Masataka Wada

All Publications

• Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia. Translational psychiatry Shibukawa, S., Kan, H., Honda, S., Wada, M., Tarumi, R., Tsugawa, S., Tobari, Y., Maikusa, N., Mimura, M., Uchida, H., Nakamura, Y., Nakajima, S., Noda, Y., Koike, S. 2024; 14 (1): 164

  Abstract

  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.

  View details for DOI 10.1038/s41398-024-02862-7

  View details for PubMedID 38531856

  View details for PubMedCentralID PMC10965930

• Decreased short-latency afferent inhibition in individuals with mild cognitive impairment: A TMS-EEG study. Progress in neuro-psychopharmacology & biological psychiatry Mimura, Y., Tobari, Y., Nakajima, S., Takano, M., Wada, M., Honda, S., Bun, S., Tabuchi, H., Ito, D., Matsui, M., Uchida, H., Mimura, M., Noda, Y. 2024; 132: 110967

  Abstract

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

  View details for DOI 10.1016/j.pnpbp.2024.110967

  View details for PubMedID 38354899

• Neuroplasticity of the left dorsolateral prefrontal cortex in patients with treatment-resistant depression as indexed with paired associative stimulation: a TMS-EEG study. Cerebral cortex (New York, N.Y. : 1991) Kaneko, N., Wada, M., Nakajima, S., Takano, M., Taniguchi, K., Honda, S., Mimura, M., Noda, Y. 2024; 34 (2)

  Abstract

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

  View details for DOI 10.1093/cercor/bhad515

  View details for PubMedID 38204301

  View details for PubMedCentralID PMC10839839

• Development of Artificial Intelligence for Determining Major Depressive Disorder Based on Resting-State EEG and Single-Pulse Transcranial Magnetic Stimulation-Evoked EEG Indices. Journal of personalized medicine Noda, Y., Sakaue, K., Wada, M., Takano, M., Nakajima, S. 2024; 14 (1)

  Abstract

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

  View details for DOI 10.3390/jpm14010101

  View details for PubMedID 38248802

  View details for PubMedCentralID PMC10817456

• Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials. General hospital psychiatry Wada, M., Yasuda, H., Nakajima, S., Etani, T., Miura, A., Asada, S., Yoshida, K., Noda, Y., Takeuchi, H. 2023; 85: 71-79

  Abstract

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

  View details for DOI 10.1016/j.genhosppsych.2023.08.011

  View details for PubMedID 37826886

• Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia. Schizophrenia research Ogyu, K., Matsushita, K., Honda, S., Wada, M., Tamura, S., Takenouchi, K., Tobari, Y., Kusudo, K., Kato, H., Koizumi, T., Arai, N., Koreki, A., Matsui, M., Uchida, H., Fujii, S., Onaya, M., Hirano, Y., Mimura, M., Nakajima, S., Noda, Y. 2023; 252: 129-137

  Abstract

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

  View details for DOI 10.1016/j.schres.2023.01.011

  View details for PubMedID 36641960

• Investigation of Spatiotemporal Profiles of Single-Pulse TMS-Evoked Potentials with Active Stimulation Compared with a Novel Sham Condition. Biosensors Takano, M., Wada, M., Zomorrodi, R., Taniguchi, K., Li, X., Honda, S., Tobari, Y., Mimura, Y., Nakajima, S., Kitahata, R., Mimura, M., Daskalakis, Z. J., Blumberger, D. M., Noda, Y. 2022; 12 (10)

  Abstract

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

  View details for DOI 10.3390/bios12100814

  View details for PubMedID 36290951

  View details for PubMedCentralID PMC9599895

• Reduced signal propagation elicited by frontal transcranial magnetic stimulation is associated with oligodendrocyte abnormalities in treatment-resistant depression. Journal of psychiatry & neuroscience : JPN Wada, M., Nakajima, S., Honda, S., Takano, M., Taniguchi, K., Tsugawa, S., Mimura, Y., Hattori, N., Koike, S., Zomorrodi, R., Blumberger, D. M., Daskalakis, Z. J., Mimura, M., Noda, Y. 2022; 47 (5): E325-E335

  Abstract

  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 (p = 0.0055). Furthermore, this decreased signal propagation was correlated with cellspecific gene expression of oligodendrocytes (p < 0.000001).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.

  View details for DOI 10.1503/jpn.220102

  View details for PubMedID 36104082

  View details for PubMedCentralID PMC9484613

• Impact of Sevoflurane and Thiopental Used Over the Course of Electroconvulsive Therapy: Propensity Score Matching Analysis. Frontiers in human neuroscience Yatomi, T., Uchida, T., Takamiya, A., Wada, M., Kudo, S., Nakajima, K., Nishida, H., Yamagata, B., Mimura, M., Hirano, J. 2022; 16: 933622

  Abstract

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

  View details for DOI 10.3389/fnhum.2022.933622

  View details for PubMedID 35880104

  View details for PubMedCentralID PMC9308003

• Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. Molecular psychiatry Wada, M., Noda, Y., Iwata, Y., Tsugawa, S., Yoshida, K., Tani, H., Hirano, Y., Koike, S., Sasabayashi, D., Katayama, H., Plitman, E., Ohi, K., Ueno, F., Caravaggio, F., Koizumi, T., Gerretsen, P., Suzuki, T., Uchida, H., Müller, D. J., Mimura, M., Remington, G., Grace, A. A., Graff-Guerrero, A., Nakajima, S. 2022; 27 (7): 2950-2967

  Abstract

  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.

  View details for DOI 10.1038/s41380-022-01572-0

  View details for PubMedID 35444257

  View details for PubMedCentralID 7175086

• Thalamic and striato-pallidal volumes in schizophrenia patients and individuals at risk for psychosis: A multi-atlas segmentation study. Schizophrenia research Takahashi, T., Tsugawa, S., Nakajima, S., Plitman, E., Chakravarty, M. M., Masuda, F., Wada, M., Kurose, S., Ochi, R., Matsushita, K., Sasabayashi, D., Nakamura, M., Nishikawa, Y., Takayanagi, Y., Nishiyama, S., Higuchi, Y., Mizukami, Y., Furuichi, A., Kido, M., Hashimoto, R., Noguchi, K., Fujii, S., Mimura, M., Noda, Y., Suzuki, M. 2022; 243: 268-275

  Abstract

  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.

  View details for DOI 10.1016/j.schres.2020.04.016

  View details for PubMedID 32448678

• Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies. Molecular psychiatry Nakahara, T., Tsugawa, S., Noda, Y., Ueno, F., Honda, S., Kinjo, M., Segawa, H., Hondo, N., Mori, Y., Watanabe, H., Nakahara, K., Yoshida, K., Wada, M., Tarumi, R., Iwata, Y., Plitman, E., Moriguchi, S., de la Fuente-Sandoval, C., Uchida, H., Mimura, M., Graff-Guerrero, A., Nakajima, S. 2022; 27 (1): 744-757

  Abstract

  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.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.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).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.

  View details for DOI 10.1038/s41380-021-01297-6

  View details for PubMedID 34584230

  View details for PubMedCentralID 5166560

• Absence of multiple sleep-onset rapid eye movement periods (SOREMPs) is not a specific feature of patients with pathological sleep prolongation. Sleep and biological rhythms Honda, M., Kimura, S., Sasaki, K., Wada, M., Ito, W. 2022; 20 (1): 107-114

  Abstract

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

  View details for DOI 10.1007/s41105-021-00346-5

  View details for PubMedID 38469062

  View details for PubMedCentralID PMC10899981

• Insights of neurophysiology on unconscious state using combined transcranial magnetic stimulation and electroencephalography: A systematic review. Neuroscience and biobehavioral reviews Arai, N., Nakanishi, T., Nakajima, S., Li, X., Wada, M., Daskalakis, Z. J., Goodman, M. S., Blumberger, D. M., Mimura, M., Noda, Y. 2021; 131: 293-312

  Abstract

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

  View details for DOI 10.1016/j.neubiorev.2021.09.029

  View details for PubMedID 34555384

• A comparison of cost-effectiveness between offering antidepressant-CBT combinations first or second, for moderate to severe depression in Japan. Journal of affective disorders Yamada, Y., Miyahara, R., Wada, M., Ninomiya, A., Kosugi, T., Mimura, M., Sado, M. 2021; 292: 574-582

  Abstract

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

  View details for DOI 10.1016/j.jad.2021.05.095

  View details for PubMedID 34147970

• Photobiological Neuromodulation of Resting-State EEG and Steady-State Visual-Evoked Potentials by 40 Hz Violet Light Optical Stimulation in Healthy Individuals. Journal of personalized medicine Noda, Y., Takano, M., Hayano, M., Li, X., Wada, M., Nakajima, S., Mimura, M., Kondo, S., Tsubota, K. 2021; 11 (6)

  Abstract

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

  View details for DOI 10.3390/jpm11060557

  View details for PubMedID 34203878

  View details for PubMedCentralID PMC8232632

• TMS-EEG Research to Elucidate the Pathophysiological Neural Bases in Patients with Schizophrenia: A Systematic Review. Journal of personalized medicine Li, X., Honda, S., Nakajima, S., Wada, M., Yoshida, K., Daskalakis, Z. J., Mimura, M., Noda, Y. 2021; 11 (5)

  Abstract

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

  View details for DOI 10.3390/jpm11050388

  View details for PubMedID 34068580

  View details for PubMedCentralID PMC8150818

• Evaluation of pathological sleepiness by Multiple Sleep Latency Test and 24-hour polysomnography in patients suspected of idiopathic hypersomnia. Psychiatry and clinical neurosciences Honda, M., Kimura, S., Sasaki, K., Wada, M., Ito, W. 2021; 75 (4): 149-151

  View details for DOI 10.1111/pcn.13196

  View details for PubMedID 33448529

  View details for PubMedCentralID PMC8048966

• Polygenic risk scores for major psychiatric and neurodevelopmental disorders contribute to sleep disturbance in childhood: Adolescent Brain Cognitive Development (ABCD) Study. Translational psychiatry Ohi, K., Ochi, R., Noda, Y., Wada, M., Sugiyama, S., Nishi, A., Shioiri, T., Mimura, M., Nakajima, S. 2021; 11 (1): 187

  Abstract

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

  View details for DOI 10.1038/s41398-021-01308-8

  View details for PubMedID 33771979

  View details for PubMedCentralID PMC7997961

• Neurophysiological biomarkers using transcranial magnetic stimulation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis. Neuroscience and biobehavioral reviews Mimura, Y., Nishida, H., Nakajima, S., Tsugawa, S., Morita, S., Yoshida, K., Tarumi, R., Ogyu, K., Wada, M., Kurose, S., Miyazaki, T., Blumberger, D. M., Daskalakis, Z. J., Chen, R., Mimura, M., Noda, Y. 2021; 121: 47-59

  Abstract

  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.

  View details for DOI 10.1016/j.neubiorev.2020.12.003

  View details for PubMedID 33307047

• Transcranial magnetic stimulation neurophysiology of patients with major depressive disorder: a systematic review and meta-analysis. Psychological medicine Kinjo, M., Wada, M., Nakajima, S., Tsugawa, S., Nakahara, T., Blumberger, D. M., Mimura, M., Noda, Y. 2021; 51 (1): 1-10

  Abstract

  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.

  View details for DOI 10.1017/S0033291720004729

  View details for PubMedID 33267920

  View details for PubMedCentralID PMC7856413

• Development and validation of the hypersomnia-specific beliefs scale. Sleep medicine Hazumi, M., Ito, W., Okubo, R., Wada, M., Honda, M. 2020; 75: 256-262

  Abstract

  Patients with Central hypersomnia, especially Narcolepsy type 1 and Idiopathic Hypersomnia (NT1 and IHS) often have psychological frustration in their daily lives. We aimed to develop the first scale of hypersomnia-specific beliefs (HSB).We developed the HSB scale consisting of three factors ("aversion toward doze", "hypersensitivity toward others" reactions about my doze", and "sense of defeat caused by doze") with 12 items through interviews to 11 patients with NT1 and IHS. Validity and reliability of the HSB were evaluated cross-sectionally with 166 patients with NT1 and IHS and 375 controls. Simultaneously, scores of patient health questionnaire -2(PHQ-2), mini-Social Phobia Inventory (mini-SPIN), and Epworth Sleepiness Scale (ESS) were obtained.This 3-factor model had enough fitness (χ2 = 60.25, df = 51, p = 0.18, TLI = 0.99, CFI = 0.99, RMSEA = 0.03), Cronbach's α coefficient being 0.90. The intraclass correlation coefficient was 0.76. Also, the area under the receiver operating characteristic curve (AUC = 0.88) confirmed good discrimination ability. A cut-off score of 38 resulted in a sensitivity of 90% and a specificity of 75%. Multiple linear regression analyses showed that these scales were independently associated with the HSB score; the PHQ-2 (β = 0.24, p = 0.002), mini-SPIN (β = 0.29, p < 0.001) and ESS (β = 0.15, p = 0.048).Our data suggest that the HSB scale measured beliefs in NT1 and IHS patients with good validity, reliability, and discrimination ability. The HSB scale assesses the negative beliefs specific to patents with NT1 and IHS. This scale could be applied to the development of novel psychotherapeutic approach to patients with NT1 and IHS.

  View details for DOI 10.1016/j.sleep.2020.06.012

  View details for PubMedID 32862014

• Resting-State Isolated Effective Connectivity of the Cingulate Cortex as a Neurophysiological Biomarker in Patients with Severe Treatment-Resistant Schizophrenia. Journal of personalized medicine Wada, M., Nakajima, S., Tarumi, R., Masuda, F., Miyazaki, T., Tsugawa, S., Ogyu, K., Honda, S., Matsushita, K., Kikuchi, Y., Fujii, S., Blumberger, D. M., Daskalakis, Z. J., Mimura, M., Noda, Y. 2020; 10 (3)

  Abstract

  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 < 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.

  View details for DOI 10.3390/jpm10030089

  View details for PubMedID 32823914

  View details for PubMedCentralID PMC7564631

• White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study. Progress in neuro-psychopharmacology & biological psychiatry Ochi, R., Noda, Y., Tsuchimoto, S., Tarumi, R., Honda, S., Matsushita, K., Tsugawa, S., Plitman, E., Masuda, F., Ogyu, K., Wada, M., Miyazaki, T., Fujii, S., Chakravarty, M. M., Graff-Guerrero, A., Uchida, H., Mimura, M., Nakajima, S. 2020; 100: 109871

  Abstract

  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.

  View details for DOI 10.1016/j.pnpbp.2020.109871

  View details for PubMedID 31962187

• Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia. Neuropsychopharmacology reports Ogyu, K., Noda, Y., Yoshida, K., Kurose, S., Masuda, F., Mimura, Y., Nishida, H., Plitman, E., Tarumi, R., Tsugawa, S., Wada, M., Miyazaki, T., Uchida, H., Graff-Guerrero, A., Mimura, M., Nakajima, S. 2020; 40 (2): 138-149

  Abstract

  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.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.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 R2 : .51, .42 and .55, .54, respectively).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.

  View details for DOI 10.1002/npr2.12103

  View details for PubMedID 32180369

  View details for PubMedCentralID PMC7722672

• Neural correlates of delay discount alterations in addiction and psychiatric disorders: A systematic review of magnetic resonance imaging studies. Progress in neuro-psychopharmacology & biological psychiatry Noda, Y., Barr, M. S., ElSalhy, M., Masuda, F., Tarumi, R., Ogyu, K., Wada, M., Tsugawa, S., Miyazaki, T., Nakajima, S., Mimura, M. 2020; 99: 109822

  Abstract

  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.

  View details for DOI 10.1016/j.pnpbp.2019.109822

  View details for PubMedID 31751662

• Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Tarumi, R., Tsugawa, S., Noda, Y., Plitman, E., Honda, S., Matsushita, K., Chavez, S., Sawada, K., Wada, M., Matsui, M., Fujii, S., Miyazaki, T., Chakravarty, M. M., Uchida, H., Remington, G., Graff-Guerrero, A., Mimura, M., Nakajima, S. 2020; 45 (4): 632-640

  Abstract

  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. 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 = 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.

  View details for DOI 10.1038/s41386-019-0589-z

  View details for PubMedID 31842203

  View details for PubMedCentralID PMC7021829

• Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis. Journal of psychopharmacology (Oxford, England) Tsugawa, S., Noda, Y., Tarumi, R., Mimura, Y., Yoshida, K., Iwata, Y., Elsalhy, M., Kuromiya, M., Kurose, S., Masuda, F., Morita, S., Ogyu, K., Plitman, E., Wada, M., Miyazaki, T., Graff-Guerrero, A., Mimura, M., Nakajima, S. 2019; 33 (10): 1199-1214

  Abstract

  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.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.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.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.

  View details for DOI 10.1177/0269881119845820

  View details for PubMedID 31039654

• Clinical effectiveness of repetitive transcranial magnetic stimulation treatment in children and adolescents with neurodevelopmental disorders: A systematic review. Autism : the international journal of research and practice Masuda, F., Nakajima, S., Miyazaki, T., Tarumi, R., Ogyu, K., Wada, M., Tsugawa, S., Croarkin, P. E., Mimura, M., Noda, Y. 2019; 23 (7): 1614-1629

  Abstract

  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.

  View details for DOI 10.1177/1362361318822502

  View details for PubMedID 30663323

• The P300 event-related potential in bipolar disorder: A systematic review and meta-analysis. Journal of affective disorders Wada, M., Kurose, S., Miyazaki, T., Nakajima, S., Masuda, F., Mimura, Y., Nishida, H., Ogyu, K., Tsugawa, S., Mashima, Y., Plitman, E., Chakravarty, M. M., Mimura, M., Noda, Y. 2019; 256: 234-249

  Abstract

  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.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.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.The difference in medication use was difficult to control and it may affect the results.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.

  View details for DOI 10.1016/j.jad.2019.06.010

  View details for PubMedID 31200163

• Does the rapid response of an antidepressant contribute to better cost-effectiveness? Comparison between mirtazapine and SSRIs for first-line treatment of depression in Japan. Psychiatry and clinical neurosciences Sado, M., Wada, M., Ninomiya, A., Nohara, H., Kosugi, T., Arai, M., Endo, R., Mimura, M. 2019; 73 (7): 400-408

  Abstract

  Previous studies indicate that mirtazapine is unique in its quick responsiveness compared to other antidepressants. Although some other studies have evaluated its cost-effectiveness, they have not considered its early stage remission rate. The aim of this study was to address this research gap by using precise clinical data to evaluate the cost-effectiveness of mirtazapine in Japan.We developed a Markov model to reflect the week-by-week transition probabilities. The Markov cycle was set as 1 week. While our clinical parameters were obtained largely from existing meta-analyses, cost data were derived from government reports. Cost-effectiveness was evaluated by incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year estimated based on the probability sensitivity analyses. The ICERs were estimated at 2, 8, 26, and 52 weeks.In severe depression, the ICERs ranged between JPY 872 153 and 1 772 723. The probability of mirtazapine being cost-effective ranged from 0.75 to 0.99 when the ICER threshold was JPY 5 000 000. In moderate depression, the ICERs ranged between JPY 2 356 499 and 4 770 145. The probability of mirtazapine being cost-effective ranged from 0.55 to 0.83 when the ICER threshold was JPY 5 000 000.When considering the early stage efficacy of mirtazapine, it appeared to be cost-effective compared to selective serotonin reuptake inhibitors, especially for severe depression and in the early stage treatment in the Japanese setting. However, our study has some limitations. First, mirtazapine is compared with batched selective serotonin reuptake inhibitors rather than individual ones. Second, we did not consider antidepressant combination therapy as treatment options.

  View details for DOI 10.1111/pcn.12851

  View details for PubMedID 30973181

• Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Molecular psychiatry Moriguchi, S., Takamiya, A., Noda, Y., Horita, N., Wada, M., Tsugawa, S., Plitman, E., Sano, Y., Tarumi, R., ElSalhy, M., Katayama, N., Ogyu, K., Miyazaki, T., Kishimoto, T., Graff-Guerrero, A., Meyer, J. H., Blumberger, D. M., Daskalakis, Z. J., Mimura, M., Nakajima, S. 2019; 24 (7): 952-964

  Abstract

  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.

  View details for DOI 10.1038/s41380-018-0252-9

  View details for PubMedID 30315224

  View details for PubMedCentralID PMC6755980

• Actigraphy for evaluation of mood disorders: A systematic review and meta-analysis. Journal of affective disorders Tazawa, Y., Wada, M., Mitsukura, Y., Takamiya, A., Kitazawa, M., Yoshimura, M., Mimura, M., Kishimoto, T. 2019; 253: 257-269

  Abstract

  Actigraphy has enabled consecutive observation of individual health conditions such as sleep or daily activity. This study aimed to examine the usefulness of actigraphy in evaluating depressive and/or bipolar disorder symptoms.A systematic review and meta-analysis was conducted. We selected studies that used actigraphy to compare either patients vs. healthy controls, or pre- vs. post-treatment data from the same patient group. Common actigraphy measurements, namely daily activity and sleep-related data, were extracted and synthesized.Thirty-eight studies (n = 3,758) were included in the analysis. Compared with healthy controls, depressive patients were less active (standardized mean difference; SMD=1.27, 95%CI=[0.97, 1.57], P<0.001) and had longer wake after sleep onset (SMD= - 0.729, 95%CI=[- 1.20, - 0.25], p = 0.003). Total sleep time (SMD= - 0.33, 95%CI=[- 0.55, - 0.11], P = 0.004), sleep latency (SMD= - 0.22, 95%CI=[- 0.42, - 0.02], P = 0.032), and wake after sleep onset (SMD= - 0.22, 95%CI=[- 0.39, - 0.04], P = 0.015) were longer in euthymic/remitted patients compared to healthy controls. In pre- and post-treatment comparisons, sleep latency (SMD=- 0.85, 95%CI=[- 1.53, - 0.17], P = 0.015), wake after sleep onset (SMD= - 0.65, 95%CI=[- 1.20, - 0.10], P = 0.022), and sleep efficiency (SMD=0.77, 95%CI=[0.29, 1.24], P = 0.002) showed significant improvement.The sample sizes for each outcome were small. The type of actigraphy devices and patients' illness severity differed across studies. It is possible that hospitalizations and medication influenced the outcomes.We found significant differences between healthy controls and mood disorders patients for some actigraphy-measured modalities. Specific measurement patterns characterizing each mood disorder/status were also found. Additional actigraphy data linked to severity and/or treatment could enhance the clinical utility of actigraphy.

  View details for DOI 10.1016/j.jad.2019.04.087

  View details for PubMedID 31060012

• Neuroimaging correlates of narcolepsy with cataplexy: A systematic review. Neuroscience research Wada, M., Mimura, M., Noda, Y., Takasu, S., Plitman, E., Honda, M., Natsubori, A., Ogyu, K., Tarumi, R., Graff-Guerrero, A., Nakajima, S. 2019; 142: 16-29

  Abstract

  Recent developments in neuroimaging techniques have advanced our understanding of biological mechanisms underpinning narcolepsy. We used MEDLINE to retrieve neuroimaging studies to compare patients with narcolepsy and healthy controls. Thirty-seven studies were identified and demonstrated several replicated abnormalities: (1) gray matter reductions in superior frontal, superior and inferior temporal, and middle occipital gyri, hypothalamus, amygdala, insula, hippocampus, cingulate cortex, thalamus, and nucleus accumbens, (2) decreased fractional anisotropy in white matter of fronto-orbital and cingulate area, (3) reduced brain metabolism or cerebral blood flow in middle and superior frontal, and cingulate cortex (4) increased activity in inferior frontal gyri, insula, amygdala, and nucleus accumbens, and (5) N-acetylaspartate/creatine-phosphocreatine level reduction in hypothalamus. In conclusion, all the replicated findings are still controversial due to the limitations such as heterogeneity or size of the samples and lack of multimodal imaging or follow-up. Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets.

  View details for DOI 10.1016/j.neures.2018.03.005

  View details for PubMedID 29580887

• Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review. Translational psychiatry Masuda, F., Nakajima, S., Miyazaki, T., Yoshida, K., Tsugawa, S., Wada, M., Ogyu, K., Croarkin, P. E., Blumberger, D. M., Daskalakis, Z. J., Mimura, M., Noda, Y. 2019; 9 (1): 110

  Abstract

  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.

  View details for DOI 10.1038/s41398-019-0444-3

  View details for PubMedID 30846682

  View details for PubMedCentralID PMC6405856

• Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer's disease: A systematic review. Progress in neuro-psychopharmacology & biological psychiatry Iimori, T., Nakajima, S., Miyazaki, T., Tarumi, R., Ogyu, K., Wada, M., Tsugawa, S., Masuda, F., Daskalakis, Z. J., Blumberger, D. M., Mimura, M., Noda, Y. 2019; 88: 31-40

  Abstract

  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.

  View details for DOI 10.1016/j.pnpbp.2018.06.014

  View details for PubMedID 29953934

• Kynurenine pathway in depression: A systematic review and meta-analysis. Neuroscience and biobehavioral reviews Ogyu, K., Kubo, K., Noda, Y., Iwata, Y., Tsugawa, S., Omura, Y., Wada, M., Tarumi, R., Plitman, E., Moriguchi, S., Miyazaki, T., Uchida, H., Graff-Guerrero, A., Mimura, M., Nakajima, S. 2018; 90: 16-25

  Abstract

  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.

  View details for DOI 10.1016/j.neubiorev.2018.03.023

  View details for PubMedID 29608993

• Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study. Journal of Alzheimer's disease : JAD Wada, M., Noda, Y., Shinagawa, S., Chung, J. K., Sawada, K., Ogyu, K., Tarumi, R., Tsugawa, S., Miyazaki, T., Yamagata, B., Graff-Guerrero, A., Mimura, M., Nakajima, S. 2018; 63 (2): 861-869

  Abstract

  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.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.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.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.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.

  View details for DOI 10.3233/JAD-171168

  View details for PubMedID 29689728