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We studied the complete set of elastic constants Cij and internal frictions tensor Qij-1 of anisotropic decagonal Al72Ni18Co8 single quasicrystal by electromagnetic acoustic resonance at low temperatures, to 5 K. Most Cij(T) showed usual stiffening upon cooling and their temperature behaviors are well characterized by an Einstein-lattice-vibration model. The average Grüneisen parameter estimated from the bulk modulus is 2.4, almost identical to crystalline Al. Ambient temperature Qij-1 show a linear relationship to the elastic-constants temperature derivatives |dCij/dT|/Cij with a slope of 1.28 K-1, suggesting that lattice anharmonicity plays a dominant role for Qij-1. The longitudinal modulus for the decagonal axis C33 and corresponding internal friction Q33-1, however, showed significant deviation from such ideal behavior, suggesting additional low-frequency phonon-excitation modes along the decagonal axis. [ABSTRACT FROM AUTHOR]

The electromagnetic acoustic resonance approach is employed to determine the complete elastic constants and internal fricitions of the decagonal [Al.sub.72][Ni.sub.18][Co.sub.8] single quasicrystal at low temperatures. The elastic constants are shown to get stiffened upon cooling.

Physically isolated and crystallographically oriented single-variant nanocrystals (NCs) have been successfully formed in an Ni–P amorphous alloy using focused ion-beam (FIB) irradiation. The amorphous alloy was irradiated by the FIB at an incident ion beam angle of 35° to the specimen surface. Transmission electron microscopy observation has shown the formation of a large amount of NCs, approximately 20  nm in size, throughout the irradiated area. Electron diffraction analysis has revealed that the NCs have an fcc structure, with the irradiated-plane normal parallel to [111] fcc and the FIB direction parallel to [001] fcc , indicating that the NCs are single variant. [ABSTRACT FROM AUTHOR]

Structural changes of a Ni-P amorphous alloy under focused-ion-beam (FIB) irradiation have been examined using transmission electron microscopy. On the irradiated plane, the formation of crystallographically orientated nanosized crystals (NCs), with the particle size of approximately 10 nm, was observed. A series of electron diffraction analyses have revealed that NCs have a face-centered-cubic (fcc) structure and the following orientation relationships between the NCs and the FIB direction were found. These are, irradiated plane//(111)[sub fcc] and FIB direction//〈110〉[sub fcc]. [ABSTRACT FROM AUTHOR]

Universal mechanical principles may exist behind seemingly unrelated physical phenomena, providing novel insights into their underlying mechanisms. This study sheds light on the geometrical theory of dislocations through an analogy with electromagnetics. In this theory, solving Cartan's first structure equation is essential for connecting the dislocation density to the plastic deformation field of the dislocations. The additional constraint of a divergence-free condition, derived from the Helmholtz decomposition, forms the governing equations that mirror Ampère's and Gauss's law in electromagnetics. This allows for the analytical integration of the equations using the Biot-Savart law. The plastic deformation fields of screw and edge dislocations obtained through this process form both a vortex and an orthogonal coordinate system on the cross-section perpendicular to the dislocation line. This orthogonality is rooted in the conformal property of the corresponding complex function that satisfies the Cauchy-Riemann equations, leading to the complex potential of plastic deformation. We validate the results by comparing them with the classical dislocation theory. The incompatibility tensor is crucial in the generation of the mechanical field. These findings reveal a profound unification of dislocation theories, electromagnetics and complex functions through their underlying mathematical parallels., Competing Interests: We declare we have no competing interests., (© 2025 The Authors.)

Background: Bilateral repetitive transcranial magnetic stimulation (BL-rTMS) over the dorsolateral prefrontal cortex is effective for treatment-resistant depression (TRD). Owing to a shorter treatment time, bilateral theta burst stimulation (BL-TBS) can be more efficient protocol. The non-inferiority of BL-TBS to BL-rTMS was established in late-life TRD; however, this has not been determined in adults of other age groups. Therefore, we investigated the non-inferiority in efficacy of BL-TBS versus BL-rTMS for TRD across a wide range of ages in a randomized, single-blind, multicenter trial., Methods: The study included 180 participants with major depressive disorder (moderate or greater severity) who were unresponsive to at least one antidepressant treatment between September 2018 and July 2022. Following venlafaxine treatment, patients were randomly assigned to BL-rTMS or BL-TBS (1:1 ratio). The primary outcome was baseline-adjusted Montgomery-Åsberg Depression Rating Scale scores at 6 weeks. The non-inferiority margin of -3.86 was compared against the baseline-adjusted difference. Secondary outcomes included other depression rating scales., Results: Seventy-seven patients were randomly assigned to BL-rTMS and 81 to BL-TBS, of whom 73 and 76 were assessed for the primary outcome, respectively. There was a -2.44 point difference, favoring BL-rTMS (one-tailed lower 95 % CI = -4.19, p = 0.091 for non-inferiority), and non-inferiority of BL-TBS was not established. However, non-inferiority was observed for secondary outcomes. The all-cause dropout rates and number of adverse effects were similar between them., Conclusion: Our study could not establish the non-inferiority of BL-TBS compared to BL-rTMS in terms of efficacy for patients with TRD across the adult lifespan., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshihiro Noda reports financial support was provided by Teijin Pharma Limited. Masataka Wada reports a relationship with Japan Society for the Promotion of Science that includes: funding grants. Masataka Wada reports a relationship with Takeda Science Foundation that includes: funding grants. Masataka Wada reports a relationship with Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering that includes: funding grants. Masataka Wada reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Masataka Wada reports a relationship with Eisai Inc that includes: speaking and lecture fees. Masataka Wada reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Japan Agency for Medical Research and Development that includes: funding grants. Shinichiro Nakajima reports a relationship with Japan Research Foundation for Clinical Pharmacology that includes: funding grants. Shinichiro Nakajima reports a relationship with Naito Foundation that includes: funding grants. Shinichiro Nakajima reports a relationship with Takeda Science Foundation that includes: funding grants. Shinichiro Nakajima reports a relationship with Watanabe foundation that includes: funding grants. Shinichiro Nakajima reports a relationship with Osake-no-Kagaku Foundation that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Astellas Foundation for Research on Metabolic Disorders that includes: funding grants. Shinichiro Nakajima reports a relationship with Asahi Quality and Innovations Ltd that includes: funding grants. Shinichiro Nakajima reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Otsuka Holdings Co Ltd that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with PDR pharma that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. Naohiro Arai reports a relationship with Japan Society for the Promotion of Science that includes: funding grants. Naohiro Arai reports a relationship with Meiji Yasuda Life Foundation of Health and Welfare that includes: funding grants. Naohiro Arai reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Hiroyuki Uchida reports a relationship with Daiichi Sankyo Inc that includes: funding grants. Hiroyuki Uchida reports a relationship with Eisai Inc that includes: funding grants and speaking and lecture fees. Hiroyuki Uchida reports a relationship with Mochida Pharmaceutical Co Ltd that includes: funding grants. Hiroyuki Uchida reports a relationship with Otsuka Holdings Co Ltd that includes: funding grants and speaking and lecture fees. Hiroyuki Uchida reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Shinsuke Koike reports a relationship with Japan Agency for Medical Research and Development Department of Innovative Drug Discovery and Development that includes: funding grants. Zafiris J. Daskalakis reports a relationship with BrainsWay Ltd that includes: consulting or advisory and non-financial support. Zafiris J. Daskalakis reports a relationship with MagVenture Inc that includes: non-financial support. Zafiris J. Daskalakis reports a relationship with National Institute of Mental Health that includes: funding grants. Zafiris J. Daskalakis reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Zafiris J. Daskalakis reports a relationship with Brain Canada Foundation that includes: funding grants. Masaru Mimura reports a relationship with Biogen Inc that includes: speaking and lecture fees. Masaru Mimura reports a relationship with BYERLYS PHARMACY that includes: speaking and lecture fees. Daniel M. Blumberger reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Daniel M. Blumberger reports a relationship with National Institutes of Health that includes: funding grants. Daniel M. Blumberger reports a relationship with Brain Canada Foundation that includes: funding grants. Daniel M. Blumberger reports a relationship with BrainsWay Ltd that includes: funding grants and non-financial support. Daniel M. Blumberger reports a relationship with MagVenture Inc that includes: non-financial support. Yoshihiro Noda reports a relationship with Japan Society for the Promotion of Science that includes: funding grants. Yoshihiro Noda reports a relationship with Japan Agency for Medical Research and Development that includes: funding grants. Japan Agency for Medical Research and Development reports a relationship with Teijin Pharma Limited that includes: funding grants. Japan Agency for Medical Research and Development reports a relationship with Inter Reha Co Ltd that includes: funding grants and non-financial support. Japan Agency for Medical Research and Development reports a relationship with MagVenture Inc that includes: non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The existence of stress singularities and reliance on linear approximations pose significant challenges in comprehending the stress field generation mechanism around dislocations. This study employs differential geometry and calculus of variations to mathematically model and numerically analyse screw dislocations. The kinematics of the dislocation are expressed by the diffeomorphism of the Riemann-Cartan manifold, which includes both the Riemannian metric and affine connection. The modelling begins with a continuous distribution of dislocation density, which is transformed into torsion τ through the Hodge duality. The plasticity functional is constructed by applying the Helmholtz decomposition to bundle isomorphism, which is equivalent to the Cartan first structure equation for the intermediate configuration B . The current configuration is derived by the elastic embedding of B into the standard Euclidean space ℝ 3 . The numerical analysis reveals that the elastic stress fields effectively eliminate the singularity along the dislocation line and exhibit excellent conformity with Volterra's theory beyond the dislocation core. Geometrical frustration is the direct source of dislocation stress fields, as demonstrated through the multiplicative decomposition of deformation gradients. By leveraging the mathematical properties of the Riemann-Cartan manifold, we demonstrate that the Ricci curvature determines the symmetry of stress fields. These results substantiate a long-standing mathematical hypothesis: the duality between stress and curvature., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[ 18 F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([ 18 F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [ 18 F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background and Hypothesis: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance., Study Design: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. 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 analysis., Study Results: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), 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), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), 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 than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009)., Conclusions: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Hypothesis: Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia., Study Design: We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinico-demographics was also explored., Study Results: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and fronto-occipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group., Conclusions: These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Glutamatergic neurometabolites play important roles in the basal ganglia, a hub of the brain networks involved in musical rhythm processing. We aimed to investigate the relationship between rhythm processing abilities and glutamatergic neurometabolites in the caudate., Methods: We aquired Glutamatergic function in healthy individuals employing proton magnetic resonance spectroscopy. We targeted the right caudate and the dorsal anterior cingulate cortex (dACC) as a control region. Rhythm processing ability was assessed by the Harvard Beat Assessment Test (H-BAT)., Results: We found negative correlations between the production part of the Beat Saliency Test in the H-BAT and glutamate and glutamine levels in the caudate ( r  = -0.693, p  = 0.002) whereas there was no such association in the dACC., Conclusion: These results suggest that higher glutamatergic neurometabolite levels in the caudate may contribute to rhythm processing, especially the ability to produce meter in music precisely., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Honda, Noda, Matsushita, Tarumi, Nomiyama, Tsugawa, Tobari, Hondo, Saito, Mimura, Fujii and Nakajima.)

Background/aim: CDK inhibitor p16 plays a pivotal role in the induction of cellular senescence and functions as a tumor suppressor. Here, we demonstrate that histone H1.2 is involved in p16 repression., Materials and Methods: Cells were transfected with siRNAs and subjected to quantitative reverse transcription-polymerase chain reaction, immunoblotting and chromatin immunoprecipitation (ChIP) assay., Results: The decrease in H1.2 by oncogenic RAS was associated with increased levels of p16. Depletion of H1.2 selectively increased p16, but not alternative reading frame (ARF) mRNA. ChIP assay showed that H1.2 directly bound to the p16 promoter. Interestingly, silencing YB-1, a component of H1.2 complex, decreased the expression levels of H1.2, resulting in decreased binding of H1.2 on the p16 promoter., Conclusion: These results provide a model in which H1.2 is positively regulated by YB-1 and directly binds to and represses the transcription of p16., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Hypothesis: Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels., Study Design: This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy., Study Results: Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group., Conclusions: The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Accumulating evidence indicates that pathophysiology of schizophrenia involves abnormalities in the dopamine and glutamatergic neuronal systems. Antipsychotic medications are currently used to normalize dopaminergic function for schizophrenia. However, approximately 30 % of the patients have no response to antipsychotic medications, which is classified as treatment-resistant schizophrenia (TRS). Furthermore, dopamine and glutamate levels in the neural basis have been reported to differ between TRS and non-TRS. In this study, we assumed that these differences may affect music rhythm perception and production abilities between the two groups. We examined fifty-seven schizophrenia (26 TRS, 31 non-TRS) and thirty-one healthy controls (HCs) by using the Harvard Beat Assessment Test (H-BAT). As a result, we found that rhythm production was worse in patients with TRS compared to patients with non-TRS and HCs, while no difference was observed between patients with non-TRS and HCs. In addition, rhythm perception and production abilities were impaired in the whole patient group compared with HCs. Furthermore, in the patient group, the deficits were correlated with cognitive impairments. Collectively, these results suggest that patients with schizophrenia may have rhythm processing deficits, with particular a rhythm production problem in the TRS group., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Limitations: Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study., Conclusion: 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., Competing Interests: Conflict of interest: E. Plitman has received research support from an Ontario Graduate Scholarship (OGS), a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship–Master’s, a CIHR Vanier Canada Graduate Scholarship and the Healthy Brains for Healthy Lives Postdoctoral Fellowship. Y. Iwata has received fellowship grants from the CIHR, research support from the Japan Society for the Promotion of Science, the Japanese Society of Clinical Neuropsychopharmacology, Inokashira Hospital Grants for psychiatry research, manuscript fees from Dainippon Sumitomo Pharma and speaker’s fees from Eli Lilly, Meiji-Seika Pharma, Mochida Pharmaceutical and Yoshitomi Yakuhin within the past 3 years. Y. Noda has received a Grant-in-Aid for Young Scientists (KAKENHI); research grants from AMED; an investigator-initiated clinical study grant from Teijin Pharma Ltd.; research grants from the Japan Health Foundation, the Meiji Yasuda Mental Health Foundation, the Mitsui Life Social Welfare Foundation, the Takeda Science Foundation, the Senshin Medical Research Foundation, the Health Science Center Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Taiju Life Social Welfare Foundation, and Daiichi Sankyo Scholarship Donation Program; and equipment-in-kind support for an investigator-initiated study from Magventure Inc, Inter Reha Co., Ltd., Rogue Resolutions Ltd. and Miyuki Giken Co., Ltd. H. Uchida has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Mochida Pharmaceutical, Meiji-Seika Pharmaceutical and Novartis; speaker’s honoraria from Otsuka Pharmaceutical, Eli Lilly, Shionogi, Pfizer, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, MSD and Janssen Pharmaceutical; and advisory panel payments from Dainippon-Sumitomo Pharma within the past 3 years. M. Mimura has received research support from the Japan Society for the Promotion of Science and grants or speaker’s honoraria from Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Takeda Yakuhin, Tsumura and Yoshitomi Yakuhin within the past 3 years. A. Graff-Guerrero has received research support from the following external funding agencies: CIHR, the US National Institutes of Health, the Ontario Mental Health Foundation, the National Alliance for Research on Schizophrenia and Depression, Mexico Instituto de Ciencia y Tecnología del Distrito Federal, Consejo Nacional de Ciencia y Tecnología, the Ministry of Economic Development and Innovation of Ontario, the Ontario Academic Health Science Center Alternate Funding Plan Innovation Fund and the W. Garfield Weston Foundation. M. Chakravarty has received research funding from the Weston Brain Institute, the Alzheimer’s Association and the Michael J. Fox Foundation. He is currently receiving support from the CIHR, the National Sciences and Engineering Research Council of Canada and McGill University’s Healthy Brains for Healthy Lives Initiative. He is an associated editor of JPN, but was not involved in the review or decision to accept this paper for publication. S. Nakajima has received grants from the Japan Society for the Promotion of Science, AMED, the Japan Research Foundation for Clinical Pharmacology, the Naito Foundation, the Takeda Science Foundation, the Uehara Memorial Foundation and the Daiichi Sankyo Scholarship Donation Program within the past 3 years, as well as research support, manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi and Yoshitomi Yakuhin within the past 3 years. No other competing interests declared., (© 2022 CMA Impact Inc. or its licensors.)

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 ( 1 H-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 1 H-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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge., Methods: A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of ≤15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group., Results: We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0-15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8-8.3) and DCD-CD (5.3%, 95% CI: 3.6-7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39-0.95 and 0.49, 95% CI: 0.25-0.95, respectively), although these significances did not find in the subgroup analysis including only patients with ≥ 6 years old., Conclusions: Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations., Competing Interests: KN has received honoraria (lecture fees) from Janssen Pharmaceutical, Eli Lilly, Shire, and Shionogi within the past three years. RT declares no conflicts of interest associated with this manuscript. KY has received honoraria (manuscript fees) from Sumitomo Dainippon Pharma, fellowship grants from the Japan Research Foundation for Clinical Pharmacology and Azrieli Adult Neurodevelopmental Centre Postdoctoral Fellowship at CAMH, and consultant fees from Signant Health and VeraSci within the past three years. MS has received honoraria (lecture fees) from Meiji Seika Pharma, Shionogi, Kumon Institute of Education, and Mochida Pharma within the past three years. TS has received manuscript or speaker fees from Astellas, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Mochida Pharmaceutical, Meiji Seika Pharma, and Shionogi within the past three years. MM has received speaker’s honoraria from Byer Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Kyowa Pharmaceutical, Mochida Pharmaceutical, MSD, Mylan EPD, Nihon Medi-physics, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Santen Pharmaceutical, Shire Japan, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. Also, he received grants from Daiichi Sankyo, Eisai, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi and Tsumura within the past three years outside the submitted work. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, and Meiji-Seika Pharma, speaker’s honoraria from Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Eisai, and Meiji-Seika Pharma, and advisory panel payments from Dainippon-Sumitomo Pharma within the past three years. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [ 11 C]PBB3, and an Aβ radioligand, [ 11 C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [ 11 C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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 < 0.001, corrected), respectively. The left planum temporale (PT) and left anterior insula/inferior frontal gyrus (IFG) contributed to both NTRS and TRS classifiers. The left supramarginal gyrus only contributed to NTRS and right superior temporal sulcus and right lateral orbitofrontal cortex only to the TRS. The NTRS classifiers successfully distinguished those with TRS from HCs with the AUC of 0.78 (p < 0.001), while the TRS classifiers classified those with NTRS from HCs with the AUC of 0.69 (p = 0.015)., Conclusion: Both NTRS and TRS could be distinguished from HCs on the basis of CT. The CT pathological basis of NTRS and TRS has commonalities, and TRS presents unique CT features., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To identify important clinical or imaging features predictive of an individual's response to electroconvulsive therapy (ECT) by utilizing a machine learning approach., Methods: Twenty-seven depressed patients who received ECT were recruited. Clinical demographics and pretreatment structural magnetic resonance imaging (MRI) data were used as candidate features to build models to predict remission and post-ECT Hamilton Depression Rating Scale scores. Support vector machine and support vector regression with elastic-net regularization were used to build models using (i) only clinical features, (ii) only MRI features, and (iii) both clinical and MRI features. Consistently selected features across all individuals were identified through leave-one-out cross-validation., Results: Compared with models that include only clinical variables, the models including MRI data improved the prediction of ECT remission: the prediction accuracy improved from 70% to 93%. Features selected consistently across all individuals included volumes in the gyrus rectus, the right anterior lateral temporal lobe, the cuneus, and the third ventricle, as well as 2 clinical features: psychotic features and family history of mood disorder., Conclusions: Pretreatment structural MRI data improved the individual predictive accuracy of ECT remission, and only a small subset of features was important for prediction.

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 ( t 45 = 7.659, p = 0.008) and theta ( t 45 = 8.066, p = 0.007) bands in the left side (TRS < 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.

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., Competing Interests: Declaration of Competing Interest YN has received a Grant-in-Aid for Young Scientists (KAKENHI), a research grant from Japan Agency for Medical Research and Development (AMED), an investigator-initiated clinical study grant from TEIJIN PHARMA LIMITED. YN also receives research grants from Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi Sankyo Scholarship Donation Program. He has received research supports from Otsuka Pharmaceutical, Shionogi, and Meiji Seika Pharma. YN also receives equipment-in-kind supports for an investigator-initiated study from Magventure Inc., Inter Reha Co., Ltd., Rogue Resolutions Ltd., and Miyuki Giken Co., Ltd. EP has received research support from an Ontario Graduate Scholarship (OGS), a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship-Master's, a CIHR Vanier Canada Graduate Scholarship, and he currently receives research support from the Healthy Brains for Healthy Lives Postdoctoral Fellowship. MMC has received research funding from the Weston Brain Institute, Alzheimer's Association, and Michael J. Fox Foundation. He is currently receiving support from the Canadian Institutes of Health Research, National Sciences and Engineering Research Council of Canada, and McGill University's Healthy Brains for Healthy Lives Initiative. AG-G has received research support from the following external funding agencies: CIHR, U.S National Institutes of Health, Ontario Mental Health Foundation, National Alliance for Research on Schizophrenia and Depression, Mexico Instituto de Ciencia y Tecnología del Distrito Federal, Consejo Nacional de Ciencia y Tecnología, Ministry of Economic Development and Innovation of Ontario, Ontario Academic Health Science Center Alternate Funding Plan Innovation Fund, and W. Garfield Weston Foundation. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Mochida Pharmaceutical, Meiji-Seika Pharmaceutical, and Novartis; speaker's honoraria from Otsuka Pharmaceutical, Eli Lilly, Shionogi, Pfizer, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, MSD, and Janssen Pharmaceutical; and advisory panel payments from Dainippon-Sumitomo Pharma within the past three years. MM has received research support from Japan Society for the Promotion of Science and grants or speaker's honoraria from Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. SN has received fellowship grants from CIHR, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past three years. SN has also received research supports, manuscript fees or speaker's honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past three years. Other authors have no financial or other relationship relevant to the subject of this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology.)

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., Competing Interests: Declaration of Competing Interest YN has received a Grant-in-Aid for Young Scientists (KAKENHI), a research grant from Japan Agency for Medical Research and development (AMED), an investigator-initiated clinical study grant from TEIJIN PHARMA LIMITED. YN also receives research grants from Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi Sankyo Scholarship Donation Program. He has received research supports from Otsuka Pharmaceutical, Shionogi, and Meiji Seika Pharma. YN also receives equipment-in-kind supports for an investigator-initiated study from Magventure Inc., Inter Reha Co., Ltd., Rogue Resolutions Ltd., and Miyuki Giken Co., Ltd. SN has received research support from Japan Society for the Promotion of Science (Grant-in-Aid for Young Scientists A, Grants-in-Aid for Scientific Research B, and Grants-in-Aid for Scientific Research C), Japan Agency for Medical Research and development (AMED), Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Uehara Memorial Foundation, Takeda Science Foundation, Daiichi Sankyo Research Program, and Novartis Research Program, manuscript fees or speaker's honoraria from Meiji-Seika Pharma, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma and Yoshitomi Yakuhin within the past three years. MM has received grants or speaker's honoraria from Asahi Kasei Pharma, Astellas Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji-Seika Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi Pharma, and Yoshitomi Yakuhin within 3 years. Other authors have no financial or other relationship relevant to the subject of this manuscript., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

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.

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.