMS could exert pro-cognitive effects on executive function and attention in some patients with depression but inconsistent cognitive impacts in any of the examined domains especially in patients with schizophrenia and Alzheimer's disease. The results warrant further rTMS studies that include systematic assessment of cognition across various neuropsychiatric diseases.

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR “magnetic resonance spectroscopy”). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = −0.38; 95% CI, −0.69 to −0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.

Given that approximately one-third of patients with schizophrenia do not respond to antipsychotics, different neurobiological bases may underlie treatment resistance in schizophrenia. Previous studies showed that treatment response is associated with both frontostriatal connectivity and glutamatergic neurometabolite levels in the caudate in patients with schizophrenia, which leads to the hypothesis that the relationship between them may be altered, specifically in patients with treatment-resistant schizophrenia (TRS). Employing analyses of covariance and subsequent partial correlation analyses, we compared the relationship between glutamate+glutamine (Glx) levels in the caudate and fractional anisotropy (FA) values in the tract between the dorsolateral prefrontal cortex and caudate in 19 patients with TRS, 20 patients responsive to first-line antipsychotics (FL-Resp), and 19 healthy controls (HCs). TRS was defined by severe positive symptomatology despite first-line antipsychotic treatment. Patients with TRS had lower FA values in the bilateral frontostriatal tracts than patients with FL-Resp and HCs (P < .001), while no group differences were found in caudate Glx levels. There was a significant frontostriatal FA value-by-group interaction on caudate Glx levels (F = 7.37, P = .009). Frontostriatal FA values positively correlated with caudate Glx levels in HCs (r = −.55, P = .028), while they were negatively associated with caudate Glx levels in the TRS group (r = .53, P = .043). Furthermore, in the FL-Resp group, frontostriatal FA values did not significantly correlated with caudate Glx levels. The altered relationship between white matter integrity and the glutamate system in the frontostriatal circuit in the TRS group may reflect the pathophysiology underlying treatment response/resistance in schizophrenia.

Aim It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6‐week double‐blind, placebo‐controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R 2: .51, .42 and .55, .54, respectively). Conclusion Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity., This study found that treatment response to asenapine was predicted by early improvements of individual symptoms such as negative symptoms, poor attention and impulse control, and lack of insight in patients with schizophrenia. In addition, prediction accuracy was almost comparable between the model with individual symptoms and the model with the PANSS total score, supporting the importance to assess both individual symptoms and the whole severity in the clinical settings.

Delay discounting (DD) represents decreased subjective value for delayed reward relative to the same reward at present. The concept of DD has been applied for pathophysiology of addiction and psychiatric disorders. However, the detailed neuroimaging correlates of DD underlying pathophysiology still remain unclear. Thus, we conducted a systematic review to investigate neural correlates of DD on magnetic resonance imaging studies among addiction and psychiatric disorders. Specific search terms were set on PubMed to identify relevant articles. Initial search identified 551 records and 31 studies met the inclusion criteria. The present review revealed that greater DD was correlated with increased activity in areas related to reward evaluation and prediction as well as decreased activity in areas related to cognitive control. Healthy controls showed smaller changes in activities of these areas associated with DD when compared to patient groups. As the neural basis related to DD, three neural networks have been proposed that are associated with the actions of short-term interests and long-term benefits. Among the three potential neural networks on DD, the first one included the ventromedial prefrontal cortex and ventral striatum and implicated in evaluating reward values, the second network included the anterior cingulate cortex and linked to cognitive control, and the third network included the middle temporal gyrus and was involved in predictions and affection. This review generated consistent findings on the neural basis of DD among patients with addiction and psychiatric disorders, which may represent the pathophysiology related to DD and impulsivity of mental illness.

Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p .05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy ((1)H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T (1)H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

Aim Stress-related disorders and severe stress exposure can cause atrophy of the whole hippocampus and its subfields. However, the impact of stress coping strategies on the hippocampus remains unclear. Therefore, we aimed to examine the relation between approach- and avoidance-oriented coping strategies and hippocampal volume in elderly persons. Methods A total of 1045 elderly persons living in Arakawa-ward, Tokyo (mean ± SD age: 72.8 ± 5.2 years; 569 females [54.4%]) were included in the study and completed several questionnaires and face-to-face interviews and underwent magnetic resonance imaging. Approach- or avoidance-oriented coping strategies were assessed with the Stress and Coping Inventory, while cognitive function and depressive symptoms were assessed with the Mini-Mental State Examination and Geriatric Depression Scale, respectively. The volume of the whole hippocampus on T1-weighted images was delineated and calculated using FreeSurfer 6.0. Multiple regression analyses were performed to examine the relation between Stress and Coping Inventory scores and whole hippocampal volume. Results Approach-oriented coping strategy scores were positively correlated with whole hippocampal volume. Furthermore, these relations remained significant after controlling for the influence of cognitive function and depressive symptoms on these volumetric variables. In contrast, avoidance-oriented coping strategy scores were not correlated with whole hippocampal volume. Conclusion This study demonstrated that hippocampal volume may be associated with the approach-oriented coping strategy; therefore, this strategy may preserve hippocampal volume in the elderly.

Background:Glutathione is among the important antioxidants to prevent oxidative stress. However, the relationships between abnormality in the glutathione system and pathophysiology of schizophrenia remain uncertain due to inconsistent findings on glutathione levels and/or glutathione-related enzyme activities in patients with schizophrenia.Methods:A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies, in which three metabolite levels (glutathione, glutathione disulfide, and total glutathione (glutathione+glutathione disulfide)) and five enzyme activities (glutathione peroxidase, glutathione reductase, glutamate-cysteine ligase, glutathione synthetase, and glutathione S-transferase) were measured with any techniques in both patients with schizophrenia and healthy controls, were included. Standardized mean differences were calculated to determine the group differences in the glutathione levels with a random-effects model.Results:We identified 41, 9, 15, 38, and seven studies which examined glutathione, glutathione disulfide, total glutathione, glutathione peroxidase, and glutathione reductase, respectively. Patients with schizophrenia had lower levels of both glutathione and total glutathione and decreased activity of glutathione peroxidase compared to controls. Glutathione levels were lower in unmedicated patients with schizophrenia than those in controls while glutathione levels did not differ between patients with first-episode psychosis and controls.Conclusions:Our findings suggested that there may be glutathione deficits and abnormalities in the glutathione redox cycle in patients with schizophrenia. However, given the small number of studies examined the entire glutathione system, further studies are needed to elucidate a better understanding of disrupted glutathione function in schizophrenia, which may pave the way for the development of novel therapeutic strategies in this disorder.

Background Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD. Method A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices. Result Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices. Limitation The difference in medication use was difficult to control and it may affect the results. Conclusion This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness.

Background Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild to moderate illness severity, which is not entirely reflective of what is observed in clinical practice. Methods In this present work, we compared glutamate+glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE=35ms). TRS criteria were defined by severe positive symptoms (i.e. ≥5 on 2 Positive and Negative Syndrome Scale (PANSS) positive symptom items or ≥4 on 3 PANSS positive symptom items) despite standard antipsychotic treatment. Results A total of 95 participants were included (29 TRS patients [PANSS=111.2±20.4], 33 non-TRS patients [PANSS=49.8±13.7], and 33 HCs). dACC Glx levels were higher in the TRS group versus HCs (group effect: F[2,75]=4.74, p=0.011; TRS vs. HCs: p=0.012). No group differences were identified in the caudate. There were no associations between Glx levels in these regions and clinical severity in either patient group. Discussion Our results confirm that higher dACC Glx might be related to the pathophysiology underlying TRS, by demonstrating this phenomenon in a TRS patient population reflective of clinical practice.

Background Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. Objective The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. Methods We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n = 825), brain metabolism (n = 1,304), and brain volumes (n = 1,606) among three groups using data for 18F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. Results Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. Conclusions Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

Background Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. Objectives The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. Methods We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. Results At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. Conclusions The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.