論文 - 野田　賀大

Effects of short-term exposure to moderate amounts of alcohol on brain volume

Tsugawa S., Ueno F., Sakuma M., Tani H., Ochi R., Graff-Guerrero A., Noda Y., Uchida H., Mimura M., Oshima S., Matsushita S., Nakajima S.

Neuropsychopharmacology Reports 45 （ 1 ） e12500 2025年03月

査読有り

　概要を見る

Aim: Although numerous studies have reported that chronic alcohol consumption causes brain volume reduction and cerebrospinal fluid volume increase, few studies have examined the acute effects of alcohol on brain structure. This study aims to investigate the short-term brain volume changes following alcohol administration. Methods: Moderate doses of alcohol were administered intravenously to 18 healthy volunteers for a total of 90 min to achieve a blood alcohol concentration of 0.5 mg/mL. An alcohol clamp method combined with physiologically based pharmacokinetic modeling was used to achieve fine control over blood alcohol concentration. T1 images with 3T MRI were scanned at three time points: baseline, 0 min, and 90 min after the end of alcohol administration. Cortical, subcortical, and ventricular volumes were computed after segmentation with FreeSurfer. Repeated measures analysis of variance was used to evaluate longitudinal changes in brain volume at 96 regions. Results: Acute alcohol administration increased bilateral lateral ventricular volumes, which lasted until 90 min after the end of alcohol injection. On the other hand, the volumes of total gray matter, left precentral cortex, left caudal middle frontal cortex, and left superior frontal cortex decreased after alcohol administration, but these changes disappeared 90 min after the end of alcohol administration. Conclusion: Acute injection of moderate doses of alcohol may enlarge ventricle volumes and reduce gray matter volumes. The transient volume changes caused by acute administration of alcohol may be related to changes in CSF flow and water content of brain tissue, which warrants further study.

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Clinical comparison and genetic analysis in pheochromocytoma with primary aldosteronism.

Mai X, Kometani M, Kato T, Aiga K, Karashima S, Aono D, Konishi S, Nishimoto K, Hosomichi K, Watanabe A, Noda Y, Takeda Y, Yoneda T

Endocrine journal 72 （ 2 ） 193 - 203 2025年02月

ISSN  0918-8959

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Left prefrontal intermittent theta-burst stimulation therapy for major depressive disorder: A real-world, multisite observational study in Japan.

Noda Y, Osawa R, Takeda Y, Fujii K, Saijo Y, Kajiya T, Takeishi K, Moriyama S, Saeki T, Nakajima S, Kitahata R

Journal of affective disorders 2025年01月

筆頭著者, 責任著者, 査読有り,  ISSN  0165-0327

　概要を見る

BACKGROUND: Although approved for treatment in 2018, the effectiveness of intermittent theta-burst stimulation (iTBS) in a real-world setting remains inadequately studied. This observational study investigated the real-world use of iTBS, a usual medical practice for depression, factors influencing its effectiveness, and differences in effectiveness between 600 and 1200 pulses. METHODS: Data from patients who received iTBS therapy for depression at four private clinics between January 2021 and April 2024 were extracted. Patients were assessed using the 17-item Hamilton Depression Rating Scale at baseline and after treatment completion. Correlation and multiple regression analyses were performed to investigate clinico-demographic factors and stimulation parameters associated with iTBS effectiveness. Safety was assessed using all relevant data, and effectiveness was evaluated using eligible samples. RESULTS: Among 538 patients meeting eligibility criteria for effectiveness evaluation (mean age 40.8 ± 13.8 years, 44.1 % women), 63 completed iTBS with 600 pulses, and 475 completed iTBS with 1200 pulses. Overall response and remission rates were 69.1 % and 53.7 %, respectively, with no significant difference in effectiveness between iTBS-600 and iTBS-1200. Multiple regression analysis indicated fewer depressive episodes (β = -0.103, t = -2.080, p = 0.038) and more treatment sessions (β = 0.134, t = 3.155, p = 0.002) may have contributed to the positive effect of iTBS therapy. The most common adverse event was stimulation site pain. No severe adverse events, such as seizure induction or manic switch, were observed. CONCLUSION: The results suggest the highly favorable effectiveness of iTBS therapy for major depressive disorder in real-world settings.

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Cognitive Outcomes After Transcranial Magnetic Stimulation for the Treatment of Late-Life Depression: Résultats cognitifs après la stimulation magnétique transcrânienne pour le traitement de la dépression chez les personnes âgées.

Göke K, McClintock SM, Mah L, Rajji TK, Lee HH, Nestor SM, Downar J, Noda Y, Daskalakis ZJ, Mulsant BH, Blumberger DM

Canadian journal of psychiatry. Revue canadienne de psychiatrie    7067437251315515 - 7067437251315515 2025年01月

査読有り,  ISSN  0706-7437

　概要を見る

BACKGROUND: Late-life depression (LLD) is often accompanied by cognitive impairment, which may persist despite antidepressant treatment. Repetitive transcranial magnetic stimulation (rTMS) is an efficacious treatment for depression, with potential benefits on cognitive functioning. However, research on cognitive effects is inconclusive, relatively sparse in LLD, and predominantly focused on group-level cognitive changes. This study aimed to explore individual-level cognitive changes following rTMS treatment in patients with LLD. METHOD: Data were analyzed from 153 patients with LLD from the FOUR-D study (ClinicalTrials.gov identifier: NCT02998580) who received bilateral standard rTMS or theta burst stimulation (TBS) targeting the dorsolateral prefrontal cortex (DLPFC). Cognitive function was assessed pre- and post-treatment using measures of executive function, information processing speed, and learning and memory. Reliable change indices, adjusted for practice effects and test-retest reliability, were employed to evaluate individual-level cognitive changes. Chi-square tests examined if proportions of cognitive improvers differed from expected proportions. RESULTS: Cognitive performance from baseline to end of treatment remained stable for most patients. Reliably improved performance was observed in 0.0% to 20.0% of participants across cognitive measures, while worsened performance was observed in 0.0% to 2.7%. A small but significant proportion (20.0%) of participants showed improvement in verbal learning. CONCLUSIONS: Bilateral standard rTMS or TBS of the DLPFC in LLD yielded no substantial cognitive enhancing effects, although a small proportion showed improved verbal learning after treatment. Importantly, both interventions were cognitively safe with relatively stable performance across time. Future research is needed to explore approaches to enhance the cognitive benefits of standard rTMS and TBS in patients with LLD.

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Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A randomized non-inferiority clinical trial

Wada M., Nakajima S., Taniguchi K., Honda S., Mimura Y., Takemura R., Thorpe K.E., Tsugawa S., Tarumi R., Moriyama S., Arai N., Kitahata R., Uchida H., Koike S., Daskalakis Z.J., Mimura M., Blumberger D.M., Noda Y.

Brain Stimulation 18 （ 1 ） 25 - 33 2025年01月

最終著者, 責任著者, 査読有り,  ISSN  1935861X

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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.

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Optimizing the identification of long-interval intracortical inhibition from the dorsolateral prefrontal cortex

Takano M., Wada M., Nakajima S., Taniguchi K., Honda S., Mimura Y., Kitahata R., Zomorrodi R., Blumberger D.M., Daskalakis Z.J., Uchida H., Mimura M., Noda Y.

Clinical Neurophysiology 169   102 - 113 2025年01月

最終著者, 責任著者, 査読有り,  ISSN  13882457

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Objective: This study aimed to optimally evaluate the effect of the long-interval intracortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) through transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) by eliminating the volume conductance with signal source estimation and using a realistic sham coil as a control. Methods: We compared the LICI effects from the DLPFC between the active and sham stimulation conditions in 27 healthy participants. Evoked responses between the two conditions were evaluated at the sensor and source levels. Results: At the sensor level, a significant LICI effect was confirmed in the active condition in the global mean field power analysis; however, in the local mean field power analysis focused on the DLPFC, no LICI effect was observed in the active condition. However, in the signal source estimation analysis for the DLPFC, we could reconfirm a significant LICI effect (p = 0.023) in the interval 30–250 ms post-stimulus, compared to the sham condition. Conclusions: Our results demonstrate that application of realistic sham stimulation condition and source estimation method allows for a robust and optimal identification of the LICI effect in the DLPFC. Significance: The optimal DLPFC-LICI effect was identified by the use of the sophisticated sham coil.

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Cognitive Outcomes After Transcranial Magnetic Stimulation for the Treatment of Late-Life Depression: Résultats cognitifs après la stimulation magnétique transcrânienne pour le …

K Göke, SM McClintock, L Mah, TK Rajji, HH Lee, SM Nestor, J Downar, ...

The Canadian Journal of Psychiatry, 07067437251315515 2025年

Prevention and early intervention strategies for perinatal mental health disorders mediated by neuroimmune modulation and anti-inflammatory mechanisms through non-invasive …

Y Noda, S Nakajima

Brain Behavior and Immunity Integrative, 100103 2025年

Effects of short‐term exposure to moderate amounts of alcohol on brain volume

S Tsugawa, F Ueno, M Sakuma, H Tani, R Ochi, A Graff‐Guerrero, ...

Neuropsychopharmacology Reports 2025年

Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A …

M Wada, S Nakajima, K Taniguchi, S Honda, Y Mimura, R Takemura, ...

Brain Stimulation 18 (1), 25-33 2025年

Exploring the interplay between addiction and time perception: A systematic review and meta-analysis

Gu Y., Shan J., Huang T., Yu C., Wu H., Hu X., Tong X., Jia R., Noda Y., Du J., Yuan T.F., Luo W., Zhao D.

Progress in Neuro-Psychopharmacology and Biological Psychiatry 135   111104 - 111104 2024年12月

査読有り,  ISSN  02785846

　概要を見る

Prior studies have investigated the immediate impacts of substances on temporal perception, the impact of temporal outlook, and the consequences of modified temporal perception on addictive behaviors. These inquiries have provided valuable perspectives on the intricate associations between addiction and time perception, enriching the groundwork for forthcoming research and therapeutic strategies. This comprehensive review aims to further explore intricate correlation among diverse addictive substances—namely alcohol, cannabis, nicotine, opioids—and non-substance addictions such as internet gaming, elucidating their influence on temporal perception. Adhering to the PICOS method and adhering to PRISMA guidelines, we systematically reviewed and critically evaluated all existing research concerning temporal perception in individuals with substance and non-substance use disorders. Specifically, our analyses involved 31 pertinent articles encompassing six unique groups—alcohol, nicotine, cannabis, stimulants, opioids, and internet-related addictions—sourced from a pool of 551 papers. The findings revealed differences in time perception between addicts and control groups, as indicated by medium to large effect sizes (Hedge's g = 0.8, p < 0.001). However, the nature of these differences—whether they predominantly involve time overestimation or underestimation—is not yet definitively clear. This variability underscores the complexity of the relationship between addiction and temporal perception, paving the way for further research to unravel these intricate dynamics.

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A multisite observational real-world study on the effectiveness of repetitive transcranial magnetic stimulation therapy for patients with treatment-resistant depression in Japan

Matsuda Y., Kito S., Hiraki F., Izuno T., Yoshida K., Nakamura M., Kodaka F., Yamazaki R., Taruishi N., Imazu S., Kanazawa T., Mekata T., Moriyama S., Wada M., Nakajima S., Sawada K., Watanabe S., Takahashi S., Toi Y., Hayashi D., Igarashi S., Fujiyama K., Ikeda S., Tateishi H., Kojima R., Sato K., Boku S., Takebayashi M., Ogura M., Takaya A., Endo K., Kita A., Arai H., Kamimura H., Matsuo K., Denda K., Yamashiro S., Yoshioka D., Kizaki J., Mimura M., Noda Y.

Psychiatry Research （Elsevier BV）  342   116263 - 116263 2024年12月

最終著者, 責任著者, 査読有り,  ISSN  01651781

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The objective of this study was to reveal the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for Japanese patients with treatment-resistant depression (TRD) in clinical practice, based on real-world data from a nationwide multicenter observational study in Japan. Clinical data of patients with TRD treated with rTMS (NeuroStar TMS treatment system) under public insurance coverage were retrospectively collected from 21 institutes nationwide between June 2019 and December 2023. Depression severity was assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). Response and remission were defined as ≥50 % reduction from baseline and ≤7 points on the HAMD-17, respectively. The primary outcome was the changes in the HAMD-17 score from baseline to the endpoint following rTMS. Data from 497 patients with TRD were candidates for this study. The HAMD-17 scores (mean (SD)) improved significantly from 18.9 (5.3) to 9.7 (6.6), respectively. The response and remission rates at the end of rTMS therapy as assessed by the HAMD-17 were 53.5 % and 42.8 %, respectively. The dropout rate due to adverse effects was 4.2 %, and the treatment was generally well tolerated. No convulsive seizures or manic changes were observed. These results indicate that conventional rTMS is effective and safe in Japanese patients with TRD.

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Decreased prefrontal glutamatergic function is associated with a reduced astrocyte-related gene expression in treatment-resistant depression

Wada M., Nakajima S., Honda S., Takano M., Taniguchi K., Homma S., Ueda R., Tobari Y., Mimura Y., Fujii S., Mimura M., Noda Y.

Translational Psychiatry 14 （ 1 ） 478 - 478 2024年12月

最終著者, 責任著者, 査読有り

　概要を見る

Glutamatergic dysfunction is involved in the pathophysiology of treatment-resistant depression (TRD). However, few physiological studies have evaluated its pathophysiology in vivo in individuals with TRD. Transcranial magnetic stimulation-electroencephalography (TMS-EEG) techniques can assess intracortical facilitation (ICF), which reflects glutamatergic neurophysiological function in specific cortical regions. The objectives of this study were (1) to compare glutamatergic receptor-mediated function as indexed with ICF TMS-EEG in the dorsolateral prefrontal cortex (DLPFC) between participants with TRD and healthy controls (HCs) and (2) to explore the relationships between cell-specific gene expression levels and the group difference in glutamatergic neural propagation using virtual histology approach. Sixty participants with TRD and thirty HCs were examined with ICF TMS-EEG measure (80 single-pulse TMS and paired-pulse ICF) in the left DLPFC. Both sensor and source-level ICF measures were computed to compare them between the TRD and HC groups. Furthermore, we conducted spatial correlation analyses interregionally between ICF glutamatergic activity and cell-specific gene expression levels employing the Allen Human Brain Atlas dataset. DLPFC-ICF at the sensor level was not significantly different between the two groups, whereas DLPFC-ICF at the source level was reduced in the TRD group compared with the HC group (p = 0.026). Moreover, the reduced ICF signal propagation of TRD correlated with astrocyte-specific gene expression level (p < 0.0001). The glutamatergic neural activities indexed by ICF in the left DLPFC were decreased in participants with TRD. Additionally, a relative reduction in glutamatergic signal propagation originating from the DLPFC in TRD may be associated with astrocytic abnormality.

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Cognitive Profiles in Treatment-Resistant Late-Life Depression and their Impact on Treatment Outcomes.

Göke K, McClintock SM, Mah L, Rajji TK, Lee HH, Nestor SM, Downar J, Noda Y, Daskalakis ZJ, Mulsant BH, Blumberger DM

Biological psychiatry. Cognitive neuroscience and neuroimaging 9 （ 11 ） 1199 - 1210 2024年07月

査読有り,  ISSN  2451-9022

　概要を見る

Background: Late-life depression (LLD) is associated with cognitive impairment, but substantial heterogeneity exists among patients. Data on the extent of cognitive impairments are inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant versus nonresistant LLD and aimed to identify distinct cognitive subgroups. We also examined whether cognitive subgroups responded differentially to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS). Methods: A total of 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared with healthy control participants on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups. Results: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than healthy controls. A 3-cluster solution was found, including cognitively intact (n = 89), cognitively diminished (n = 29), and impaired memory (n = 47) subgroups. Both the cognitively diminished and impaired memory subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the cognitively intact group, although the latter difference did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment. Conclusions: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationships among cognitive subgroups, cognitive decline, and neurodegeneration.

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Validation of the number of pulses required for TMS-EEG in the prefrontal cortex considering test feasibility.

Noda Y, Takano M, Wada M, Mimura Y, Nakajima S

Neuroscience 554   63 - 71 2024年07月

筆頭著者, 責任著者, 査読有り,  ISSN  0306-4522

　概要を見る

Background: Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG), TMS-EEG, is a useful neuroscientific tool for the assessment of neurophysiology in the human cerebral cortex. Theoretically, TMS-EEG data is expected to have a better data quality as the number of stimulation pulses increases. However, since TMS-EEG testing is a modality that is examined on human subjects, the burden on the subject and tolerability of the test must also be carefully considered. Method: In this study, we aimed to determine the number of stimulation pulses that satisfy the reliability and validity of data quality in single-pulse TMS (spTMS) for the dorsolateral prefrontal cortex (DLPFC). TMS-EEG data for (1) 40-pulse, (2) 80-pulse, (3) 160-pulse, and (4) 240-pulse conditions were extracted from spTMS experimental data for the left DLPFC of 20 healthy subjects, and the similarities between TMS-evoked potentials (TEP) and oscillations across the conditions were evaluated. Results: As a result, (2) 80-pulse and (3) 160-pulse conditions showed highly equivalent to the benchmark condition of (4) 240-pulse condition. However, (1) 40-pulse condition showed only weak to moderate equivalence to the (4) 240-pulse condition. Thus, in the DLPFC TMS-EEG experiment, 80 pulses of stimulations was found to be a reasonable enough number of pulses to extract reliable TEPs, compared to 160 or 240 pulses. Conclusions: This is the first substantial study to examine the appropriate number of stimulus pulses that are reasonable and feasible for TMS-EEG testing of the DLPFC.

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Real-World Case Series of Maintenance Theta Burst Stimulation Therapy Following Response to Acute Theta Burst Stimulation Therapy for Difficult-to-Treat Depression.

Y Noda, K Fujii, S Nakajima, R Kitahata

CNS spectrums, 1-38 （CNS Spectrums）  29 （ 4 ） 1 - 38 2024年05月

筆頭著者, 責任著者, 査読有り,  ISSN  10928529

　概要を見る

Objective: Treatment and management for difficult-to-treat depression are challenging, especially in a subset of patients who are at high risk for relapse and recurrence. The conditions that represent this subset are recurrent depressive disorder (RDD) and bipolar disorder (BD). In this context, we aimed to examine the effectiveness of maintenance transcranial magnetic stimulation (TMS) on a real-world clinical basis by retrospectively extracting data from the TMS registry data in Tokyo, Japan. Methods: Data on patients diagnosed with treatment-resistant RDD and BD who received maintenance intermittent theta burst stimulation (iTBS) weekly after successful treatment with acute iTBS between March, 2020 and October, 2023 were extracted from the registry. Results: All patients (21 cases: 10 cases with RDD and 11 cases with BD) could sustain response and 19 of them further maintained remission. In this study, maintenance iTBS did not exacerbate depressive symptoms in any of the cases, but may rather have the effect of stabilizing the mental condition and preventing recurrence. Conclusion: This case series is of great clinical significance because it is the first study to report on the effectiveness of maintenance iTBS for RDD and BD, with a follow-up of more than 2 years. Further validation with a randomized controlled trial design with a larger sample size is warranted.

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

Kinjo M, Honda S, Wada M, Nakajima S, Koike S, Noda Y

Brain research （Brain Research）  1838   148989 - 148989 2024年05月

最終著者, 責任著者, 査読有り,  ISSN  0006-8993

　概要を見る

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

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Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression

Göke K., Trevizol A.P., Ma C., Mah L., Rajji T.K., Daskalakis Z.J., Downar J., McClintock S.M., Nestor S.M., Noda Y., Mulsant B.H., Blumberger D.M.

Psychiatry Research （Psychiatry Research）  334   115822 - 115822 2024年04月

査読有り,  ISSN  01651781

　概要を見る

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

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Single candidate gene for salt tolerance of Vigna nakashimae (Ohwi) Ohwi & Ohashi identified by QTL mapping, whole genome sequencing and triplicated RNA-seq analyses.

Ito M, Ohashi H, Takemoto M, Muto C, Seiko T, Noda Y, Ogiso-Tanaka E, Nagano AJ, Takahashi Y, Furukawa J, Monden Y, Naito K

Breeding science 74 （ 2 ） 93 - 102 2024年04月

ISSN  1344-7610

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Real-world retrospective study of repetitive transcranial magnetic stimulation (TMS) treatment for bipolar and unipolar depression using TMS registry data in Tokyo

Ikawa H., Osawa R., Takeda Y., Sato A., Mizuno H., Noda Y.

Heliyon （Heliyon）  10 （ 5 ） e27288 2024年03月

査読有り,  ISSN  24058440

　概要を見る

Despite the prevalence of empirical practice, evidence supporting the use of repetitive transcranial magnetic stimulation (rTMS) in treating bipolar depression (BD) is sparse compared to that for unipolar depression. Therefore, this study aimed to conduct a retrospective observational analysis using TMS registry data to compare the efficacy of rTMS treatment for BD and unipolar depression. Data from 20 patients diagnosed with unipolar and BD were retrospectively extracted from the TMS registry to ensure age and sex matching. The primary outcomes of this registry study were measured using the 21-item Hamilton Depression Rating Scale (HAM-D21) and Montgomery−Åsberg Depression Rating Scale (MADRS). Analysis did not reveal significant differences between the two groups in terms of depression severity, motor threshold, or stimulus intensity at baseline. Similarly, no significant differences were observed in absolute or relative changes in the total HAM-D21 and MADRS scores. Furthermore, the response and remission rates following rTMS treatment did not differ significantly between groups. The only adverse event reported in this study was scalp pain at the stimulation site; however, the incidence and severity were not significantly different between the groups. In conclusion, this retrospective study, using real-world TMS registry data, suggests that rTMS treatment for BD could be as effective as that for unipolar depression. These findings underscore the need for further validation in prospective randomized controlled trials with larger sample sizes.

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Aberrant heartbeat-evoked potential in schizophrenia.

Koreki A, Ogyu K, Miyazaki T, Takenouchi K, Matsushita K, Honda S, Koizumi T, Onaya M, Uchida H, Mimura M, Nakajima S, Noda Y

Progress in neuro-psychopharmacology & biological psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  132   110969 - 110969 2024年02月

最終著者, 責任著者, 査読有り,  ISSN  0278-5846

　概要を見る

Self-disturbance is considered a core feature underlying the psychopathology of schizophrenia. Interoception has an important role in the development of a sense of self, leading to increased interest in the potential contribution of abnormal interoception to self-disturbances in schizophrenia. Several neuropsychological studies have demonstrated aberrant interoception in schizophrenia. However, cortical interoceptive processing has not yet been thoroughly investigated. Thus, we sought to examine resting-state heartbeat-evoked potential (HEP) in this population. We hypothesized that patients with schizophrenia would exhibit significant alterations in HEP compared to healthy controls (HCs). In this cross-sectional electroencephalogram (EEG) study, we compared the HEPs between age- and sex-matched groups of patients with schizophrenia and HCs. A 10-min resting-state EEG with eyes closed and an electrocardiogram (ECG) were recorded and analyzed for the time window of 450 ms to 500 ms after an ECG R peak. A positive HEP shift was observed in the frontal-central regions (F [1, 82] = 7.402, p = 0.008, partial η2 = 0.009) in patients with schizophrenia (n = 61) when compared with HCs (n = 31) after adjusting for confounders such as age, sex, and heart rate. A cluster-based correction analysis revealed that the HEP around the right frontal area (Fp2, F4, and F8) showed the most significant group differences (F [1, 82] = 10.079, p = 0.002, partial η2 = 0.021), with a peak at the F4 electrode site (F [1, 82] = 12.646, p < 0.001, partial η2 = 0.069). We observed no correlation between HEP and symptoms in patients with schizophrenia. A positive shift of HEP during the late component could reflect a trait abnormality in schizophrenia. Further research is required to determine the association between the altered cortical interoceptive processing indexed with HEP and self-disturbances in schizophrenia.

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

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

Progress in neuro-psychopharmacology & biological psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  132   110967 - 110967 2024年02月

最終著者, 責任著者, 査読有り,  ISSN  0278-5846

　概要を見る

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.

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

Noda Y, Sakaue K, Wada M, Takano M, Nakajima S

Journal of personalized medicine （Journal of Personalized Medicine）  14 （ 1 ）  2024年01月

筆頭著者, 責任著者, 査読有り,  ISSN  2075-4426

　概要を見る

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.

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A Retrospective Case-Control Study on the Differences in the Effectiveness of Theta-Burst Stimulation Therapy for Depression with and without Antidepressant Medication.

Ikawa H, Takeda Y, Osawa R, Sato A, Mizuno H, Noda Y

Journal of clinical medicine 13 （ 2 ）  2024年01月

最終著者, 責任著者, 査読有り,  ISSN  2077-0383

　概要を見る

Transcranial magnetic stimulation (TMS) therapy has few side effects and comparable therapeutic effects to antidepressant treatment, but few studies have introduced TMS therapy as an initial treatment for MDD. The objective of this study was to retrospectively compare the clinical outcomes between 50 MDD patients without antidepressants (i.e., TMS monotherapy) and 50 MDD patients with antidepressants plus TMS therapy, matched for age, sex, and depression severity. The presence or absence of antidepressant therapy in first-line treatment was determined via a detailed interview by psychiatrists. The study design was a retrospective observational case-control study using the TMS registry data. The key inclusion criteria were adult patients who met the diagnosis of MDD and received 20-30 sessions of intermittent theta-burst stimulation (iTBS) therapy to the left dorsolateral prefrontal cortex (DLPFC). In this study, the Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary outcome measure. No significant group differences existed in the baseline MADRS total score between the unmedicated and medicated patient groups. Following TMS therapy, no significant group differences in response rate, remission rate, or relative total score change in the MADRS were observed. The main limitations were the retrospective design and the use of registry data as a source. Our findings suggest that TMS monotherapy may be as effective as TMS add-on therapy to antidepressants when used as the first-line therapy for MDD, but randomized controlled trials are needed.

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

Kaneko N, Wada M, Nakajima S, Takano M, Taniguchi K, Honda S, Mimura M, Noda Y

Cerebral cortex (New York, N.Y. : 1991) 2024年01月

最終著者, 責任著者, 査読有り,  ISSN  1047-3211

　概要を見る

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.

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A Retrospective Case–Control Study on the Differences in the Effectiveness of Theta-Burst Stimulation Therapy for Depression with and without Antidepressant Medication

H Ikawa, Y Takeda, R Osawa, A Sato, H Mizuno, Y Noda

Journal of Clinical Medicine 13 (2), 399 2024年

Acetaldehyde‐mediated increase in glutamatergic and N‐acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young …

F Ueno, M Sakuma, S Nakajima, S Tsugawa, R Ochi, H Tani, Y Noda, ...

Alcohol: Clinical and Experimental Research 48 (1), 58-71 2024年

Short-Term Effect of Auditory Stimulation on Neural Activities: A Scoping Review of Longitudinal Electroencephalography and Magnetoencephalography Studies

K Kobayashi, Y Shiba, S Honda, S Nakajima, S Fujii, M Mimura, Y Noda

Brain Sciences 14 (2), 131 （Brain Sciences）  14 （ 2 ）  2024年

査読有り,  ISSN  2076-3425

　概要を見る

Explored through EEG/MEG, auditory stimuli function as a suitable research probe to reveal various neural activities, including event-related potentials, brain oscillations and functional connectivity. Accumulating evidence in this field stems from studies investigating neuroplasticity induced by long-term auditory training, specifically cross-sectional studies comparing musicians and non-musicians as well as longitudinal studies with musicians. In contrast, studies that address the neural effects of short-term interventions whose duration lasts from minutes to hours are only beginning to be featured. Over the past decade, an increasing body of evidence has shown that short-term auditory interventions evoke rapid changes in neural activities, and oscillatory fluctuations can be observed even in the prestimulus period. In this scoping review, we divided the extracted neurophysiological studies into three groups to discuss neural activities with short-term auditory interventions: the pre-stimulus period, during stimulation, and a comparison of before and after stimulation. We show that oscillatory activities vary depending on the context of the stimuli and are greatly affected by the interplay of bottom-up and top-down modulational mechanisms, including attention. We conclude that the observed rapid changes in neural activitiesin the auditory cortex and the higher-order cognitive part of the brain are causally attributed to short-term auditory interventions.

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Real-world retrospective study of transcranial magnetic stimulation (TMS) therapy for bipolar and unipolar depression using TMS registry data in the tokyo metropolitan area

H Ikawa, R Osawa, Y Takeda, A Sato, H Mizuno, Y Noda

Heliyon, e27288 2024年

17. Predictors of Remission After Repetitive Transcranial Magnetic Stimulation for the Treatment of Late-Life Depression

K Göke, AP Trevizol, C Ma, L Mah, TK Rajji, ZJ Daskalakis, J Downar, ...

Biological Psychiatry 95 (10), S81-S82 2024年

149. Prediction of Postoperative Delirium by Blood Metabolome

N Arai, Y Sugiura, S Nakajima, M Wada, S Moriyama, Y Mimura, ...

Biological Psychiatry 95 (10), S160 2024年

The New Ethics of Neuromodulation with Transcranial Magnetic Stimulation: A Critical Appraisal

Noda Y.

Journal of Integrative Neuroscience （Journal of Integrative Neuroscience）  23 （ 6 ） 112 - 112 2024年

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  02196352

　概要を見る

With over 16 years of experience in clinical, research, and educational activities related to transcranial magnetic stimulation (TMS), I have written this article exploring the ethical dimensions of TMS. This article aims to provide valuable and informative content for those unfamiliar with TMS as well as those just starting in the field. Specifically, this article elaborates on four principles of medical ethics, including those applicable to TMS therapy, the disparity between public medical insurance coverage and medical indications in private practice for TMS therapy, and issues concerning research ethics in practice. I also provide recommendations regarding roles and strategies for adoption by academia and those in this field dedicated to making TMS therapy accessible to a larger patient population in a suitable manner. Lastly, it is my hope that this article will serve as a contemporary “Ethics of TMS Neuromodulation”, resonating with the inherent human pursuit of “truth, goodness, and beauty” for a sound mind and spirit.

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Neurophysiological profiles of patients with bipolar disorders as probed with transcranial magnetic stimulation: A systematic review

Taniguchi K., Kaneko N., Wada M., Moriyama S., Nakajima S., Mimura M., Noda Y.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports）  44 （ 3 ） 572 - 584 2024年

最終著者, 責任著者, 査読有り

　概要を見る

Aim: Bipolar disorder (BD) has a significant impact on global health, yet its neurophysiological basis remains poorly understood. Conventional treatments have limitations, highlighting the need for a better understanding of the neurophysiology of BD for early diagnosis and novel therapeutic strategies. Design: Employing a systematic review approach of the PRISMA guidelines, this study assessed the usefulness and validity of transcranial magnetic stimulation (TMS) neurophysiology in patients with BD. Methods: Databases searched included PubMed, MEDLINE, Embase, and PsycINFO, covering studies from January 1985 to January 2024. Results: Out of 6597 articles screened, nine studies met the inclusion criteria, providing neurophysiological insights into the pathophysiological basis of BD using TMS–electromyography and TMS–electroencephalography methods. Findings revealed significant neurophysiological impairments in patients with BD compared to healthy controls, specifically in cortical inhibition and excitability. In particular, short-interval cortical inhibition (SICI) was consistently diminished in BD across the studies, which suggests a fundamental impairment of cortical inhibitory function in BD. This systematic review corroborates the potential utility of TMS neurophysiology in elucidating the pathophysiological basis of BD. Specifically, the reduced cortical inhibition in the SICI paradigm observed in patients with BD suggests gamma-aminobutyric acid (GABA)-A receptor-mediated dysfunction, but results from other TMS paradigms have been inconsistent. Thus, complex neurophysiological processes may be involved in the pathological basis underlying BD. This study demonstrated that BD has a neural basis involving impaired GABAergic function, and it is highly expected that further research on TMS neurophysiology will further elucidate the pathophysiological basis of BD.

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Development of Transcranial Magnetic Stimulator Coils that Physically Achieve the Deepest Stimulation Based on the Inverse Problem Approach

Iino A., Fushimi M., Tabata J., Kikuchi T., Soejima Y., Wada M., Nakajima S., Noda Y., Sekino M.

IEEE Transactions on Magnetics （IEEE Transactions on Magnetics）  60 （ 9 ）  2024年

査読有り,  ISSN  00189464

　概要を見る

The stimulation of deeper brain regions with transcranial magnetic stimulation (TMS) is a promising treatment for depression with higher remission rates. The focality of the stimulation area is essential to reduce the risk of side effects; however, there is a physical trade-off between depth and focality. Because existent studies have searched for depth by iteratively designing a coil and then calculating the electric field in the brain, the theoretical maximum depth has not yet been determined. In this study, we propose a methodology to derive the coil based on an inverse problem approach from an analytical description of the desired electric field in the brain. This new method has allowed us to theoretically derive the maximum depth of the electric field, which was previously only determined empirically. Based on this, we designed and built a coil that can deliver the electric field to the deepest depth. Numerical simulations of the proposed coils derived show that they have the highest electric field depth of any coil feasible in the existing medical field. Moreover, the balance between depth and focality was also the best of the existing coils.

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Brain wave and cell activity control device and method based on light stimulation, and device for improvement, prevention, or increase in brain function

M Hayano, K Tsubota, Y Noda

US Patent App. 18/741,929 2024年

Global Framework for Scientific Event: A 32-Country & 118-Expert Collaborative Effort

FH Kakamad, FH Fattah, AM Salih, BA Abdalla, SH Mohammed, ...

Barw Medical Journal 2024年

CRISIS AFAR: an international collaborative study of the impact of the COVID-19 pandemic on mental health and service access in youth with autism and neurodevelopmental conditions

Vibert B., Segura P., Gallagher L., Georgiades S., Pervanidou P., Thurm A., Alexander L., Anagnostou E., Aoki Y., Birken C.S., Bishop S.L., Boi J., Bravaccio C., Brentani H., Canevini P., Carta A., Charach A., Costantino A., Cost K.T., Cravo E.A., Crosbie J., Davico C., Donno F., Fujino J., Gabellone A., Geyer C.T., Hirota T., Kanne S., Kawashima M., Kelley E., Kim H., Kim Y.S., Kim S.H., Korczak D.J., Lai M.C., Margari L., Marzulli L., Masi G., Mazzone L., McGrath J., Monga S., Morosini P., Nakajima S., Narzisi A., Nicolson R., Nikolaidis A., Noda Y., Nowell K., Polizzi M., Portolese J., Riccio M.P., Saito M., Schwartz I., Simhal A.K., Siracusano M., Sotgiu S., Stroud J., Sumiya F., Tachibana Y., Takahashi N., Takahashi R., Tamon H., Tancredi R., Vitiello B., Zuddas A., Leventhal B., Merikangas K., Milham M.P., Di Martino A.

Molecular Autism （Molecular Autism）  14 （ 1 ） 7 - 7 2023年12月

査読有り

　概要を見る

Background: Heterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services. Methods: Using a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups. Results: Clustering revealed four subgroups. One subgroup—broad symptom worsening only (20%)—included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup. Limitations: Notable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic. Conclusions: Concomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis.

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The relationship between sleep, gut microbiota, and metabolome in patients with depression and anxiety: A secondary analysis of the observational study

Tanaka A., Sanada K., Miyaho K., Tachibana T., Kurokawa S., Ishii C., Noda Y., Nakajima S., Fukuda S., Mimura M., Kishimoto T., Iwanami A.

PLoS ONE （PLoS ONE）  18 （ 12 December ） e0296047 2023年12月

査読有り

　概要を見る

Background Growing attention is paid to the association between alterations in the gut microbiota and their metabolites in patients with psychiatric disorders. Our study aimed to determine how gut microbiota and metabolomes are related to the sleep quality among patients with depression and anxiety disorders by analyzing the datasets of our previous study. Methods Samples were collected from 40 patients (depression: 32 patients [80.0%]); anxiety disorders: 8 patients [20.0%]) in this study. Gut microbiomes were analyzed using 16S rRNA gene sequencing and gut metabolomes were analyzed by a mass spectrometry approach. Based on the Pittsburgh Sleep Quality Index (PSQI), patients were categorized into two groups: the insomnia group (PSQI score ≥ 9, n = 20) and the non-insomnia group (PSQI score < 9, n = 20). Results The insomnia group showed a lower alpha diversity in the Chao1 and Shannon indices than the non-insomnia group after the false discovery rate (FDR) correction. The relative abundance of genus Bacteroides showed a positive correlation with PSQI scores in the non-insomnia group. The concentrations of glucosamine and N-methylglutamate were significantly higher in the insomnia group than in the non-insomnia group. Conclusions Our findings suggest that specific taxa could affect the sleep quality among patients with depression and anxiety disorders. Further studies are needed to elucidate the impact of sleep on specific gut microbiota and metabolomes in depression and anxiety disorders.

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Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults

Ueno F., Sakuma M., Nakajima S., Tsugawa S., Ochi R., Tani H., Noda Y., Graff-Guerrero A., Uchida H., Mimura M., Oshima S., Matsushita S.

Alcohol: Clinical and Experimental Research （Alcohol: Clinical and Experimental Research）  48 （ 1 ） 58 - 71 2023年11月

査読有り,  ISSN  2993-7175

　概要を見る

Background: To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. Methods: Eighteen healthy Japanese participants (7 males/11 females) aged 20–30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Results: Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. Conclusions: Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

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Transcranial magnetic stimulation neurophysiology in patients with non-Alzheimer's neurodegenerative diseases: A systematic review and meta-analysis.

Mimura Y, Tobari Y, Nakahara K, Nakajima S, Yoshida K, Mimura M, Noda Y

Neuroscience and biobehavioral reviews （Neuroscience and Biobehavioral Reviews）  155   105451 - 105451 2023年11月

最終著者, 責任著者, 査読有り,  ISSN  0149-7634

　概要を見る

Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing NAD remains challenging due to the lack of established biomarkers. 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 NAD and healthy controls. Our meta-analyses indicated that TMS neurophysiological examinations revealed decreased glutamatergic function in patients with frontotemporal dementia (FTD) and decreased GABAergic function in patients with FTD, progressive supranuclear palsy, Huntington's disease, cortico-basal syndrome, and multiple system atrophy-parkinsonian type. In addition, decreased cholinergic function was found in dementia with Lewy body and vascular dementia. These results suggest the potential of TMS as an additional diagnostic tool to differentiate NAD.

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

Wada M., Yasuda H., Nakajima S., Etani T., Miura A., Asada S., Yoshida K., Noda Y., Takeuchi H.

General Hospital Psychiatry （General Hospital Psychiatry）  85   71 - 79 2023年11月

査読有り,  ISSN  01638343

　概要を見る

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

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Glutamatergic neurometabolite levels in the caudate are associated with the ability of rhythm production.

Honda S, Noda Y, Matsushita K, Tarumi R, Nomiyama N, Tsugawa S, Tobari Y, Hondo N, Saito K, Mimura M, Fujii S, Nakajima S

Frontiers in neuroscience （Frontiers in Neuroscience）  17   1196805 - 1196805 2023年08月

責任著者,  ISSN  1662-4548

　概要を見る

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.

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Retrospective study on the trajectories of lower limb volume after outpatient-based complex decongestive therapy in post-operative gynecological cancer patients with lymphedema

Masui A., Harada T., Noda Y., Soeda R., Kida H., Tsuji T.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer （Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer）  31 （ 6 ） 318 - 318 2023年05月

査読有り,  ISSN  0941-4355

　概要を見る

PURPOSE: To determine the effect of outpatient-based complex decongestive therapy in patients with secondary lower limb lymphedema (LLL) after gynecologic cancer surgery using group-based trajectory modeling (GBTM), and to examine factors predictive of the treatment course. METHODS: This retrospective study included participants who underwent surgery for gynecological cancer with pelvic lymph node dissection and subsequently visited the outpatient clinic for the treatment of stage II LLL according to the International Society of Lymphology. The improvement rate of edema at the initial visit and 3, 6, and 12 months later was assessed by calculating the volume of the lower extremity using the circumferential method. For evaluation of the patterns of treatment course, logistic regression analysis was performed after group estimation by the trend of the treatment course using GBTM. RESULTS: A total of 148 women (mean age 60.6 years (standard deviation: 13.4 years)) were analyzed. Three improvement trajectories were identified: (1) no response group, with worsening rather than improvement (n = 26); (2) moderate response group, with a slow improvement rate (n = 89); and (3) high response group, with a high improvement rate (n = 33). In addition, adherence to compression therapy at 3 months post-intervention was found to be a predictor in the no response group. CONCLUSIONS: GBTM estimated that there are three patterns of the treatment course in patients with LLL after gynecologic cancer surgery. Adherence to compression therapy at 3 months post-intervention is a predictor of the treatment effectiveness.

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A Case Series of Continuous Theta Burst Stimulation Treatment for the Supplementary Motor Area Twice a Day in Patients with Obsessive-Compulsive Disorder: A Real World TMS Registry Study in Japan

Noda Y., Fujii K., Tokura F., Nakajima S., Kitahata R.

Journal of Personalized Medicine （Journal of Personalized Medicine）  13 （ 5 ）  2023年05月

筆頭著者, 責任著者, 査読有り,  ISSN  2075-4426

　概要を見る

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by patterns in which unwanted thoughts and fears are evoked as obsessions and furthermore, compulsive behaviors are provoked repeatedly, with a prevalence rate of 2% of the population. These obsessive-compulsive symptoms disrupt daily life and cause great distress to the individual. At present, OCD is treated with antidepressants, mainly selective serotonin reuptake inhibitors, and psychotherapy, including the exposure and response prevention method. However, these approaches may only show a certain level of efficacy, and approximately 50% of patients with OCD show treatment resistance. This situation has led to the research and development of neuromodulation therapies, including transcranial magnetic stimulation treatment, for OCD worldwide in recent years. In this case series, we retrospectively analyzed the TMS registry data of continuous theta burst stimulation (cTBS) therapy targeting the bilateral supplementary motor cortex for six patients with OCD whose obsessive-compulsive symptoms had not improved with pharmacotherapy. The results suggest that treatment with cTBS for the bilateral supplementary motor area may reduce obsessive-compulsive symptoms in patients with OCD, despite the limitations of an open-label preliminary case series. The present findings warrant further validation with a randomized, sham-controlled trial with a larger sample size in the future.

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Identifying Neurophysiological Markers of Intermittent Theta-Burst Stimulation in Treatment-Resistant Depression using Transcranial Magnetic Stimulation- Electroencephalography.

Strafella R, Momi D, Zomorrodi R, Lissemore J, Noda Y, Chen R, Rajji TK, Griffiths JD, Vila-Rodriguez F, Downar J, Daskalakis ZJ, Blumberger DM, Voineskos D

Biological psychiatry （Biological Psychiatry）  94 （ 6 ） 454 - 465 2023年04月

査読有り,  ISSN  0006-3223

　概要を見る

Background: Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex is effective for treatment-resistant depression, but the effects of iTBS on neurophysiological markers remain unclear. Here, we indexed transcranial magnetic stimulation–electroencephalography (TMS-EEG) markers, specifically, the N45 and N100 amplitudes, at baseline and post-iTBS, comparing separated and contiguous iTBS schedules. TMS-EEG markers were also compared between iTBS responders and nonresponders. Methods: TMS-EEG was analyzed from a triple-blind 1:1 randomized trial for treatment-resistant depression, comparing a separated (54-minute interval) and contiguous (0-minute interval) schedule of 2 × 600-pulse iTBS for 30 treatments. Participants underwent TMS-EEG over the left dorsolateral prefrontal cortex at baseline and posttreatment. One hundred fourteen participants had usable TMS-EEG at baseline, and 98 at posttreatment. TMS-evoked potential components (N45, N100) were examined via global mean field analysis. Results: The N100 amplitude decreased from baseline to posttreatment, regardless of the treatment group (F1,106 = 5.20, p =.02). There were no changes in N45 amplitude in either treatment group. In responders, the N100 amplitude decreased after iTBS (F1,102 = 11.30, p =.001, pcorrected =.0004). Responders showed higher posttreatment N45 amplitude than nonresponders (F1,94 = 4.11, p =.045, pcorrected =.016). Higher baseline N100 amplitude predicted lower post-iTBS depression scores (F4,106 = 6.28, p =.00014). Conclusions: These results provide further evidence for an association between the neurophysiological effects of iTBS and treatment efficacy in treatment-resistant depression. Future studies are needed to test the predictive potential for clinical applications of TMS-EEG markers.

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Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy.

Eiro T, Miyazaki T, Hatano M, Nakajima W, Arisawa T, Takada Y, Kimura K, Sano A, Nakano K, Mihara T, Takayama Y, Ikegaya N, Iwasaki M, Hishimoto A, Noda Y, Miyazaki T, Uchida H, Tani H, Nagai N, Koizumi T, Nakajima S, Mimura M, Matsuda N, Kanai K, Takahashi K, Ito H, Hirano Y, Kimura Y, Matsumoto R, Ikeda A, Takahashi T

Cell reports. Medicine （Cell Reports Medicine）  4 （ 5 ） 101020 - 101020 2023年04月

査読有り

　概要を見る

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

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Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with long-COVID in Japan

Noda Y., Sato A., Shichi M., Sato A., Fujii K., Iwasa M., Nagano Y., Kitahata R., Osawa R.

Asian Journal of Psychiatry （Asian Journal of Psychiatry）  81   103438 - 103438 2023年03月

筆頭著者, 責任著者, 査読有り,  ISSN  18762018

　概要を見る

The number of patients suffering from long-COVID is currently increasing rapidly, even after the acute symptoms of COVID-19 have improved. The objective of this study was to investigate the effects of a pilot transcranial magnetic stimulation (TMS) treatment on neuropsychiatric symptoms caused by long-COVID. In this study, we examined the efficacy of the TMS treatment protocol, which has been established to be effective in refractory depression, by applying it to patients who sought TMS treatment for neuropsychiatric symptoms caused by long-COVID at TMS clinics in Tokyo, Japan in the context of the real world TMS registry study in Japan. Of the 23 patients (13 females) with long-COVID included in this case series, the main neuropsychiatric symptoms were chronic fatigue (n = 12) and cognitive dysfunction (n = 11), but most patients also showed mild depressive symptoms. The mean score on the Montgomery-Åsberg Depression Rating Scale before TMS treatment was 21.2, which improved to 9.8 after treatment. Similarly, the score on the Performance Status, which assesses the degree of fatigue, improved from 5.4 to 4.2, and the score on the Perceived Deficits Questionnaire–Depression 5-item, which reflects cognitive function, improved from 10.0 to 6.3. Although a few patients complained of pain at the stimulation site during the TMS as a side effect, there were no serious adverse events. Despite the limitations of this open-label pilot study, the TMS protocol implemented in this study may have beneficial effects on neuropsychiatric symptoms caused by long-COVID, including depressive symptoms, chronic fatigue, and cognitive impairment. These preliminary findings warrant further validation in randomized controlled trials.

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

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.

Schizophrenia Research （Schizophrenia Research）  252   129 - 137 2023年02月

最終著者, 責任著者, 査読有り,  ISSN  09209964

　概要を見る

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

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Music rhythm perception and production relate to treatment response in schizophrenia

Honda S., Matsushita K., Noda Y., Tarumi R., Nomiyama N., Tsugawa S., Nakajima S., Mimura M., Fujii S.

Schizophrenia Research （Schizophrenia Research）  252   69 - 76 2023年02月

責任著者, 査読有り,  ISSN  09209964

　概要を見る

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.

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A Case Series of Intermittent Theta Burst Stimulation Treatment for Depressive Symptoms in Individuals with Autistic Spectrum Disorder: Real World TMS Study in the Tokyo Metropolitan Area.

Noda Y, Fujii K, Mimura Y, Taniguchi K, Nakajima S, Kitahata R

Journal of personalized medicine （Journal of Personalized Medicine）  13 （ 1 ）  2023年01月

筆頭著者, 責任著者, 査読有り,  ISSN  2075-4426

　概要を見る

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behaviors. While the symptoms of ASD are present from early childhood, there has been an increase in the number of adults with ASD in recent years who visit healthcare professionals to seek the treatment of depression due to maladjustment resulting from the core symptoms and are eventually diagnosed with ASD. Currently, no treatment is available for the core symptoms of ASD, and pharmacotherapy and psychotherapy are often provided mainly for secondary disorders such as depression and anxiety. However, the effectiveness of these therapies is often limited in individuals with ASD compared to those with major depression. In this context, neuromodulation therapies such as transcranial magnetic stimulation (TMS) have gained increasing attention as potential treatments. In this case series, we retrospectively analyzed 18 cases with ASD from the TMS registry data who had failed to improve depressive symptoms with pharmacotherapy and were treated with intermittent theta burst stimulation (iTBS) therapy to the left dorsolateral prefrontal cortex (DLPFC). We also explored the relationship between treatment efficacy and clinical epidemiological profile. Our results indicated that, despite the limitations of an open-label preliminary case series, TMS therapy in the form of iTBS may have some beneficial therapeutic effects on depressive symptoms in individuals with ASD. The present findings warrant further validation through randomized, sham-controlled trials with larger sample sizes.

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A pilot study on the effect of transcranial magnetic stimulation treatment on cognitive dysfunction associated with long-COVID.

Noda Y, Sato A, Fujii K, Nagano Y, Iwasa M, Hirahata K, Kitahata R, Osawa R

Psychiatry and clinical neurosciences 77 （ 4 ） 241 - 242 2023年01月

筆頭著者, 責任著者, 査読有り,  ISSN  1323-1316

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Impaired neuroplasticity in the dorsolateral prefrontal cortex of patients with treatment-resistant depression indexed by paired associative stimulation paradigm and a combined TMS-EEG measurements

Naotsugu Kaneko, Masakata Wada, Mayuko Takano, Keita Taniguchi, Shiori Honda, Shinichiro Nakajima, Masaru Mimura, Yoshihiro Noda

Brain Stimulation （Elsevier BV）  16 （ 1 ） 240 - 240 2023年01月

ISSN  1935-861X

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When the brain goes quiet: cortical silence inhibition in schizophrenia

M Mikail, R Zomorrodi, Y Noda, J Daskalakis

Royal College of Surgeons in Ireland 2023年

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

S Koike, S Shibukawa, H Kan, S Honda, M Wada, R Tarumi, S Tsugawa, ...

Translational psychiatry （Translational Psychiatry）  14 （ 1 ） 164 - 164 2023年

査読有り

　概要を見る

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.

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A pilot study of the effect of transcranial magnetic stimulation treatment on cognitive dysfunction associated with post COVID‐19 condition

Y Noda, A Sato, K Fujii, Y Nagano, M Iwasa, K Hirahata, R Kitahata, ...

Psychiatry and Clinical Neurosciences 77 (4), 241-242 2023年

Reduced signal propagation from the left dorsolateral prefrontal cortex to the salience network associated with oligodendrocyte abnormalities in treatment-resistant depression

M Wada, S Nakajima, S Honda, M Takano, K Taniguchi, S Tsugawa, ...

Brain Stimulation: Basic, Translational, and Clinical Research in … 2023年

A pilot study on the effect of transcranial magnetic stimulation treatment on cognitive dysfunction associated with long‐COVID

Y Noda, A Sato, K Fujii, Y Nagano, M Iwasa, K Hirahata, R Kitahata, ...

Psychiatry and Clinical Neurosciences 2023年

A Case Series of Intermittent Theta Burst Stimulation Treatment for Depressive Symptoms in Individuals with Autistic Spectrum Disorder: Real World TMS Study in the Tokyo …

Y Noda, K Fujii, Y Mimura, K Taniguchi, S Nakajima, R Kitahata

Journal of Personalized Medicine 13 (1), 145 2023年

Decreased cholinergic function in the dorsolateral prefrontal cortex of amnestic mild cognitive impairment assessed by TMS-evoked potentials in the short-latency afferent …

Y Mimura, Y Tobari, M Takano, M Wada, S Honda, S Bun, H Tabuchi, ...

Brain Stimulation: Basic, Translational, and Clinical Research in … 2023年

Disease progression patterns of brain morphology in schizophrenia: More progressed stages in treatment-resistance

D Sone, A Young, S Shinagawa, S Tsugawa, Y Iwata, R Tarumi, K Ogyu, ...

Schizophrenia bulletin （Schizophrenia Bulletin）  50 （ 2 ） 393 - 402 2023年

査読有り,  ISSN  0586-7614

　概要を見る

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 machinelearning 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.

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Impaired neuroplasticity in the dorsolateral prefrontal cortex of patients with treatment-resistant depression indexed by paired associative stimulation paradigm and a combined …

N Kaneko, M Wada, M Takano, K Taniguchi, S Honda, S Nakajima, ...

Brain Stimulation: Basic, Translational, and Clinical Research in … 2023年

Neurophysiological evaluation of single-pulse TMS-EEG in the left dorsolateral prefrontal cortex in healthy subjects by comparing active and sham stimulation coils

M Takano, M Wada, S Honda, K Taniguchi, Y Mimura, Y Tobari, ...

Brain Stimulation: Basic, Translational, and Clinical Research in … （Elsevier BV）  16 （ 1 ） 247 - 247 2023年

ISSN  1935-861X

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A Case Series of Continuous Theta Burst Stimulation Treatment for the Supplementary Motor Area Twice a Day in Patients with Obsessive-Compulsive Disorder: A Real World TMS …

Y Noda, K Fujii, F Tokura, S Nakajima, R Kitahata

Journal of Personalized Medicine 13 (5), 875 2023年

Associations Between Neuromelanin Accumulation in Patients With Schizophrenia and Treatment Responsiveness: A Cross-Sectional NM-MRI Study

F Ueno, Y Iwata, S Honda, G Horga, C Cassidy, E Torres-Carmona, ...

NEUROPSYCHOPHARMACOLOGY 48, 379-379 2023年

Biotyping of Neuroanatomical Signatures by Machine Learning of Brain MRI Data in Treatment-Resistant Depression

N Hondo, Y Noda, M Wada, S Honda, S Tsugawa, K Takahashi, S Koike, ...

NEUROPSYCHOPHARMACOLOGY 48, 214-215 2023年

Disease Progression Modeling of Cortical Macrostructure in Treatment-Resistant Depression

K Takahashi, Y Noda, S Honda, M Wada, N Hondo, D Sone, S Tsugawa, ...

NEUROPSYCHOPHARMACOLOGY 48, 229-230 2023年

Evaluation of GABA and Glutamate plus Glutamine Levels in the Dorsal Anterior Cingulate Cortex of Patients With Bipolar Disorder: A Cross-Sectional 1H-MRS Study

S Moriyama, Y Noda, S Honda, R Edden, K Saito, K Taniguchi, M Wada, ...

NEUROPSYCHOPHARMACOLOGY 48, 266-267 2023年

Roles of Glutamate, GABA, Dopamine, and Norepinephrine in Pathological Basis of Treatment-Resistant Depression: A Multimodal MRI Study

S Honda, Y Noda, M Wada, Y Tobari, Y Mimura, S Tsugawa, S Koike, ...

NEUROPSYCHOPHARMACOLOGY 48, 289-290 2023年

P177: Motoric cognitive risk syndrome is associated with MRI-derived brain age: the Arakawa Geriatric Cohort Study

S Bun, D Sone, R Shikimoto, H Kida, S Nakajima, Y Noda, H Niimura, ...

International Psychogeriatrics 35 (S1), 223-224 2023年

Effectiveness of Conventional Sequential Bilateral Repetitive Transcranial Stimulation Versus Bilateral Theta Burst Stimulation for Patients With Treatment-Resistant Depression …

M Wada, S Nakajima, Taniguchi, keita, S Honda, Y Mimura, K Thorpe, ...

NEUROPSYCHOPHARMACOLOGY 48, 194-195 2023年

A meta-analytic review of gut microbiota in neurodevelopmental disorders

S Hirose, K Sanada, S Kurokawa, A Tanaka, D Ikuse, T Nagai, T Tateishi, ...

Neuroscience Applied 2, 103440 2023年

Music reward sensitivity in patients with bipolar disorder: a Barcelona Music Reward Questionnaire study

S HONMA, Y NODA, S KONDO, T ETANI, S HONDA, S MORIYAMA, ...

電子情報通信学会技術研究報告 (Web) 123 (278 (EA2023 28-48)), 68-71 2023年

Identifying neurophysiological markers of intermittent theta burst stimulation in treatment-resistant depression using transcranial magnetic stimulation–electroencephalography

R Strafella, D Momi, R Zomorrodi, J Lissemore, Y Noda, R Chen, TK Rajji, ...

Biological psychiatry 94 (6), 454-465 2023年

The Association between Electroencephalography with Auditory Steady-State Response and Postoperative Delirium.

Arai N, Miyazaki T, Nakajima S, Okamoto S, Moriyama S, Niinomi K, Takayama K, Kato J, Nakamura I, Hirano Y, Kitago M, Kitagawa Y, Takahashi T, Shimizu H, Mimura M, Noda Y

Journal of personalized medicine （Journal of Personalized Medicine）  13 （ 1 ）  2022年12月

最終著者, 責任著者, 査読有り,  ISSN  2075-4426

　概要を見る

Delirium is a disorder of consciousness and a risk factor for cognitive dysfunction and poor prognosis. We hypothesized that preoperative gamma activities would be linked to postoperative delirium. We enrolled 71 subjects for elective surgery and recorded auditory steady-state response (ASSR) by electroencephalography (EEG) before the surgery and examined postoperative delirium with DSM-5. The EEG data were analyzed for baseline power, and ASSR evoked power (EP) and phase-locking factor (PLF) within the gamma range. Postoperative delirium was found in 18 patients (delirium group) but not in 53 patients (non-delirium group). There were no significant differences in the 40-Hz EP or PLF between the two groups. The baseline gamma activity negatively correlated with the 40-Hz PLF in the non-delirium group (ρ = −0.444, p < 0.01). The correlation between baseline gamma activity and 40-Hz EP was not significant in either the delirium or non-delirium group. In all patients, both preoperative PLF and EP had no significant correlations with the Delirium Rating Scale Revised-98 and the Memorial Delirium Assessment Measure at the post-operation, respectively. The disruption of the neurophysiological relationship between baseline gamma activity before sound stimuli and the PLF of the 40-Hz ASSR may be one of the potential neurophysiological indicators associated with postoperative delirium.

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Neuroimaging-derived brain age is associated with life satisfaction in cognitively unimpaired elderly: A community-based study

Sone D., Beheshti I., Shinagawa S., Niimura H., Kobayashi N., Kida H., Shikimoto R., Noda Y., Nakajima S., Bun S., Mimura M., Shigeta M.

Translational Psychiatry （Translational Psychiatry）  12 （ 1 ） 25 - 25 2022年12月

査読有り

　概要を見る

With the widespread increase in elderly populations, the quality of life and mental health in old age are issues of great interest. The human brain changes with age, and the brain aging process is biologically complex and varies widely among individuals. In this cross-sectional study, to clarify the effects of mental health, as well as common metabolic factors (e.g., diabetes) on healthy brain aging in late life, we analyzed structural brain MRI findings to examine the relationship between predicted brain age and life satisfaction, depressive symptoms, resilience, and lifestyle-related factors in elderly community-living individuals with unimpaired cognitive function. We extracted data from a community-based cohort study in Arakawa Ward, Tokyo. T1-weighted images of 773 elderly participants aged ≥65 years were analyzed, and the predicted brain age of each subject was calculated by machine learning from anatomically standardized gray-matter images. Specifically, we examined the relationships between the brain-predicted age difference (Brain-PAD: real age subtracted from predicted age) and life satisfaction, depressive symptoms, resilience, alcohol consumption, smoking, diabetes, hypertension, and dyslipidemia. Brain-PAD showed significant negative correlations with life satisfaction (Spearman’s rs= −0.102, p = 0.005) and resilience (rs= −0.105, p = 0.004). In a multiple regression analysis, life satisfaction (p = 0.038), alcohol use (p = 0.040), and diabetes (p = 0.002) were independently correlated with Brain-PAD. Thus, in the cognitively unimpaired elderly, higher life satisfaction was associated with a ‘younger’ brain, whereas diabetes and alcohol use had negative impacts on life satisfaction. Subjective life satisfaction, as well as the prevention of diabetes and alcohol use, may protect the brain from accelerated aging.

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The Potential Impact of Age on Gut Microbiota in Patients with Major Depressive Disorder: A Secondary Analysis of the Prospective Observational Study

Miyaho K., Sanada K., Kurokawa S., Tanaka A., Tachibana T., Ishii C., Noda Y., Nakajima S., Fukuda S., Mimura M., Kishimoto T., Iwanami A.

Journal of Personalized Medicine （Journal of Personalized Medicine）  12 （ 11 ）  2022年11月

査読有り,  ISSN  2075-4426

　概要を見る

We aimed to investigate the impact of aging on the relationship among the composition of gut microbiota, gastrointestinal (GI) symptoms, and the course of treatment for major depressive disorder (MDD) by analyzing the datasets from our previous study. Patients with MDD were recruited, and their stools were collected at three time points (baseline, midterm, and endpoint) following the usual antidepressant treatment. Gut microbiota were analyzed using 16S rRNA gene sequencing. Patients were categorized into two groups based on their age: the late-life group over 60 years and the middle-aged group under 60 years. GI symptoms were assessed with scores of item 11 of the Hamilton Anxiety Rating Scale. One hundred and ninety samples were collected from 32 patients with MDD. Several gut microbes had higher relative abundances in the late-life group than in the middle-aged group. In addition, the late-life group showed significantly higher diversity in the Chao1 index at baseline compared with the middle-aged group. We further found possible microbial taxa related to GI symptoms in patients with late-life depression. The abundance of several bacterial taxa may contribute to GI symptoms in the late-life depression, and our findings suggest that the therapeutic targets for the application of gut microbiota may differ depending on the age group of patients with depression.

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

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.

Biosensors （Biosensors）  12 （ 10 ） 814 - 814 2022年10月

最終著者, 責任著者, 査読有り

　概要を見る

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.

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Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

H Ino, S Honda, K Yamada, N Horita, S Tsugawa, K Yoshida, Y Noda, ...

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging （Biological Psychiatry: Cognitive Neuroscience and Neuroimaging）  8 （ 2 ） 140 - 150 2022年10月

査読有り,  ISSN  2451-9022

　概要を見る

Background: The glutamatergic system is thought to play an important role in the pathophysiology of bipolar disorder (BD). While there has been an increase in proton magnetic resonance spectroscopy studies examining this neurotransmission system, the results are inconsistent. Possible reasons for the inconsistency, including clinical features such as mood state and childhood versus adulthood age, were not addressed in previous meta-analyses. Methods: This systematic review and meta-analysis of proton magnetic resonance spectroscopy studies of BD included 40 studies, with 1135 patients with BD and 964 healthy control (HC) subjects. Results: Glutamate plus glutamine and glutamine levels in the anterior cingulate cortex of patients with BD were significantly elevated compared with those of HC subjects (standardized mean difference = 0.42, 0.48, respectively). Subgroup analyses showed that adult BD patients had significantly higher levels of glutamate plus glutamine than adult HC subjects, but this was not the case in pediatric patients. For mood states, anterior cingulate cortex glutamate plus glutamine levels were higher in patients with bipolar depression than those in HC subjects. Conclusions: Our results imply that glutamatergic dysfunction in the anterior cingulate cortex may be implicated in the pathophysiology of BD, which is most evident in adult BD patients and patients with bipolar depression.

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A Case Series of Deep Transcranial Magnetic Stimulation Treatment for Patients with Obsessive-Compulsive Disorder in the Tokyo Metropolitan Area

Ikawa H., Osawa R., Sato A., Mizuno H., Noda Y.

Journal of Clinical Medicine （Journal of Clinical Medicine）  11 （ 20 ） 6133 - 6133 2022年10月

最終著者, 責任著者, 査読有り,  ISSN  2077-0383

　概要を見る

Obsessive-compulsive disorder (OCD) is a chronic illness in which patients do not achieve remission sufficiently with conventional medication. Deep repetitive transcranial magnetic stimulation (dTMS) for OCD neuromodulates the bilateral anterior cingulate cortex (ACC) and dorsal medial prefrontal cortex (mPFC), which are known to be impaired in OCD. While dTMS treatment for OCD has shown effective results overseas, TMS treatment for OCD has rarely been implemented in Japan, and its effectiveness is unknown. We conducted an FDA-approved dTMS protocol to 26 patients with OCD. In addition, individual exposure stimulation that elicited each patient’s obsessive thoughts was also combined during dTMS treatment. Before and after 30 sessions of TMS treatment, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess changes in the severity of each patient’s obsessive-compulsive disorder. Response to dTMS treatment in patients with OCD was determined by whether the total score on the Y-BOCS after a course of treatment was reduced by 30% or more compared with the score at baseline. The percentage of responders in this case series following the 30 sessions of dTMS treatment was 53.9%. In addition, total Y-BOCS scores and scores on each item were significantly improved. The percent changes in total Y-BOCS scores did not differ between the sexes or between on- and off-medication patients. No obvious adverse events were observed in this case series. In line with the results of TMS studies for OCD patients reported overseas, dTMS treatment for Japanese patients with OCD may have a favorable therapeutic effect.

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Decreased Cortical Gyrification and Surface Area in the Left Medial Parietal Cortex in Patients with Treatment-Resistant and Ultra-Treatment-Resistant Schizophrenia.

Kitajima K, Tamura S, Sasabayashi D, Nakajima S, Iwata Y, Ueno F, Takai Y, Takahashi J, Caravaggio F, Mar W, Torres-Carmona E, Noda Y, Gerretsen P, Luca V, Mimura M, Hirano S, Nakao T, Onitsuka T, Remington G, Graff-Guerrero A, Hirano Y

Psychiatry and clinical neurosciences （Psychiatry and Clinical Neurosciences）  77 （ 1 ） 2 - 11 2022年09月

査読有り,  ISSN  1323-1316

　概要を見る

Aim: Validating the vulnerabilities and pathologies underlying treatment-resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS. Methods: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first-line antipsychotics (FL-Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ-Resp) and 22 FL- and clozapine-resistant patients (patients with ultratreatment-resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis. Results: Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [gH] = 0.75; P = 0.013, gH = 0.96) and FL-Resp (P = 0.007, gH = 1.00; P = 0.002, gH = 1.31) in the left medial parietal cortex (Lt-MPC). In addition, both CLZ-Resp and URS had lower SA in the Lt-MPC than FL-Resp (P < 0.001, gH = 1.22; P < 0.001, gH = 1.75). LGI and SA were positively correlated in non-TRS (FL-Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ-Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non-TRS versus TRS with LGI and SA in the Lt-MPC were 0.79 and 0.85, respectively. SA in the Lt-MPC was inversely correlated with negative symptoms (ρ = −0.40, P = 0.018) and clozapine plasma levels (ρ = −0.35, P = 0.042) in TRS. Conclusion: LGI and SA in the Lt-MPC, a functional hub in the default-mode network, were abnormally reduced in TRS compared with non-TRS. Thus, altered LGI and SA in the Lt-MPC might be structural features associated with genetic vulnerability to TRS.

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Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression: The FOUR-D Randomized Noninferiority Clinical Trial.

Blumberger DM, Mulsant BH, Thorpe KE, McClintock SM, Konstantinou GN, Lee HH, Nestor SM, Noda Y, Rajji TK, Trevizol AP, Vila-Rodriguez F, Daskalakis ZJ, Downar J

JAMA psychiatry （JAMA Psychiatry）  79 （ 11 ） 1065 - 1073 2022年09月

査読有り,  ISSN  2168-622X

　概要を見る

Importance: Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes. Objective: To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD. Design, Setting, and Participants: In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials. Interventions: Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS. Main Outcomes and Measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed. Results: A total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI -0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P =.14; χ2= 2.2). Conclusions and Relevance: In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD. Trial Registration: ClinicalTrials.gov Identifier: NCT02998580.

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Autistic children and adolescents with frequent restricted interest and repetitive behavior showed more difficulty in social cognition during mask-wearing during the COVID-19 pandemic: a multisite survey

Tamon H., Itahashi T., Yamaguchi S., Tachibana Y., Fujino J., Igarashi M., Kawashima M., Takahashi R., Shinohara N.A., Noda Y., Nakajima S., Hirota T., Aoki Y.Y.

BMC psychiatry （BMC psychiatry）  22 （ 1 ） 608 - 608 2022年09月

査読有り

　概要を見る

BACKGROUND: The public health measures enacted in order to control the coronavirus disease (COVID-19) pandemic have caused considerable changes to daily life. For autistic children and adolescents, adapting to the "new normal," including mask-wearing, may be difficult because of their restricted interest and repetitive behavior (RRB) characteristics. We aimed to examine the relationships between RRB characteristics and the impact of mask-wearing on their social communications during the pandemic. METHODS: We recruited participants with a clinical diagnosis of autism spectrum disorder based on DSM-5 diagnostic criteria from two outpatient clinics in Tokyo, Japan, between November 2020 and April 2021 using a convenience sampling methodology. As a result, the participants consisted of 102 children and adolescents (mean (SD) age = 11.6 (5.3)). We collected data on RRB characteristics frequency before and during the pandemic using the CoRonavIruS Health Impact Survey (CRISIS) - Adapted for Autism and Related Neurodevelopmental conditions (AFAR). We then conducted factor analyses to compute the RRB severity composite scores, which are divided into lower- (e.g., sensory seeking), and higher-order (e.g., restricted interest). We also investigated mask-wearing culture using a bespoke questionnaire, and using Spearman's rank correlation analyses, we examined the relationships between before pandemic RRB characteristics, and the impact of mask-wearing on social communications during the pandemic. RESULTS: We found that children and adolescents who exhibited lower-order RRB before the pandemic had difficulties in going-out with mask-wearing (rho = -0.25, q = .031), more challenges with mask-wearing (rho =  - 0.34, q = .0018), and difficulty in referring to others' emotions while wearing masks (rho =  - 0.36, q = .0016). We also found an association between higher-order RRB before the pandemic and an uncomfortable sensation (rho =  - 0.42, q = .0002) and difficulties in referring to other's emotions while wearing masks (rho =  - 0.25, q = .031). CONCLUSIONS: We revealed that various behaviors, such as sensory seeking, repetitive motor mannerisms and movements, and rituals and routines, undertaken before the pandemic could be important predictors of difficulties with mask-wearing and social communication for autistic children and adolescents during the pandemic. Caregivers and teachers wearing masks may need to provide extra support for social communication to autistic children and adolescents showing RRB characteristics frequently.

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

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.

Journal of psychiatry &amp; neuroscience : JPN （Journal of psychiatry &amp; neuroscience : JPN）  47 （ 5 ） E325 - E335 2022年09月

最終著者, 責任著者, 査読有り,  ISSN  1180-4882

　概要を見る

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

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

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.

Molecular Psychiatry （Molecular Psychiatry）  27 （ 7 ） 2950 - 2967 2022年07月

査読有り,  ISSN  13594184

　概要を見る

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.

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TMS Database Registry Consortium Research Project in Japan (TReC-J) for Future Personalized Psychiatry

Noda Y., Kizaki J., Takahashi S., Mimura M.

Journal of Personalized Medicine （Journal of Personalized Medicine）  12 （ 5 ） 844 - 844 2022年05月

筆頭著者, 責任著者, 査読有り,  ISSN  2075-4426

　概要を見る

The registry project led by the Japanese Society for Clinical Transcranial Magnetic Stimulation (TMS) Research aims to establish a centralized database of epidemiological, clinical, and biological data on TMS therapy for refractory psychiatric disorders, including treatment-resistant depression, as well as to contribute to the elucidation of the therapeutic mechanism of TMS therapy and to the validation of its efficacy by analyzing and evaluating these data in a systematic approach. The objective of this registry project is to collect a wide range of complex data linked to patients with various neuropsychiatric disorders who received TMS therapy throughout Japan, and to make effective use of these data to promote cross-sectional and longitudinal exploratory observational studies. Research utilizing this registry project will be conducted in a multicenter, non-invasive, retrospective, and prospective observational research study design, regardless of the framework of insurance medical care, private practice, or clinical research. Through the establishment of the registry, which aims to make use of data, we will advance the elucidation of treatment mechanisms and identification of predictors of therapeutic response to TMS therapy for refractory psychiatric disorders on a more real-world research basis. Furthermore, as a future vision, we aim to develop novel neuromodulation medical devices, algorithms for predicting treatment efficacy, and digital therapeutics based on the knowledge generated from this TMS registry database.

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The impact of mask-wearing influenced by restricted interest and repetitive behavior on the mental distress of individuals with autism spectrum disorder during the COVID-19 pandemic: a multisite survey

Hiroki Tamon, Takashi Itahashi, Sosei Yamaguchi, Yoshiyuki Tachibana, Junya Fujino, Miki Igarashi, Makiko Kawashima, Riina Takahashi, Nozomi Shinohara, Yoshihiro Noda, Shinichiro Nakajima, Tomoya Hirota, Yuta Aoki

（Research Square Platform LLC）  2022年04月

　概要を見る

Abstract

Background The coronavirus disease of 2019 pandemic has caused considerable changes in daily life. For children with autism spectrum disorder, adapting to the “new normal,” including mask-wearing, may be difficult because of their restricted interest and repetitive behaviors symptoms. We aimed to examine the relationships between restricted interest and repetitive behaviors symptoms and the impact of mask-wearing on their social communications during the pandemic.Methods We recruited 102 children with autism spectrum disorder and collected data on sleep and exercise and the restricted interest and repetitive behaviors symptom frequency before and during the pandemic using an international questionnaire. Then, we conducted factor analyses to compute the restricted interest and repetitive behaviors severity composite scores, which are divided into lower-, such as sensory seeking, and higher-order, such as restricted interest. We also asked about the mask-wearing culture using a bespoke questionnaire. Using Spearman’s rank correlation analyses, we examined the relationships between the before pandemic restricted interest and repetitive behaviors symptoms and the impact of mask-wearing on their social communications during the pandemic.Results The current participants spent significantly less time outdoors during the pandemic than before (rho = 0.75, p = 0.005). We also revealed children who exhibited lower-order restricted interest and repetitive behaviors before the pandemic had more challenges with mask-wearing. Mask-wearing was associated with an uncomfortable sensation (rho=-0.34, p = 0.0004) and difficulty in referring to others’ emotions while wearing masks (rho=-0.30, p = 0.0002). We also found an association between higher-order restricted interest and repetitive behaviors and an uncomfortable sensation (rho=-0.42, p = 0.00001).Conclusions These symptoms could be an important predictor for children with autism to adapt to the new normal.

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Influence of External Natural Environment Including Sunshine Exposure on Public Mental Health: A Systematic Review

K Taniguchi, M Takano, Y Tobari, M Hayano, S Nakajima, M Mimura, ...

Psychiatry International 3 (1), 91-113 （Psychiatry International）  3 （ 1 ） 91 - 113 2022年03月

最終著者, 責任著者, 査読有り

　概要を見る

The COVID-19 pandemic has been raging around the world and public health measures such as lockdowns have forced people to go out less often, reducing sunlight exposure time, green space use, and physical activity. It is well known that exercise has a positive impact on mental health, but the impact of external environmental factors such as sunlight exposure and green space use on mental health has not been systematically reviewed. In this review, we categorized the major factors that may affect people’s mental health into (1) external environmental factors such as exposure to sunlight and green spaces, (2) internal life factors such as physical activity and lifestyle, and (3) mixed external and internal factors, and systematically examined the relationship between each factor and people’s mental health. The results showed that exposure to sunlight, spending leisure time in green spaces, and physical activity each had a positive impact on people’s mental health, including depression, anxiety, and stress states. Specifically, moderate physical activity in an external environment with sunlight exposure or green space was found to be an important factor. The study found that exposure to the natural environment through sunbathing and exercise is important for people’s mental health.

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Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels

Ochi R., Plitman E., Patel R., Tarumi R., Iwata Y., Tsugawa S., Kim J., Honda S., Noda Y., Uchida H., Devenyi G.A., Mimura M., Graff-Guerrero A., Chakravarty M.M., Nakajima S.

Journal of Psychiatry and Neuroscience （Journal of Psychiatry and Neuroscience）  47 （ 1 ） E1 - E10 2022年01月

査読有り,  ISSN  11804882

　概要を見る

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.

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Trends in big data analyses by multicenter collaborative translational research in psychiatry

Onitsuka T., Hirano Y., Nemoto K., Hashimoto N., Kushima I., Koshiyama D., Koeda M., Takahashi T., Noda Y., Matsumoto J., Miura K., Nakazawa T., Hikida T., Kasai K., Ozaki N., Hashimoto R.

Psychiatry and clinical neurosciences （Psychiatry and clinical neurosciences）  76 （ 1 ） 1 - 14 2022年01月

査読有り,  ISSN  1323-1316

　概要を見る

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory-based research that incorporates the latest findings, it is necessary to conduct large-sample-size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders.

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

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.

Molecular Psychiatry （Molecular Psychiatry）  27 （ 1 ） 744 - 757 2022年01月

責任著者, 査読有り,  ISSN  13594184

　概要を見る

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

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Neuromelanin accumulation in patients with schizophrenia: A systematic review and meta-analysis

Ueno F., Iwata Y., Nakajima S., Caravaggio F., Rubio J.M., Horga G., Cassidy C.M., Torres-Carmona E., de Luca V., Tsugawa S., Honda S., Moriguchi S., Noda Y., Gerretsen P., Graff-Guerrero A.

Neuroscience and Biobehavioral Reviews （Neuroscience and Biobehavioral Reviews）  132   1205 - 1213 2022年01月

査読有り,  ISSN  01497634

　概要を見る

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

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Pharmacotherapeutic combinations for the treatment of Alzheimer’s disease

Nagata T., Shinagawa S., Nakajima S., Noda Y., Mimura M.

Expert Opinion on Pharmacotherapy （Expert Opinion on Pharmacotherapy）  23 （ 6 ） 727 - 737 2022年

査読有り,  ISSN  14656566

　概要を見る

Introduction: Alzheimer’s disease (AD) is the most common form of dementia, and four medications are currently available as symptomatic therapies: three cholinesterase inhibitors (ChEI) and memantine. In June 2021, aducanumab was approved in the United States under an accelerated approval pathway as the first novel putative disease-modifying therapy (p-DMT) targeting the β-amyloid (Aβ) cascade in the brain. The combination of several monotherapies to address the multifactorial pathogenesis of neurodegenerative diseases is an anticipated next step. Areas covered: The cholinergic hypothesis and the amyloid cascade hypothesis have been proposed as explanations for the pathogenesis of AD. Given the limited effectiveness of monotherapies based on these hypotheses, approaches using combination therapy are attempting to address the complexity of AD pathogenesis, including putative causative proteins-related neurodegeneration, neurotransmitters, and neuroinflammation, in a comprehensive manner. Expert opinion: The efficacy of an initial or add-on combination approach to counteracting neurodegenerative processes and functional deterioration has been investigated. The combination of symptomatic therapies with approved anti-dementia medicines (one ChEI and memantine) has been found to be functionally effective for a moderately severe disease stage. Furthermore, combination strategies involving p-DMTs, symptomatic therapies, and neuro-regeneration may be useful in the future.

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A preliminary study on predictors of treatment response to repetitive transcranial magnetic stimulation in patients with treatment-resistant depression in Japan

Ikawa H., Tochigi M., Noda Y., Oba H., Kaminaga T., Sakurai K., Ikebuchi E., Hayashi N., Kunugi H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports）  42 （ 4 ） 478 - 484 2022年

査読有り,  ISSN  2574-173X

　概要を見る

Background: Brain imaging studies have reported that the effect of repetitive transcranial magnetic stimulation (rTMS) is associated with the activities of the dorsolateral prefrontal cortex (DLPFC) and ventral medial prefrontal cortex (VMPFC). However, few studies have been conducted in Japanese patients. Aim: We aimed to identify brain regions associated with depressive symptom changes by measuring regional cerebral blood flow (rCBF) in the DLPFC and VMPFC before and after the high-frequency rTMS to the left DLPFC in Japanese patients with treatment-resistant depression. Method: Fourteen patients participated in the rTMS study and were assessed with the 17-item Hamilton depression rating scale (HAM-D17). Among them, 13 participants underwent magnetic resonance imaging scan of the brain using the arterial spin labeling method. The rCBF was calculated using the fine stereotactic region of interest template (FineSRT) program for automated analysis. We focused on eight regions reported in previous studies. Results: Depression severity significantly decreased after 2 week (HAM-D17:11.4 ± 2.8, P = 0.00027) and 4 week (HAM-D17: 11.0 ± 3.7, P = 0.0023) of rTMS treatment. There was no significant change in rCBF at each region in the pre-post design. However, there was a significantly negative correlation between baseline rCBF in the right DLPFC and the improvement in HAM-D17 score (r = −0.559, P = 0.047). Conclusion: We obtained supportive evidence for the effectiveness of rTMS to the prefrontal cortex in treatment-resistant depression, which may be associated with reduced rCBF of the right DLPFC before initiation of rTMS.

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Gamma-aminobutyric acid (GABA) levels in the midcingulate cortex and clozapine response in patients with treatment-resistant schizophrenia: A proton magnetic resonance spectroscopy (¹H-MRS) study

Ueno F., Nakajima S., Iwata Y., Honda S., Torres-Carmona E., Mar W., Tsugawa S., Truong P., Plitman E., Noda Y., Mimura M., Sailasuta N., Mikkelsen M., Edden R.A.E., De Luca V., Remington G., Gerretsen P., Graff-Guerrero A.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  76 （ 11 ） 587 - 594 2022年

査読有り,  ISSN  13231316

　概要を見る

Background: Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment-resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1H-MRS), and clozapine response in patients with TRS. Methods: This study enrolled patients with TRS who did not respond to clozapine (ultra-resistant schizophrenia: URS) and who responded to clozapine (non-URS), patients with schizophrenia who responded to first-line antipsychotics (first-line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1H-MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. Results: A total of 98 participants (URS: n = 22; non-URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels (F(3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non-URS (F(1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. Conclusion: Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.

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CRISIS AFAR: An International Collaborative Study of the Impact of the COVID-19 Pandemic on Youth with Autism and Neurodevelopmental Conditions.

B Vibert, P Segura, L Gallagher, S Georgiades, P Pervanidou, A Thurm, ...

medRxiv 2022年

P550. GABA Alteration in Patients With Treatment-Resistant Schizophrenia: A 1H-MRS Study

F Ueno, S Nakajima, Y Iwata, S Honda, J Kim, F Caravaggio, E Brown, ...

Biological Psychiatry 91 (9), S311 2022年

P549. MRI Neuromelanin Accumulation in Patients with Treatment-Resistant Schizophrenia: A Cross-Sectional Pilot Study

F Ueno, Y Iwata, S Nakajima, S Chavez, F Caravaggio, G Horga, ...

Biological Psychiatry 91 (9), S311 2022年

P548. Glymphatic System in Schizophrenia: An H-MRS High-Molecular-Weight Macromolecules Study

A Abdolizadeh, ET Carmona, F Ueno, S Nakajima, R Tarumi, S Tsugawa, ...

Biological Psychiatry 91 (9), S310-S311 2022年

P291. Effects of Sleep on the Gut Microbiota and Metabolome in Patients With Depression and Anxiety: A Prospective Observational Study

A Tanaka, K Sanada, S Kurokawa, K Miyaho, T Tachibana, Y Noda, ...

Biological Psychiatry 91 (9), S205 2022年

Gamma‐aminobutyric acid (GABA) levels in the midcingulate cortex and clozapine response in patients with treatment‐resistant schizophrenia: A proton magnetic resonance …

F Ueno, S Nakajima, Y Iwata, S Honda, E Torres‐Carmona, W Mar, ...

Psychiatry and Clinical Neurosciences 76 (11), 587-594 2022年

Effectiveness of standard sequential bilateral repetitive transcranial magnetic stimulation vs bilateral theta burst stimulation in older adults with depression: the FOUR-D …

DM Blumberger, BH Mulsant, KE Thorpe, SM McClintock, ...

JAMA psychiatry 79 (11), 1065-1073 2022年

Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment‐resistant and ultratreatment‐resistant schizophrenia

K Kitajima, S Tamura, D Sasabayashi, S Nakajima, Y Iwata, F Ueno, ...

Psychiatry and clinical neurosciences 2022年

Cost-effectiveness analysis comparing repetitive transcranial magnetic stimulation therapy with antidepressant treatment in patients with treatment-resistant depression in Japan

Y Noda, C Miyashita, Y Komatsu, S Kito, M Mimura

medRxiv, 2022.12. 02.22282995 （Psychiatry Research）  330   115573 - 115573 2022年

査読有り,  ISSN  01651781

　概要を見る

Repetitive transcranial magnetic stimulation (rTMS) for patients with treatment-resistant depression (TRD) became covered by the National Health Insurance (NHI) in Japan since 2019. Although the evidence of rTMS for TRD is well established, the cost-effectiveness of rTMS versus antidepressants has not been thoroughly analyzed in Japan. Thus, we aimed to evaluate the cost-effectiveness of rTMS for TRD under the NHI system using a microsimulation model to compare the direct costs and quality-adjusted life years (QALYs). Model inputs of clinical parameters and the utility were derived from published literature. Cost parameters were estimated from the Japanese Claim Database. The robustness of the analyses was evaluated with sensitivity analysis and scenario analysis. The analysis estimated that rTMS increased effectiveness by 0.101QALYs and total cost by ¥94,370 ($689) compared with antidepressant medications. As a result, the incremental cost-effectiveness ratio (ICER) of rTMS was estimated to be ¥935,984 ($6,832)/QALY. In the sensitivity and scenario analyses, ICER did not exceed ¥5 million ($36,496)/QALY as the reference value of the Japanese public cost-effectiveness evaluation system. rTMS therapy for TRD can be a cost-effective treatment strategy compared to antidepressant medication under the NHI system in Japan.

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Autistic children and adolescents with frequent restricted interest and repetitive behavior showed more difficulty in social cognition during mask-wearing during the COVID-19 …

H Tamon, T Itahashi, S Yamaguchi, Y Tachibana, J Fujino, M Igarashi, ...

BMC psychiatry 22 (1), 608 2022年

Associations Between Structural Covariance Network and Antipsychotic Treatment Response in Schizophrenia

S Tsugawa, E Plitman, C Wannan, A Zalesky, Y Noda, R Tarumi, S Honda, ...

NEUROPSYCHOPHARMACOLOGY 47, 374-374 （Schizophrenia Bulletin）  50 （ 2 ） 382 - 392 2022年

査読有り,  ISSN  0586-7614

　概要を見る

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 clinicodemographics was also explored. Study Results: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and frontooccipital 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.

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Reduced Glutamatergic Cortical Facilitation Associated With Glutamate-Related Gene Expression Abnormalities in Treatment-Resistant Depression

M Wada, S Nakajima, S Honda, M Takano, K Taniguchi, Y Mimura, ...

NEUROPSYCHOPHARMACOLOGY 47 (SUPPL 1), 273-274 2022年

TMS-EEG Indices as High Potential Predictive Markers of iTBS Response in MDD

R Strafella, R Zomorrodi, J Lissemore, Y Noda, Z Daskalakis, ...

NEUROPSYCHOPHARMACOLOGY 47 (SUPPL 1), 251-251 2022年

The impact of mask-wearing influenced by restricted interest and repetitive behavior on the mental distress of individuals with autism spectrum disorder during the COVID-19 …

H Tamon, T Itahashi, S Yamaguchi, Y Tachibana, J Fujino, M Igarashi, ...

2022年

DATA-DRIVEN DISEASE PROGRESSION PATTERNS OF BRAIN MORPHOLOGY IN SCHIZOPHRENIA: A MACHINE-LEARNING APPROACH

D Sone, A Young, S Shinagawa, Y Noda, Y Iwata, R Tarumi, K Ogyu, ...

AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY 56 (1_ SUPPL), 247-247 2022年

The role of gamma oscillations in the pathophysiology of substance use disorders

Ramlakhan J.U., Ma M., Zomorrodi R., Blumberger D.M., Noda Y., Barr M.S.

Journal of Personalized Medicine （Journal of Personalized Medicine）  11 （ 1 ） 1 - 18 2021年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Substance use disorders (SUDs) are a major public health problem—with over 200 million people reporting drug use in 2016. Electroencephalography (EEG) is a powerful tool that can provide insights into the impact of SUDs on cognition. Specifically, modulated gamma activity may provide an index of the pathophysiology of SUDs. Thus, the purpose of this review was to investigate the impact of alcohol, tobacco, cannabis, cocaine, and amphetamine on gamma activity, among pre-clinical and clinical populations during acute and chronic exposure and withdrawal states. We searched multiple databases for key terms related to SUDs, EEG, and gamma and ensured rigorous methods by using a standardized review reporting tool. We included 30 studies in this review and found that all substances were associated with modulation of gamma activity, across states and in both preclinical and clinical populations. Gamma oscillations appeared to be differentially modulated in clinical versus preclinical populations and had the most complex relationship with alcohol, indicating that it may act differently than other substances. The findings of this review offer insights into the pathophysiology of SUDs, providing a potential window into novel treatments for SUDs via modulation of gamma activity.

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

Arai N., Nakanishi T., Nakajima S., Li X., Wada M., Daskalakis Z.J., Goodman M.S., Blumberger D.M., Mimura M., Noda Y.

Neuroscience and Biobehavioral Reviews （Neuroscience and Biobehavioral Reviews）  131   293 - 312 2021年12月

最終著者, 責任著者, 査読有り,  ISSN  01497634

　概要を見る

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.

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Clinical Neurophysiology, Neuroimaging, and Neuromodulation of Neuropsychiatric Disorders

Yoshihiro Noda

Journal of Personalized Medicine （MDPI AG）  11 （ 11 ） 1193 - 1193 2021年11月

筆頭著者, 最終著者, 責任著者, 査読有り

　概要を見る

The goal of this Special Issue is to introduce the cutting-edge research in clinical neurophysiology, neuroimaging, and neuromodulation. We were able to publish 11 original articles and 3 review papers that utilize the latest neuroscience approaches in the abovementioned fields. I would like to introduce these excellent works below.

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Clinical Neurophysiology, Neuroimaging, and Neuromodulation of Neuropsychiatric Disorders.

Noda Y

Journal of personalized medicine 11 （ 11 ）  2021年11月

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A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study

Blumberger D.M., Vila-Rodriguez F., Wang W., Knyahnytska Y., Butterfield M., Noda Y., Yariv S., Isserles M., Voineskos D., Ainsworth N.J., Kennedy S.H., Lam R.W., Daskalakis Z.J., Downar J.

Brain Stimulation （Brain Stimulation）  14 （ 6 ） 1447 - 1455 2021年11月

査読有り,  ISSN  1935861X

　概要を見る

Background: Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly. Objective: We compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS. Methods: 208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments. Results: HRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups. Conclusions: These results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD. Clinicaltrials.gov ID: NCT02729792 (https://clinicaltrials.gov/ct2/show/NCT02729792)

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Development of an advanced sham coil for transcranial magnetic stimulation and examination of its specifications

Takano M., Havlicek J., Phillips D., Nakajima S., Mimura M., Noda Y.

Journal of Personalized Medicine （Journal of Personalized Medicine）  11 （ 11 ） 1058 - 1058 2021年11月

最終著者, 責任著者, 査読有り,  ISSN  2075-4426

　概要を見る

Transcranial magnetic stimulation (TMS) neurophysiology has been widely applied worldwide, but it is often contaminated by confounders other than cortical stimulus-evoked activities. Although advanced sham coils that elaborately mimic active stimulation have recently been developed, their performance is not examined in detail. Developing such sham coils is crucial to improve the accuracy of TMS neurophysiology. Herein, we examined the specifications of the sham coil by comparison with the active coil. The magnetic flux and click sound pressure changes were measured when the stimulus intensity was varied from 10% to 100% maximum stimulator output (MSO), and the changes in coil surface temperature over time with continuous stimulation at 50% MSO for each coil. The magnetic flux change at the center of the coil showed a peak of 12.51 (kT/s) for the active coil, whereas it was 0.41 (kT/s) for the sham coil. Although both coils showed a linear change in magnetic flux as the stimulus intensity increased, due to the difference in coil winding structure, the sham coil took less than half the time to overheat and had 5 dB louder coil click sounds than the active coil. The sham coil showed a sufficiently small flux change at the center of the coil, but the flux change from the periphery of the coil was comparable to that of the active coil. Future use of high-quality sham coil will extend our understanding of the TMS neurophysiology of the cortex at the stimulation site.

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Association between resilience and cortical thickness in the posterior cingulate cortex and the temporal pole in Japanese older people: A population-based cross-sectional study

Shikimoto R., Noda Y., Kida H., Nakajima S., Tsugawa S., Mimura Y., Ochi R., Takayama M., Niimura H., Mimura M.

Journal of Psychiatric Research （Journal of Psychiatric Research）  142   89 - 100 2021年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00223956

　概要を見る

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

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Recent Advances and Future Directions in Brain MR Imaging Studies in Schizophrenia: Toward Elucidating Brain Pathology and Developing Clinical Tools.

Shinsuke Koike, Akiko Uematsu, Daiki Sasabayashi, Norihide Maikusa, Tsutomu Takahashi, Kazutaka Ohi, Shinichiro Nakajima, Yoshihiro Noda, Yoji Hirano

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine （Magnetic Resonance in Medical Sciences）  21 （ 4 ） 539 - 552 2021年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1347-3182

　概要を見る

Schizophrenia is a common severe psychiatric disorder that affects approximately 1% of general population through the life course. Historically, in Kraepelin’s time, schizophrenia was a disease unit conceptualized as dementia praecox; however, since then, the disease concept has changed. Recent MRI studies had shown that the neuropathology of the brain in this disorder was characterized by mild progression before and after the onset of the disease, and that the brain alterations were relatively smaller than assumed. Although genetic factors contribute to the brain alterations in schizophrenia, which are thought to be trait differences, other changes include factors that are common in psychiatric diseases. Furthermore, it has been shown that the brain differences specific to schizophrenia were relatively small compared to other changes, such as those caused by brain development, aging, and gender. In addition, compared to the disease and participant factors, machine and imaging protocol differences could affect MRI signals, which should be addressed in multi-site studies. Recent advances in MRI modalities, such as multi-shell diffusion-weighted imaging, magnetic resonance spectroscopy, and multimodal brain imaging analysis, may be candidates to sharpen the characterization of schizophrenia-specific factors and provide new insights. The Brain/MINDS Beyond Human Brain MRI (BMB-HBM) project has been launched considering the differences and noises irrespective of the disease pathologies and includes the future perspectives of MRI studies for various psychiatric and neurological disorders. The sites use restricted MRI machines and harmonized multi-modal protocols, standardized image preprocessing, and traveling subject harmonization. Data sharing to the public will be planned in FY 2024. In the future, we believe that combining a high-quality human MRI dataset with genetic data, randomized controlled trials, and MRI for non-human primates and animal models will enable us to understand schizo-phrenia, elucidate its neural bases and therapeutic targets, and provide tools for clinical application at bedside.

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

Ohi K., Ochi R., Noda Y., Wada M., Sugiyama S., Nishi A., Shioiri T., Mimura M., Nakajima S.

Translational Psychiatry （Translational Psychiatry）  11 （ 1 ） 187 - 187 2021年06月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

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.

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Photobiological neuromodulation of resting-state eeg and steady-state visual-evoked potentials by 40 hz violet light optical stimulation in healthy individuals

Noda Y., Takano M., Hayano M., Li X., Wada M., Nakajima S., Mimura M., Kondo S., Tsubota K.

Journal of Personalized Medicine （Journal of Personalized Medicine）  11 （ 6 ） 557 - 557 2021年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2075-4426

　概要を見る

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.

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Tms-eeg research to elucidate the pathophysiological neural bases in patients with schizophrenia: A systematic review

Li X., Honda S., Nakajima S., Wada M., Yoshida K., Daskalakis Z.J., Mimura M., Noda Y.

Journal of Personalized Medicine （Journal of Personalized Medicine）  11 （ 5 ）  2021年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2075-4426

　概要を見る

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 pub-lished 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.

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Neurophysiological biomarkers using transcranial magnetic stimulation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis

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.

Neuroscience and Biobehavioral Reviews （Neuroscience and Biobehavioral Reviews）  121   47 - 59 2021年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01497634

　概要を見る

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.

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Potential neurophysiological mechanisms of 1hz-tms to the right prefrontal cortex for depression: An exploratory tms-eeg study in healthy participants

Noda Y.

Journal of Personalized Medicine （Journal of Personalized Medicine）  11 （ 2 ） 1 - 13 2021年01月

研究論文（学術雑誌）, 単著, 査読有り,  ISSN  2075-4426

　概要を見る

Background: The present study aimed to examine the acute neurophysiological effects of 1Hz transcranial magnetic stimulation (TMS) administered to the right dorsolateral prefrontal cortex (DLPFC) in healthy participants. Methods: TMS combined with simultaneous electroen-cephalography (EEG) recording was conducted for 21 healthy participants. For the right DLPFC, 1Hz-TMS (100 pulses/block × 17 sessions) was applied in the resting-state, while for the left DLPFC, 1Hz-TMS (100 pulses/block × 2 sessions) was administered during the verbal fluency tasks (VFTs). For TMS-EEG data, independent component analysis (ICA) was applied to extract TMS-evoked EEG potentials to calculate TMS-related power as well as TMS-related coherence from the F4 and F3 electrode sites during the resting-state and VFTs. Results: TMS-related power was significantly increased in alpha, beta, and gamma bands by 1Hz-TMS at the stimulation site during the resting-state, while TMS-related power was significantly increased in alpha and beta bands but not in the gamma band during the VFTs. On the other hand, TMS-related coherence in alpha and beta bands significantly increased but not in gamma band by 1Hz-TMS that was administered to the right DLPFC in resting-state, whereas there were no significant changes in coherence for all frequency bands by 1Hz-TMS that applied to the left DLPFC during the VFTs. Conclusions: Collectively, 1Hz-repetitive TMS (rTMS) to the right DLPFC may rapidly neuromodulate EEG activity, which might be associated with a therapeutic mechanism for depression.

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Transcranial magnetic stimulation neurophysiology of patients with major depressive disorder: A systematic review and meta-analysis

Kinjo M., Wada M., Nakajima S., Tsugawa S., Nakahara T., Blumberger D.M., Mimura M., Noda Y.

Psychological Medicine （Psychological Medicine）  51 （ 1 ） 1 - 10 2021年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00332917

　概要を見る

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.

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Single-pulse transcranial magnetic stimulation-evoked potential amplitudes and latencies in the motor and dorsolateral prefrontal cortex among young, older healthy participants, and schizophrenia patients

Noda Y., Barr M.S., Zomorrodi R., Cash R.F.H., Lioumis P., Chen R., Daskalakis Z.J., Blumberger D.M.

Journal of Personalized Medicine （Journal of Personalized Medicine）  11 （ 1 ） 1 - 12 2021年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2075-4426

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Background: The combination of transcranial magnetic stimulation (TMS) with electroen-cephalography (EEG) allows for non-invasive investigation of cortical response and connectivity in human cortex. This study aimed to examine the amplitudes and latencies of each TMS-evoked potential (TEP) component induced by single-pulse TMS (spTMS) to the left motor (M1) and dorsolateral prefrontal cortex (DLPFC) among healthy young participants (YNG), older participants (OLD), and patients with schizophrenia (SCZ). Methods: We compared the spatiotemporal characteristics of TEPs induced by spTMS among the groups. Results: Compared to YNG, M1-spTMS induced lower amplitudes of N45 and P180 in OLD and a lower amplitude of P180 in SCZ, whereas the DLPFC-spTMS induced a lower N45 in OLD. Further, OLD demonstrated latency delays in P60 after M1-spTMS and in N45-P60 over the right central region after left DLPFC-spTMS, whereas SCZ demonstrated latency delays in N45-P60 over the midline and right central regions after DLPFC-spTMS. Conclusions: These findings suggest that inhibitory and excitatory mechanisms mediating TEPs may be altered in OLD and SCZ. The amplitude and latency changes of TEPs with spTMS may reflect underlying neurophysiological changes in OLD and SCZ, respectively. The spTMS administered to M1 and the DLPFC can probe cortical functions by examining TEPs. Thus, TMS-EEG can be used to study changes in cortical connectivity and signal propagation from healthy to pathological brains.

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Dimensional distribution of cortical abnormality across antipsychotics treatment-resistant and responsive schizophrenia

Itahashi T., Noda Y., Iwata Y., Tarumi R., Tsugawa S., Plitman E., Honda S., Caravaggio F., Kim J., Matsushita K., Gerretsen P., Uchida H., Remington G., Mimura M., Aoki Y.Y., Graff-Guerrero A., Nakajima S.

NeuroImage: Clinical （NeuroImage: Clinical）  32   102852 - 102852 2021年01月

査読有り

　概要を見る

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.

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Use of repetitive transcranial magnetic stimulation in neurodevelopment: a narrative review

Y Noda

Diagnosis, Management and Modeling of Neurodevelopmental Disorders, 429-436 2021年

研究論文（学術雑誌）, 査読有り

The Potential Impact of Age on the Gut Microbiota in Patients With Major Depressive Disorders: A Prospective Observational Study

K Miyaho, K Sanada, S Kurokawa, A Tanaka, Y Noda, S Nakajima, ...

Biological Psychiatry 89 (9), S341 （Elsevier BV）  89 （ 9 ） S341 - S341 2021年

研究論文（学術雑誌）, 査読有り,  ISSN  0006-3223

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Single-pulse transcranial magnetic stimulation-evoked potential amplitudes and latencies in the motor and dorsolateral prefrontal cortex among young, older healthy participants …

Y Noda, MS Barr, R Zomorrodi, RFH Cash, P Lioumis, R Chen, ...

Journal of personalized medicine 11 (1), 54 2021年

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

T Nakahara, S Tsugawa, Y Noda, F Ueno, S Honda, M Kinjo, H Segawa, ...

Molecular psychiatry, 1-14 2021年

Gaba Alteration in Patients With Ultra-Treatment-Resistant Schizophrenia: A 1H-MRS Study

S Nakajima, F Ueno, Y Iwata, S Honda, J Kim, F Caravaggio, E Brown, ...

NEUROPSYCHOPHARMACOLOGY 46 (SUPPL 1), 385-385 2021年

Clinical Neurophysiology, Neuroimaging, and Neuromodulation of Neuropsychiatric Disorders

Y Noda

Journal of Personalized Medicine 11 (11), 1193 2021年

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression …

DM Blumberger, F Vila-Rodriguez, W Wang, Y Knyahnytska, M Butterfield, ...

Brain Stimulation 14 (6), 1447-1455 2021年

Increased blood COASY DNA methylation levels a potential biomarker for early pathology of Alzheimer’s disease

Kobayashi N., Shinagawa S., Niimura H., Kida H., Nagata T., Tagai K., Shimada K., Oka N., Shikimoto R., Noda Y., Nakajima S., Mimura M., Shigeta M., Kondo K.

Scientific Reports （Scientific Reports）  10 （ 1 ） 12217 - 12217 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Early diagnosis of dementia including Alzheimer’s disease (AD) is an urgent medical and welfare issue. However, to date, no simple biometrics have been available. We reported that blood DNA methylation levels of the COASY gene, which encodes coenzyme A synthase, were increased in individuals with AD and amnestic mild cognitive impairment (aMCI). The present study sought to replicate these findings with larger numbers of samples. Another objective was to clarify whether COASY methylation is associated with neurodegeneration through a comparison of AD, AD with cardiovascular disease (CVD), and vascular dementia (VaD). We measured blood COASY methylation levels in normal controls (NCs) (n = 200), and individuals with aMCI (n = 22), AD (n = 151), and VaD (n = 21). Compared with NCs, they were significantly higher in individuals with aMCI and AD. Further, they were significantly higher in AD patients without cardiovascular diseases compared to AD patients with them. These findings suggest that COASY methylation levels may be related to neurodegeneration in AD.

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Resting-state isolated effective connectivity of the cingulate cortex as a neurophysiological biomarker in patients with severe treatment-resistant schizophrenia

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.

Journal of Personalized Medicine （Journal of Personalized Medicine）  10 （ 3 ） 1 - 12 2020年09月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

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.

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White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study

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., Graff-Guerrero A., Uchida H., Mimura M., Nakajima S.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  100   109871 - 109871 2020年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02785846

　概要を見る

© 2020 Elsevier Inc. 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.

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Neural correlates of delay discount alterations in addiction and psychiatric disorders: A systematic review of magnetic resonance imaging studies

Noda Y., Barr M., ElSalhy M., Masuda F., Tarumi R., Ogyu K., Wada M., Tsugawa S., Miyazaki T., Nakajima S., Mimura M.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  99   109822 - 109822 2020年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02785846

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© 2019 Elsevier Inc. 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.

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Pharmacological management of behavioral disturbances in patients with Alzheimer's disease.

Nagata T, Shinagawa S, Nakajima S, Noda Y, Mimura M

Expert opinion on pharmacotherapy （Expert Opinion on Pharmacotherapy）  21 （ 9 ） 1 - 10 2020年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1465-6566

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© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.

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Gut microbiota and majore depressive disorder: A systematic review and meta-analysis

Sanada K., Nakajima S., Kurokawa S., Barceló-Soler A., Ikuse D., Hirata A., Yoshizawa A., Tomizawa Y., Salas-Valero M., Noda Y., Mimura M., Iwanami A., Kishimoto T.

Journal of Affective Disorders （Journal of Affective Disorders）  266   1 - 13 2020年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01650327

　概要を見る

© 2020 Elsevier B.V. Background: Growing attention has been paid to the field of gut microbiota for mental disorders over the last decade. However, to our knowledge, no studies have conducted systematic reviews on the association between gut microbiota and major depressive disorder (MDD) in both interventional and non-interventional studies. Methods: We conducted a systematic review and meta-analysis of 16 studies (10 observational [701 participants] and six interventional trials [302 participants]) examining gut microbiota in patients with MDD. The primary outcome measures were differences in the profile of microbiota inthe observational studies, and symptom changes for depression between pre- and post-intervention with probiotics in the interventional trials. Results: In the observational studies, significant reductions in several taxa at the family and genus levels were observed in patients with MDD compared to non-depressed controls. In the interventional studies with probiotics, a significant improvement was found in depressive symptomatology compared to controls (SMD = .-1.62, 95% CI = .-2.73 to -0.51, p< 0.01). Limitations: Lack of consideration of the effects of diet and pharmacotherapy was a possible limitation. Conclusions: Our results indicate that several taxa at the family and genus levels, specifically family Prevotellaceae, genus Coprococcus,and Faecalibacterium, were decreased in MDD compared to non-depressed controls in observational studies, and depressive symptoms were improved compared to controls in interventional studies with probiotics. Due to the limited number of studies, further studies considering diet and pharmacotherapy are needed to explore the relationships between gut microbiota and MDD in humans.

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Early Improvements of Individual Symptoms With Antipsychotics Predict Subsequent Treatment Response of Neuropsychiatric Symptoms in Alzheimer's Disease: A Re-Analysis of the CATIE-AD Study.

Nagata T, Shinagawa S, Yoshida K, Noda Y, Shigeta M, Mimura M, Nakajima S

The Journal of clinical psychiatry （The Journal of clinical psychiatry）  81 （ 2 ）  2020年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0160-6689

　概要を見る

© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: The aim of the present study was to identify individual symptoms whose early improvements contributed to subsequent treatment response to antipsychotics for neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD) using the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD). METHODS: The CATIE-AD study was conducted between April 2001 and November 2004 at 45 sites in the United States. Data for 421 patients with DSM-IV AD with NPSs treated with antipsychotics were analyzed in the present study. Treatment response was defined as a reduction of ≥ 9 points in the Neuropsychiatric Inventory (NPI) score or a reduction of ≥ 25% from baseline in Brief Psychiatric Rating Scale (BPRS) total score at week 8. Logistic regression analyses were performed to examine associations between response and clinical and demographic characteristics, including each total or individual symptom score reduction at week 2. RESULTS: Reduction in NPI or BPRS total score at week 2 and several individual symptom score reductions (euphoria/elation, irritability, hallucinations, anxiety, agitation, apathy, disinhibition, and depression among NPI subitems; excitement, suspiciousness, disorientation, hostility, depressive mood, and emotional withdrawal among BPRS subitems) at week 2 were significantly associated with subsequent treatment response at week 8 (all P values < .05); Early non-improvements of irritability and suspiciousness were shown to be especially influential clinical markers in predicting subsequent treatment nonresponse. Furthermore, healthier condition at baseline was significantly associated with treatment response at week 8 (P < .05). CONCLUSIONS: Although further research to validate these preliminary findings is needed, focusing on early improvements of individual symptoms could help identify subsequent treatment responders to antipsychotics in AD patients with NPSs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00015548.

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Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation-evoked potentials: A systematic review

Noda Y.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  74 （ 1 ） 12 - 34 2020年01月

研究論文（学術雑誌）, 単著, 査読有り,  ISSN  13231316

　概要を見る

© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology Transcranial magnetic stimulation (TMS) can depolarize the neurons directly under the coil when applied to the cerebral cortex, and modulate the neural circuit associated with the stimulation site, which makes it possible to measure the neurophysiological index to evaluate excitability and inhibitory functions. Concurrent TMS and electroencephalography (TMS-EEG) has been developed to assess the neurophysiological characteristics of cortical regions other than the motor cortical region noninvasively. The aim of this review is to comprehensively discuss TMS-EEG research in the healthy brain focused on excitability, inhibition, and plasticity following neuromodulatory TMS paradigms from a neurophysiological perspective. A search was conducted in PubMed to identify articles that examined humans and that were written in English and published by September 2018. The search terms were as follows: (TMS OR ‘transcranial magnetic stimulation’) AND (EEG OR electroencephalog*) NOT (rTMS OR ‘repetitive transcranial magnetic stimulation’ OR TBS OR ‘theta burst stimulation’) AND (healthy). The study presents an overview of TMS-EEG methodology and neurophysiological indices and reviews previous findings from TMS-EEG in healthy individuals. Furthermore, this review discusses the potential application of TMS-EEG neurophysiology in the clinical setting to study healthy and diseased brain conditions in the future. Combined TMS-EEG is a powerful tool to probe and map neural circuits in the human brain noninvasively and represents a promising approach for determining the underlying pathophysiology of neuropsychiatric disorders.

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Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia

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.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports）  40 （ 2 ） 138 - 149 2020年

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology 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 R2:.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.

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Approach-oriented coping strategy level may be related to volume of the whole hippocampus in the elderly

Kida H., Nakajima S., Shikimoto R., Ochi R., Noda Y., Tsugawa S., Fujii S., Takayama M., Mimura M., Niimura H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  74 （ 4 ） 270 - 276 2020年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13231316

　概要を見る

© 2020 The Authors. Psychiatry and Clinical Neurosciences © 2020 Japanese Society of Psychiatry and Neurology Aim: Stress-related disorders and severe stress exposure can cause atrophy of the whole hippocampus and its subfields. However, the impact of stress coping strategies on the hippocampus remains unclear. Therefore, we aimed to examine the relation between approach- and avoidance-oriented coping strategies and hippocampal volume in elderly persons. Methods: A total of 1045 elderly persons living in Arakawa-ward, Tokyo (mean ± SD age: 72.8 ± 5.2 years; 569 females [54.4%]) were included in the study and completed several questionnaires and face-to-face interviews and underwent magnetic resonance imaging. Approach- or avoidance-oriented coping strategies were assessed with the Stress and Coping Inventory, while cognitive function and depressive symptoms were assessed with the Mini-Mental State Examination and Geriatric Depression Scale, respectively. The volume of the whole hippocampus on T1-weighted images was delineated and calculated using FreeSurfer 6.0. Multiple regression analyses were performed to examine the relation between Stress and Coping Inventory scores and whole hippocampal volume. Results: Approach-oriented coping strategy scores were positively correlated with whole hippocampal volume. Furthermore, these relations remained significant after controlling for the influence of cognitive function and depressive symptoms on these volumetric variables. In contrast, avoidance-oriented coping strategy scores were not correlated with whole hippocampal volume. Conclusion: This study demonstrated that hippocampal volume may be associated with the approach-oriented coping strategy; therefore, this strategy may preserve hippocampal volume in the elderly.

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Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation‐evoked potentials: A systematic review

Y Noda

Psychiatry and clinical neurosciences 74 (1), 12-34 2020年

研究論文（学術雑誌）, 査読有り

Treatment-emergent mania with psychosis in bipolar depression with left intermittent theta-burst rTMS

TS Kaster, Y Knyahnytska, Y Noda, J Downar, ZJ Daskalakis, ...

Brain Stimulation: Basic, Translational, and Clinical Research in … 2020年

研究論文（学術雑誌）, 査読有り

Early Improvements of Individual Symptoms With Antipsychotics Predict Subsequent Treatment Response of Neuropsychiatric Symptoms in Alzheimer's Disease: A Re-Analysis of the …

T Nagata, S Shinagawa, K Yoshida, Y Noda, M Shigeta, M Mimura, ...

The Journal of clinical psychiatry 81 (2) 2020年

研究論文（学術雑誌）, 査読有り

Approach‐oriented coping strategy level may be related to volume of the whole hippocampus in the elderly

H Kida, S Nakajima, R Shikimoto, R Ochi, Y Noda, S Tsugawa, S Fujii, ...

Psychiatry and clinical neurosciences 74 (4), 270-276 2020年

研究論文（学術雑誌）, 査読有り

Vagally Mediated Heart Rate Variability Is Associated With Executive Function Changes in Patients With Treatment‐Resistant Depression Following Magnetic Seizure Therapy

Y Noda, Y Knyahnytska, R Zomorrodi, J Downar, TK Rajji, ZJ Daskalakis, ...

Neuromodulation: Technology at the Neural Interface 2020年

研究論文（学術雑誌）, 査読有り

Vagally Mediated Heart Rate Variability Is Associated With Executive Function Changes in Patients With Treatment-Resistant Depression Following Magnetic Seizure Therapy

Noda Y., Knyahnytska Y., Zomorrodi R., Downar J., Rajji T.K., Daskalakis Z.J., Blumberger D.M.

Neuromodulation （Neuromodulation）  25 （ 8 ） 1378 - 1386 2020年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  10947159

　概要を見る

Objectives: Magnetic seizure therapy (MST) is a novel investigational brain stimulation modality for patients with treatment-resistant depression (TRD). MST is a potential alternative seizure-based treatment to electroconvulsive therapy (ECT), given that it may offer equivalent antidepressant efficacy, yet with a relative sparing of cognitive functioning. Heart rate variability (HRV) is a marker of central autonomic functioning. We aimed to explore the relationships among baseline HRV, age, clinical outcome, and executive function following MST, in patients with TRD. Materials and Methods: Eighty-eight TRD patients (55 females; 18–70 years) were enrolled and 48 patients completed a course of MST in an open-label study. Patients received MST treatments two to three times per week, using one of three stimulation frequencies (i.e., 100 Hz, 50 Hz, or 25 Hz) at 100% stimulator output. Root mean square of the successive R-R differences (RMSSD), an index of HRV, was computed from a baseline electrocardiogram (ECG) recording. Clinical symptoms were assessed using the Hamilton Depression Rating Scale (HAM-D24) and the Quick Inventory of Depressive Symptomatology (QIDS16). Executive function was assessed using the Trail Making Test and the Mazes Test from the MATRICS battery. Results: Baseline RMSSD was correlated with baseline HAM-D24 (r = −0.340, p = 0.001) and baseline Mazes Test (r = 0.417, p = 0.0007) but not with baseline Trail Making Test. Furthermore, baseline RMSSD was not correlated with changes on the HAM-D24, QIDS16, or total scores on the Trail Making Test. However, there was a significant correlation between baseline RMSSD and improvement on the Mazes Test following MST (r = 0.502, p = 0.0004). Conclusions: Since this is an open-label trial, the influence of the placebo effect cannot be excluded. However, our results suggest that baseline RMSSD may be a state-biomarker of depression and executive function impairment. Additionally, while baseline vagally mediated resting cardiac activity did not predict the outcome of depression, it may mediate executive function improvements following MST.

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Using Non-Negative Matrix Factorization to Examine Treatment Resistance and Response in Patients With Schizophrenia: A Multimodal Imaging Study

E Plitman, R Ochi, R Patel, S Tsugawa, R Tarumi, S Honda, K Matsushita, ...

Biological Psychiatry 87 (9), S350 （Elsevier {BV}）  87 （ 9 ）  2020年

研究論文（学術雑誌）, 査読有り,  ISSN  0006-3223

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

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.

Schizophrenia Research （Schizophrenia Research）  243   268 - 275 2020年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09209964

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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.

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S13-3 Clinical neurophysiology with various TMS paradigms

Y Noda

Clinical Neurophysiology 131 (10), e251 2020年

研究論文（学術雑誌）, 査読有り

S12-1 Basics of TMS and its clinical application in neuroscience

Y Noda

Clinical Neurophysiology 131 (10), e250 2020年

研究論文（学術雑誌）, 査読有り

Neurodevelopmental Disorders Induced by Maternal Immune Activation: Toward a Prevention Strategy in the Era of the COVID-19 Pandemic

K Sakurada, Y Noda

Psychiatry International 1 (1), 24-26 （MDPI AG）  1 （ 1 ） 24 - 26 2020年

研究論文（学術雑誌）, 査読有り

　概要を見る

As of summer 2020, the COVID-19 pandemic is having a major impact on our daily lives on a global scale, forcing us to change to the new normal. However, the effects are not only detrimental to our present socioeconomic conditions but also have the risk of having negative biological effects on our descendants. Of concern is the effect of maternal immune activation following maternal infection with COVID-19 on the fetus’ cerebral nervous system. While we are currently occupied with countering the imminent threats in front of us, we also need to take steps from a public health perspective to reduce the impact of maternal infection on the fetus, especially the risk of neurodevelopmental disorders. However, such a risk can be prevented and managed through the digital transformation of the nation’s health data and the strategic application of sophisticated data science approaches to those big data.

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Frontostriatal Structural Connectivity and Striatal Glutamatergic Levels in Treatment-Resistant Schizophrenia: An Integrative Analysis of DTI and 1H-MRS

R Ochi, R Tarumi, Y Noda, S Tsugawa, E Plitman, M Wada, S Honda, ...

Schizophrenia Bulletin Open 1 (1), sgaa057 （Oxford University Press (OUP)）  1 （ 1 ）  2020年

研究論文（学術雑誌）, 査読有り

　概要を見る

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

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T212. LEVELS OF GLUTAMATERGIC NEUROMETABOLITES IN PATIENTS WITH SEVERE TREATMENT-RESISTANT SCHIZOPHRENIA: A PROTON MAGNETIC RESONANCE SPECTROSCOPY STUDY

R Tarumi, S Tsugawa, Y Noda, E Plitman, S Honda, K Matshusita, ...

Schizophrenia Bulletin 46 (Suppl 1), S313 2020年

M23. ALTERATION OF REGIONAL CEREBRAL BLOOD FLOW MEASURED BY ARTERIAL SPIN LABELING IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA

K Ogyu, S Honda, K Matsushita, Y Noda, H Kato, K Kusudo, J Kim, ...

Schizophrenia Bulletin 46 (Supplement_1), S142-S142 2020年

Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review

Masuda F., Nakajima S., Miyazaki T., Yoshida K., Tsugawa S., Wada M., Ogyu K., Croarkin P., Blumberger D., Daskalakis Z., Mimura M., Noda Y.

Translational Psychiatry （Translational Psychiatry）  9 （ 1 ） 110 - 110 2019年12月

研究論文（学術雑誌）, 共著, 査読有り

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© 2019, The Author(s). 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.

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Clinical effectiveness of repetitive transcranial magnetic stimulation treatment in children and adolescents with neurodevelopmental disorders: A systematic review

Masuda F., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Croarkin P., Mimura M., Noda Y.

Autism （Autism）  23 （ 7 ） 1614 - 1629 2019年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13623613

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© The Author(s) 2019. 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.

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Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis

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.

Journal of Psychopharmacology （Journal of Psychopharmacology）  33 （ 10 ） 1199 - 1214 2019年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02698811

　概要を見る

© The Author(s) 2019. 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.

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The P300 event-related potential in bipolar disorder: A systematic review and meta-analysis

Wada M., Kurose S., Miyazaki T., Nakajima S., Masuda F., Mimura Y., Nishida H., Ogyu K., Tsugawa S., Mashima Y., Plitman E., Chakravarty M., Mimura M., Noda Y.

Journal of Affective Disorders （Journal of Affective Disorders）  256   234 - 249 2019年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01650327

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© 2019 Background: Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD. Method: A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices. Result: Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices. Limitation: The difference in medication use was difficult to control and it may affect the results. Conclusion: This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness.

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Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies

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., Blumberger D., Daskalakis Z., Mimura M., Nakajima S.

Molecular Psychiatry （Molecular Psychiatry）  24 （ 7 ） 952 - 964 2019年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13594184

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© 2018, The Author(s). 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.

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Can we predict amyloid deposition by objective cognition and regional cerebral blood flow in patients with subjective cognitive decline?

Funaki K., Nakajima S., Noda Y., Wake T., Ito D., Yamagata B., Yoshizaki T., Kameyama M., Nakahara T., Murakami K., Jinzaki M., Mimura M., Tabuchi H.

Psychogeriatrics （Psychogeriatrics）  19 （ 4 ） 325 - 332 2019年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13463500

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© 2019 Japanese Psychogeriatric Society Background: Subjective cognitive decline (SCD) may herald the first symptoms of Alzheimer's disease (AD) whereas individuals with beta-amyloid (Aβ) deposition are regarded as a high-risk group for AD. Recently, amyloid positron emission tomography (PET) studies have demonstrated clinical and cognitive feature differences between Aβ-positive and negative SCD, but details of their differences remain unclear. We aimed to investigate the relationships among Aβ deposition, clinical, and cognitive features in patients with SCD. Methods: Forty-two patients with SCD (22 women, 74.5 ± 4.7 years) were examined using fluorine-18 florbetaben PET and were divided into Aβ-positive (n = 10) and negative (n = 32) groups. We compared cognitive and psychological outcomes, and single photon emission computed tomography (SPECT) imaging data between the two groups. In addition, a linear regression analysis was performed to assess relationships between the severity of SCD and neuropsychological tests, affective scores, and demographic factors. Results: The rate of score changes from the immediate recall to delayed recall in the logical memory subtest of the Wechsler's Memory Scale Revised were different between the groups (P = 0.04). However, the binary logistic regression analysis showed no significant differences between the two. In addition, the severity of SCD was significantly strong in women (P = 0.002). Furthermore, within the Aβ-negative group, subjective memory loss correlated with word fluency category score (P = 0.023) and apathy scale (P = 0.037). Conclusions: No significant differences were observed between Aβ-positive and -negative SCD on any of the neuropsychological measures, clinical measures, or SPECT imaging. Further, the severity of SCD was not predicted by the symptoms of anxiety, depression, or neuropsychological examination.

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Neuroimaging correlates of narcolepsy with cataplexy: A systematic review

Wada M., Mimura M., Noda Y., Takasu S., Plitman E., Honda M., Natsubori A., Ogyu K., Tarumi R., Graff-Guerrero A., Nakajima S.

Neuroscience Research （Neuroscience Research）  142   16 - 29 2019年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01680102

　概要を見る

© 2018 Elsevier B.V. and Japan Neuroscience Society 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.

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Trajectories of response to dorsolateral prefrontal rTMS in major depression: A three-D study

Kaster T., Downar J., Vila-Rodriguez F., Thorpe K., Feffer K., Noda Y., Giacobbe P., Knyahnytska Y., Kennedy S., Lam R., Daskalakis Z., Blumberger D.

American Journal of Psychiatry （American Journal of Psychiatry）  176 （ 5 ） 367 - 375 2019年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0002953X

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© 2019 American Psychiatric Association. All rights reserved. Objective: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. Methods: This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score $18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4–6 weeks (20–30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. Results: Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology–Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. Conclusions: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.

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Subiculum volumes associated with memory function in the oldest-old individuals aged 95 years and older

Eguchi Y., Noda Y., Nakajima S., Tsugawa S., Kida H., Plitman E., Graff-Guerrero A., Chakravarty M., Takayama M., Arai Y., Matsuda H., Mimura M., Niimura H.

Geriatrics and Gerontology International （Geriatrics and Gerontology International）  19 （ 4 ） 347 - 351 2019年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14441586

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© 2019 Japan Geriatrics Society Aim: Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods: A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results: There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F 1, 8 = 8.67, adjusted R 2 = 0.46). Conclusions: The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347–351.

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Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer's disease: A systematic review

Iimori T., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Masuda F., Daskalakis Z., Blumberger D., Mimura M., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  88   31 - 40 2019年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02785846

　概要を見る

© 2018 Elsevier Inc. 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.

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Glutamatergic Neurometabolite Levels in Patients With Severe Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

S Nakajima, S Tsugawa, Y Noda, E Plitman, S Honda, K Matsushita, ...

NEUROPSYCHOPHARMACOLOGY 44 (SUPPL 1), 471-472 2019年

研究論文（学術雑誌）, 査読有り

Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study

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., Uchida H., Remington G., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology （Neuropsychopharmacology）  45 （ 4 ） 632 - 640 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0893133X

　概要を見る

© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. 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.

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relationships between internet addiction and clinicodemographic and behavioral factors

M ElSalhy, T Miyazaki, Y Noda, S Nakajima, H Nakayama, S Mihara, ...

Neuropsychiatric disease and treatment 15, 739 2019年

研究論文（学術雑誌）, 査読有り

GSH_meta_supplementary_table_20190320–Supplemental material for Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic …

S Tsugawa, Y Noda, R Tarumi, Y Mimura, K Yoshida, Y Iwata, M Elsalhy, ...

(No Title) 2019年

Enhanced theta-gamma coupling associated with hippocampal volume increase following high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with major depression

Noda Y., Zomorrodi R., Daskalakis Z., Blumberger D., Nakamura M.

International Journal of Psychophysiology （International Journal of Psychophysiology）  133   169 - 174 2018年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01678760

　概要を見る

© 2018 Elsevier B.V. The underlying mechanism of repetitive transcranial magnetic stimulation (rTMS) effects on cognition has not been fully examined. Previously, we have reported the left hippocampal volume increase and theta-gamma coupling (TGC) enhancement associated with working memory improvement following rTMS in depression. This study was aimed to examine whether there is a structure-function relationship in hippocampal neuroplasticity induced by prefrontal rTMS. Thirty-one patients with major depression underwent longitudinal MRI scans and resting-state EEG recordings with the 10–20 system using averaged ear-lobes reference, following 10 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex. Pearson's correlation analyses were applied for the longitudinal changes among the left and right hippocampal volumes as measured by manual volumetry, theta and gamma spectral powers, and TGC as measured by resting-state EEG. The analyses demonstrated that the left hippocampus volume increases correlated with TGC increases at the left central area (r = 0.576, p = 0.001, N = 31), whereas no significant correlations were observed among changes of right hippocampal volume, right central TGC, bilateral gamma or theta powers. These finding suggests structure-function relationship in rTMS-induced neuroplastic changes mediated through the hippocampus and prefrontal network at the stimulated side. Therefore, high-frequency prefrontal rTMS may exert its cognitive effect through the hippocampal structural-functional neuroplasticity.

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Efficacy, tolerability, and cognitive effects of deep transcranial magnetic stimulation for late-life depression: a prospective randomized controlled trial

Kaster T., Daskalakis Z., Noda Y., Knyahnytska Y., Downar J., Rajji T., Levkovitz Y., Zangen A., Butters M., Mulsant B., Blumberger D.

Neuropsychopharmacology （Neuropsychopharmacology）  43 （ 11 ） 2231 - 2238 2018年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0893133X

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© 2018, American College of Neuropsychopharmacology. Late-life depression (LLD) is a growing worldwide problem due to demographic changes, with limited treatment options due to high rates of pharmacotherapy adverse effects, accessibility of psychotherapy, and tolerability of electroconvulsive therapy. Novel neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), may overcome these limitations. The objective of this study is to determine the efficacy, tolerability, and cognitive effects of high-dose deep rTMS in LLD. In this study we randomized older adults between 60 and 85 years old with major depressive disorder (MDD) to sham or active deep rTMS (H1 coil, 6012 pulses, 18 Hz, 120% of resting motor threshold) delivered over the dorsolateral and ventrolateral prefrontal cortex 5 days per week over 4 weeks. Our primary outcome was remission of depression in an intention-to-treat analysis. We also assessed change in cognitive functioning with rTMS treatment and tolerability based on adverse effects. Fifty-two participants were randomized to active (n = 25) or sham H1 coil (n = 27). Remission rate was significantly higher with active than sham rTMS (40.0% vs 14.8%) with a number needed to treat of 4.0 (95% CI: 2.1–56.5). There was no change on any measure of executive function and no serious adverse events. Adverse effect profiles were similar between active and sham rTMS, except for reports of pain being significantly more common in the active condition (16.0% vs 0%). High-dose deep rTMS appears to be safe, well tolerated, and efficacious in the treatment of LLD.

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Assessment of neuroplasticity in late-life depression with transcranial magnetic stimulation

Bhandari A., Lissemore J., Rajji T., Mulsant B., Cash R., Noda Y., Zomorrodi R., Karp J., Lenze E., Reynolds C., Daskalakis Z., Blumberger D.

Journal of Psychiatric Research （Journal of Psychiatric Research）  105   63 - 70 2018年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00223956

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© 2018 Background: Studies using Transcranial Magnetic Stimulation (TMS), a non-invasive method of brain stimulation, have implicated impaired neuroplasticity in the pathophysiology of depression in younger adults. The role of neuroplasticity in late-life depression (LLD) has not yet been explored using TMS. Objective: This study aimed at evaluating motor cortical neuroplasticity using paired associative stimulation (PAS). Single-pulse TMS was used to induce motor-evoked potentials (MEP) in the contralateral hand muscle before and after PAS. The potentiation of MEP amplitudes after PAS was used as an indirect index of associative plasticity and long-term potentiation (LTP) (i.e. PAS-LTP). Results: 48 older adults with depression and 34 age-matched healthy controls (HC) were compared. PAS- LTP was successfully induced in 68.8% of older adults with depression and 47.1% of HC. At the group level, older adults with depression failed to show statistically significant induction of neuroplasticity, which was observed in HC. However, no significant differences were observed between the two groups for PAS-LTP. Conclusion: Our results suggest that associative plasticity does not differ substantially between older adults with depression and age-matched HC. Continued research is needed to more comprehensively understand the role of neuroplasticity in the pathophysiology of LLD.

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Characteristics of ictal EEG in Magnetic Seizure Therapy at various stimulation frequencies

Backhouse F., Noda Y., Knyahnytska Y., Farzan F., Downar J., Rajji T., Mulsant B., Daskalakis Z., Blumberger D.

Clinical Neurophysiology （Clinical Neurophysiology）  129 （ 8 ） 1770 - 1779 2018年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13882457

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© 2018 International Federation of Clinical Neurophysiology Objectives: The first objective of this study aimed to elucidate the relationship between seizure characteristics and Magnetic Seizure Therapy (MST) treatment outcome. The second objective was to determine the effect of stimulation frequency on seizure characteristics. Methods: Using a between-subjects design, we compared the seizures of patients with unipolar depression receiving MST at three separate stimulation frequencies: 25 Hz (n = 34), 50 Hz (n = 16) and 100 Hz (n = 11). Seizures were rated for overall seizure adequacy on a scale of 0–6, with one point given for each measure that was considered to be adequate according to the ECT literature: (1) seizure EEG duration (2) motor duration, (3) post-ictal suppression, (4) ictal EEG maximum amplitude, (5) Global Seizure Strength, and (6) Symmetry. Mixed-effect models were used to evaluate the effect of frequency on seizure characteristics and the relationships between seizure characteristics and clinical outcome. Results: (1) 100 Hz induced seizures that were less adequate than seizures induced with 50 Hz and 25 Hz stimulations. Seizures induced by 50 Hz stimulations had longer slow-wave phase durations and total EEG durations than the 100 Hz and 25 Hz groups. Global seizure strength was less robust in seizures induced by 100 Hz MST compared to the other stimulation frequencies. (2) Shorter polyspike durations and smaller slow-wave amplitude predicted reductions in overall symptoms of depression as measured by the 24-item Hamilton Depression Scale. Conclusion: Analysis of our first objective revealed stimulation frequency significantly influences measures of overall seizure adequacy. However, our results also revealed these descriptions of seizure adequacy based on ECT literature may not be useful for MST-induced seizures, as the characteristics of MST-induced seizure characteristics may predict clinical response in a different manner. Significance: These results may help to distinguish the biological processes impacted by stimulation frequency and may suggest different mechanisms of action between convulsive therapies and challenge the current understanding of seizure adequacy for MST.

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Kynurenine pathway in depression: A systematic review and meta-analysis

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.

Neuroscience and Biobehavioral Reviews （Neuroscience and Biobehavioral Reviews）  90   16 - 25 2018年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01497634

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© 2018 Elsevier Ltd 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.

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Relationships between socio-clinico-demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest Old Survey on Total Health (TOOTH)

Eguchi Y., Tasato K., Nakajima S., Noda Y., Tsugawa S., Shinagawa S., Niimura H., Hirose N., Arai Y., Mimura M.

International Journal of Geriatric Psychiatry （International Journal of Geriatric Psychiatry）  33 （ 7 ） 926 - 933 2018年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  08856230

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Copyright © 2018 John Wiley & Sons, Ltd. Background: Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. Objectives: The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. Methods: We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. Results: At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. Conclusions: The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.

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Impaired neuroplasticity in the prefrontal cortex in depression indexed through paired associative stimulation

Noda Y., Zomorrodi R., Vila-Rodriguez F., Downar J., Farzan F., Cash R., Rajji T., Daskalakis Z., Blumberger D.

Depression and Anxiety （Depression and Anxiety）  35 （ 5 ） 448 - 456 2018年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  10914269

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© 2018 Wiley Periodicals, Inc. Background: Dysfunctional neuroplasticity may be one of the pathophysiological mechanisms underlying major depression. We have previously established methods to assess neuroplasticity from the dorsolateral prefrontal cortex (DLPFC) using a paired associative stimulation (PAS) paradigm, which pairs a preceding peripheral nerve stimulation with subsequent transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). We aimed to investigate neuroplasticity through the PAS paradigm in the DLPFC in patients with depression compared to healthy subjects. Methods: Twenty-nine patients with depression and 28 healthy controls participated in this study. There were no significant age or sex differences between the two groups. All participants received PAS paradigm in the DLPFC. We analyzed PAS induced potentiation from the DLPFC in both groups calculating the power of TMS-evoked potentials (TEP). A two-way ANOVA with PAS effect as a within-subject factor and diagnostic group as a between-subject factor was performed to examine the group differences in the PAS paradigm. Results: DLPFC-PAS induced a significant potentiation at the stimulation site in both patients and healthy subjects (mean ± SD: 1.24 ± 0.33 [μV] vs. 1.48 ± 0.28 [μV]). However, when we compared PAS potentiation between patients and healthy subjects, there were significant main effects of PAS (F1,53= 68.63, p < 0.0001) and PAS-by-diagnostic group interaction (F1,53= 25.05, p < 0.0001). Post hoc analysis demonstrated that patients had a significantly lower PAS potentiation compared to healthy subjects (t55= 3.128, p = 0.003). Conclustions: Our findings provide evidence for impaired neuroplasticity in DLPFC in patients with depression compared to healthy subjects. Such findings may ultimately help us understand the pathophysiology of MDD and mechanisms involved in its treatment.

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Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial

Blumberger D., Vila-Rodriguez F., Thorpe K., Feffer K., Noda Y., Giacobbe P., Knyahnytska Y., Kennedy S., Lam R., Daskalakis Z., Downar J.

The Lancet （The Lancet）  391 （ 10131 ） 1683 - 1692 2018年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01406736

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© 2018 Elsevier Ltd Background: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. Methods: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Findings: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·01, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). Interpretation: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Funding: Canadian Institutes of Health Research.

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Reduced Short-Latency Afferent Inhibition in Prefrontal but not Motor Cortex and Its Association with Executive Function in Schizophrenia: A Combined TMS-EEG Study

Noda Y., Barr M., Zomorrodi R., Cash R., Rajji T., Farzan F., Chen R., George T., Daskalakis Z., Blumberger D.

Schizophrenia Bulletin （Schizophrenia Bulletin）  44 （ 1 ） 193 - 202 2018年01月

研究論文（学術雑誌）, 査読有り,  ISSN  05867614

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© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. Background: Cholinergic dysfunction is increasingly assumed to be involved in the pathophysiology of schizophrenia. Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been shown to assay central cholinergic activity from the motor cortex (M1). Recently, we established a method to index SAI from the dorsolateral prefrontal cortex (DLPFC), an area implicated in the pathophysiology of schizophrenia. We investigated SAI in M1 and DLPFC in schizophrenia. We hypothesized that modulation of N100 on TMS-evoked potentials (TEPs) from the DLPFC would be attenuated in patients with schizophrenia compared to healthy controls. Methods: SAI was examined in 12 patients, whose age was matched to controls, using TMS combined with electroencephalography (EEG). SAI was recorded with TMS applied to left M1 (M1-SAI) and DLPFC (DLPFC-SAI). For group comparison, we used the SAI data of healthy participants in our previous study. Results: In patients, N100 TEP was significantly attenuated with DLPFC-SAI, whereas P180 TEP was significantly increased with M1-SAI. Between patients and controls, there were significant differences in modulation of P180 TEP by M1-SAI (t 22 = ' '2.748, P =.012; patients > controls) and N100 TEP by DLPFC-SAI (t 22 = 5.456, P <.0001; patients < controls). Further, modulation of N100 TEP by DLPFC-SAI significantly correlated with executive function (r = ' '.740, P =.006, N = 12). Conclusion: Our findings suggest that DLPFC-SAI but not M1-SAI were reduced in patients with schizophrenia and this was linked to deficits in cognition. This may reflect prefrontal cholinergic deficits and represent a biomarker for cholinergic and executive dysfunction in patients with schizophrenia.

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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

Wada M., Noda Y., Shinagawa S., Chung J., Sawada K., Ogyu K., Tarumi R., Tsugawa S., Miyazaki T., Yamagata B., Graff-Guerrero A., Mimura M., Nakajima S.

Journal of Alzheimer's Disease （Journal of Alzheimer's Disease）  63 （ 2 ） 861 - 869 2018年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13872877

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© 2018 - IOS Press and the authors. All rights reserved. Background: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. Objective: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. Methods: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n=825), brain metabolism (n=1,304), and brain volumes (n=1,606) among three groups using data for 18 F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. Results: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. Conclusions: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

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Relationships between socio‐clinico‐demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest …

Y Eguchi, K Tasato, S Nakajima, Y Noda, S Tsugawa, S Shinagawa, ...

International journal of geriatric psychiatry 33 (7), 926-933 2018年

研究論文（学術雑誌）, 査読有り

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 …

M Wada, Y Noda, S Shinagawa, JK Chung, K Sawada, K Ogyu, R Tarumi, ...

Journal of Alzheimer's Disease 63 (2), 861-869 2018年

研究論文（学術雑誌）, 査読有り

Enhanced theta-gamma coupling associated with hippocampal volume increase following high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with …

Y Noda, R Zomorrodi, ZJ Daskalakis, DM Blumberger, M Nakamura

International Journal of Psychophysiology 133, 169-174 2018年

研究論文（学術雑誌）, 査読有り

Progress in Neuro-Psychopharmacology and Biological Psychiatry

DP Kiser, S Popp, AG Schmitt-Böhrer, T Strekalova, D Hove, KP Lesch, ...

Elsevier 2018年

Reduced prefrontal short-latency afferent inhibition in older adults and its relation to executive function: A TMS-EEG study

Noda Y., Zomorrodi R., Backhouse F., Cash R.F.H., Barr M.S., Rajji T.K., Chen R., Daskalakis Z.J., Blumberger D.M.

Frontiers in Aging Neuroscience （Frontiers in Aging Neuroscience）  9 （ MAY ）  2017年05月

研究論文（学術雑誌）, 査読有り,  ISSN  1663-4365

　概要を見る

Combining transcranial magnetic stimulation (TMS) with electroencephalography (EEG) allows for the assessment of various neurophysiological processes in the human cortex. One of these paradigms, short-latency afferent inhibition (SAI), is thought to be a sensitive measure of cholinergic activity. In a previous study, we demonstrated the temporal pattern of this paradigm from both the motor (M1) and dorsolateral prefrontal cortex (DLPFC) using simultaneous TMS-EEG recording. The SAI paradigm led to marked modulations at N100. In this study, we aimed to investigate the age-related effects on TMS-evoked potentials (TEPs) with the SAI from M1 and the DLPFC in younger (18-59 years old) and older (≥60 years old) participants. Older participants showed significantly lower N100 modulation in M1-SAI as well as DLPFC-SAI compared to the younger participants. Furthermore, the modulation of N100 by DLPFC-SAI in the older participants correlated with executive function as measured with the Trail making test. This paradigm has the potential to non-invasively identify cholinergic changes in cortical regions related to cognition in older participants.

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Characterization of Glutamatergic and GABA A-Mediated Neurotransmission in Motor and Dorsolateral Prefrontal Cortex Using Paired-Pulse TMS-EEG

Cash R.F.H., Noda Y., Zomorrodi R., Radhu N., Farzan F., Rajji T.K., Fitzgerald P.B., Chen R., Daskalakis Z.J., Blumberger D.M.

Neuropsychopharmacology （Neuropsychopharmacology）  42 （ 2 ） 502 - 511 2017年01月

研究論文（学術雑誌）, 査読有り,  ISSN  0893133X

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Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are noninvasive transcranial magnetic stimulation (TMS) measures of GABA A receptor-mediated inhibition and glutamatergic excitatory transmission, respectively. Conventionally these measures have been restricted to the motor cortex. We investigated whether SICI and ICF could be recorded from the dorsolateral prefrontal cortex (DLPFC) using combined TMS and electroencephalography (TMS-EEG). We first characterized the neural signature of SICI and ICF in M1 in terms of TMS-evoked potentials (TEPs) and spectral power modulation. Subsequently, these paradigms were applied in the DLPFC to determine whether similar neural signatures were evident. With TMS at M1, SICI and ICF led to bidirectional modulation (inhibition and facilitation, respectively) of P30 and P60 TEP amplitude, which correlated with MEP amplitude changes. With DLPFC stimulation, P60 was bidirectionally modulated by SICI and ICF in the same manner as for M1 stimulation, whereas P30 was absent. The sole modulation of early TEP components is in contradistinction to other measures such as long-interval intracortical inhibition and may reflect modulation of short latency excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Overall, the data suggest that SICI and ICF can be recorded using TMS-EEG in DLPFC providing noninvasive measures of glutamatergic and GABA A receptor-mediated neurotransmission. This may facilitate future research attempting to ascertain the role of these neurotransmitters in the pathophysiology and treatment of neurological and psychiatric disorders.

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Lateralized hippocampal volume increase following high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with major depression

野田 賀大

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  71 （ 11 ） 747 - 758 2017年

研究論文（学術雑誌）, 査読有り,  ISSN  13231316

　概要を見る

© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology Aim: Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for patients with treatment-resistant depression in recent years, and a large body of evidence has demonstrated its therapeutic efficacy through stimulating neuronal plasticity. The aim of this study was to investigate structural alterations in the hippocampus (HIPP) and amygdala (AM) following conventional rTMS in patients with depression. Methods: Twenty-eight patients with depression underwent 10 daily 20-Hz left prefrontal rTMS over 2 weeks. The left dorsolateral prefrontal cortex (DLPFC) was identified using magnetic resonance imaging-guided neuronavigation prior to stimulation. Magnetic resonance imaging scans were obtained at baseline and after the completion of rTMS sessions. The therapeutic effects of rTMS were evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D17), and the volumes of the HIPP and AM were measured by a manual tracing method. Results: Statistical analyses revealed a significant volume increase in the left HIPP (+3.4%) after rTMS but no significant volume change in the AM. No correlation was found between the left HIPP volume increase and clinical improvement, as measured by the HAM-D17. Conclusion: The present study demonstrated that conventional left prefrontal rTMS increases the HIPP volume in the stimulated side, indicating a remote neuroplastic effect through the cingulum bundle.

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Reduced prefrontal short–latency afferent inhibition in older adults and its relation to executive function: a TMS-EEG Study.

野田 賀大

Frontiers in Aging Neuroscience. 2017年

Reduced short-latency afferent inhibition in prefrontal but not motor cortex and its association with executive function in schizophrenia: a combined TMS–EEG study.

野田 賀大

Schizophrenia Bulletin. 2017年

Characterization of the influence of age on GABAA and glutamatergic mediated functions in the dorsolateral prefrontal cortex using paired-pulse TMS-EEG

野田 賀大

Aging 9 (2), 556-572 2017年

研究論文（学術雑誌）, 査読有り

Resting-state EEG gamma power and theta-gamma coupling enhancement following high-frequency left dorsolateral prefrontal rTMS in patients with depression.

野田 賀大

Clinical Neurophysiology. 2017年

Characterization of glutamatergic and GABA A-mediated neurotransmission in motor and dorsolateral prefrontal cortex using paired-pulse TMS–EEG

RFH Cash, Y Noda, R Zomorrodi, N Radhu, F Farzan, TK Rajji, ...

Neuropsychopharmacology 42 (2), 502-511 2017年

研究論文（学術雑誌）, 査読有り

Lateralized hippocampal volume increase following high‐frequency left prefrontal repetitive transcranial magnetic stimulation in patients with major depression

S Hayasaka, M Nakamura, Y Noda, T Izuno, T Saeki, H Iwanari, ...

Psychiatry and clinical neurosciences 71 (11), 747-758 2017年

研究論文（学術雑誌）, 査読有り

Cortical Inhibition and Excitation in Late-Life Depression: A TMS Study of Baseline Abnormalities and Changes With Pharmacotherapy

J Lissemore, A Bhandari, B Mulsant, E Lenze, C Reynolds, J Karp, T Rajji, ...

NEUROPSYCHOPHARMACOLOGY 43, S408-S409 2017年

研究論文（学術雑誌）, 査読有り

Evaluation of short interval cortical inhibition and intracortical facilitation from the dorsolateral prefrontal cortex in patients with schizophrenia

Y Noda, MS Barr, R Zomorrodi, RFH Cash, F Farzan, TK Rajji, R Chen, ...

Scientific reports 7 (1), 1-12 （Scientific Reports）  7 （ 1 ） 17106 2017年

研究論文（学術雑誌）, 査読有り,  ISSN  2045-2322

　概要を見る

© 2017 The Author(s). GABAergic and glutamatergic dysfunction in the dorsolateral prefrontal cortex (DLPFC) are thought to be the core pathophysiological mechanisms of schizophrenia. Recently, we have established a method to index these functions from the DLPFC using the paired transcranial magnetic stimulation (TMS) paradigms of short interval intracortical inhibition (SICI) and facilitation (ICF) combined with electroencephalography (EEG). In this study, we aimed to evaluate neurophysiological indicators related to GABAA and glutamate receptor-mediated functions respectively from the DLPFC in patients with schizophrenia using these paradigms, compared to healthy controls. Given that these activities contribute to cognitive functions, the relationship between the TMS-evoked potential (TEP) modulations by SICI/ICF and cognitive/clinical measures were explored. Compared to controls, patients showed reduced inhibition in P60 (t22 = -4.961, p < 0.0001) by SICI and reduced facilitation in P60 (t22 = 5.174, p < 0.0001) and N100 (t22 = 3.273, p = 0.003) by ICF. In patients, the modulation of P60 by SICI was correlated with the longest span of the Letter-Number Span Test (r = -0.775, p = 0.003), while the modulation of N100 by ICF was correlated with the total score of the Positive and Negative. Syndrome Scale (r = 0.817, p = 0.002). These findings may represent the pathophysiology, which may be associated with prefrontal GABAA and glutamatergic dysfunctions, in the expression of symptoms of schizophrenia.

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Resting-state EEG gamma power and theta–gamma coupling enhancement following high-frequency left dorsolateral prefrontal rTMS in patients with depression

Y Noda, R Zomorrodi, T Saeki, TK Rajji, DM Blumberger, ZJ Daskalakis, ...

Clinical Neurophysiology 128 (3), 424-432 （Clinical Neurophysiology）  128 （ 3 ） 424 - 432 2017年

研究論文（学術雑誌）, 査読有り,  ISSN  13882457

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Objective We aimed to investigate neuromodulatory effects of high-frequency left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) on resting-state electroencephalography (EEG) and their clinical and cognitive correlates in patients with depression. Methods Thirty-one patients diagnosed with depression included in the present study. Resting-state gamma power and theta–gamma coupling (TGC) were calculated before and after a course of rTMS. We explored the relationship among gamma power, TGC, and clinical/cognitive outcomes as measured with the Hamilton Rating Scale for Depression (HAM-D17), Beck Depression Inventory (BDI), and Wisconsin Card Sorting Test (WCST). Results Following rTMS, depressed patients demonstrated significant increases of resting gamma power at the F3 and F4 electrode sites and resting TGC at the C3 and T3 electrode sites. Furthermore, the increased gamma power at the F3 electrode site was significantly correlated with improved score on the HAM-D17 and BDI, while the increased TGC at the C3 electrode site was significantly correlated with reduced number of errors on the WCST. Conclusion Thus, resting-state gamma power and TGC may represent potential biomarkers of depression associated with therapeutic effects of rTMS. Significance Resting-state EEG may provide potential biomarkers related to therapeutic effects of rTMS.

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Reduced Prefrontal Short—Latency Afferent Inhibition in Older Adults and Its Relation to Executive Function: A TMS-EEG Study

Y Noda, R Zomorrodi, F Backhouse, RFH Cash, MS Barr, TK Rajji, ...

Frontiers in aging neuroscience 9, 119 2017年

研究論文（学術雑誌）, 査読有り

Characterization of the influence of age on GABA<inf>A</inf> and glutamatergic mediated functions in the dorsolateral prefrontal cortex using paired-pulse TMS-EEG

Noda Y., Zomorrodi R., Cash R.F.H., Barr M.S., Farzan F., Rajji T.K., Chen R., Daskalakis Z.J., Blumberger D.M.

Aging （Aging）  9 （ 2 ） 556 - 572 2017年

研究論文（学術雑誌）, 査読有り,  ISSN  19454589

　概要を見る

Gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmissions in the prefrontal cortex decreases with age. Further, cognitive function mediated through the dorsolateral prefrontal cortex (DLPFC) also declines with age. Although neuroimaging studies have demonstrated decreased levels of these substances, direct neurophysiological data investigating the effect of aging in the DLPFC in human subjects is lacking. The advent of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) has allowed for the assessment of functional neurotransmission in vivo. In the present study, we examined short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in a group of older adults (> 60 yrs) to evaluate the strength of GABAA and glutamate-mediated neurotransmission in the DLPFC, compared to younger adults (18-59 yrs). Older adults showed an increase of amplitude of N100 by the SICI paradigm, while N45 amplitude was increased and N100 amplitude was decreased by ICF. Moreover, these modulations significantly correlated with age. Our findings provide evidence for age-related alterations of excitatory and inhibitory functions in the prefrontal cortex in healthy adults. Future studies may aim to explore these neurophysiological relationships in the DLPFC in pathological forms of aging that affect cortical functioning such as mild cognitive impairment and Alzheimer's disease.

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Characterisation of glutamatergic and GABAA-mediated neurotransmission in motor and dorsolateral prefrontal cortex using paired-pulse TMS-EEG.

野田 賀大

Neuropsychopharmacology. 2016年

A combined TMS–EEG study of short–latency afferent inhibition in the motor and dorsolateral prefrontal cortex.

野田 賀大

Journal of neurophysiology. 2016年

A combined TMS-EEG study of short-latency afferent inhibition in the motor and dorsolateral prefrontal cortex

Y Noda, RFH Cash, R Zomorrodi, LG Dominguez, F Farzan, TK Rajji, ...

Journal of neurophysiology 116 (3), 938-948 （Journal of Neurophysiology）  116 （ 3 ） 938 - 948 2016年

研究論文（学術雑誌）, 査読有り,  ISSN  00223077

　概要を見る

© 2016 the American Physiological Society. Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) enables noninvasive neurophysiological investigation of the human cortex. A TMS paradigm of short-latency afferent inhibition (SAI) is characterized by attenuation of the motor-evoked potential (MEP) and modulation of N100 of the TMS-evoked potential (TEP) when TMS is delivered to motor cortex (M1) following median nerve stimulation. SAI is a marker of cholinergic activity in the motor cortex; however, the SAI has not been tested from the prefrontal cortex. We aimed to explore the effect of SAI in dorsolateral prefrontal cortex (DLPFC). SAI was examined in 12 healthy subjects with median nerve stimulation and TMS delivered to M1 and DLPFC at interstimulus intervals (ISIs) relative to the individual N20 latency. SAI in M1 was tested at the optimal ISI of N20 + 2 ms. SAI in DLPFC was investigated at a range of ISI from N20 + 2 to N20 + 20 ms to explore its temporal profile. For SAI in M1, the attenuation of MEP amplitude was correlated with an increase of TEP N100 from the left central area. A similar spatiotemporal neural signature of SAI in DLPFC was observed with a marked increase of N100 amplitude. SAI in DLPFC was maximal at ISI N20 + 4 ms at the left frontal area. These findings establish the neural signature of SAI in DLPFC. Future studies could explore whether DLPFC-SAI is neurophysiological marker of cholinergic dysfunction in cognitive disorders.

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POTENTIAL EEG BIOMARKERS FOR NEUROPLASTICITY INDUCTION BY A SERIES OF PREFRONTAL REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS) FOR MAJOR DEPRESSION

M Nakamura, Y Noda

AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY 50, 41-42 2016年

Magnetic seizure therapy-induced mania

Noda Y., Daskalakis Z.J., Fitzgerald P.B., Downar J., Rajji T.K., Blumberger D.M.

Journal of ECT （Journal of ECT）  31 （ 1 ） e4 - e6 2015年03月

研究論文（学術雑誌）, 査読有り,  ISSN  10950680

　概要を見る

Background Magnetic seizure therapy (MST) is a novel brain stimulation modality used to treat refractory depression through the induction of seizures. It is currently being investigated as a potential alternative treatment to electroconvulsive therapy. To our knowledge, there have not been any previous reports of MST-induced mania. Objective We aim to describe 2 cases of patients with a major depressive episode who developed acute symptoms of mania during a course of MST. Methods The current report describes 2 cases of mania that occurred in the context of an ongoing open-label study of MST in treatment-resistant depression. The MST was administered 2 or 3 times per week and applied directly over the left and right dorsolateral prefrontal cortex. Treatment is administered until patients achieve remission or a maximum of 24 treatments. A MagVenture Twin coil and MST stimulator were used for treatment. The center of each coil was placed over F3 and F4 according to the 10-20 electroencephalography system. Results Patient 1 had developed manic symptoms precipitously after the sixth MST treatment, and patient 2 developed manic symptoms after the 23rd MST treatment. In both patients, the MST treatment course was stopped. Their manic symptoms resolved rapidly with pharmacotherapy after cessation of MST treatments. Conclusions As with electroconvulsive therapy, switches to mania or hypomania should be considered as potential adverse effects of MST.

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Clinical Application of the K–Style Acupuncture Score (KSAS): Towards the Establishment of a Novel Rating Scale for Depression in Acupuncture Medicine

野田 賀大

Neuropsychiatry (London) 5 (1), 50-58 2015年

Clinical application of repetitive transcranial magnetic stimulation and magnetic seizure therapy to　 patients with treatment-resistant depression.

野田 賀大

The Journal of Japanese Society of General Hospital Psychiatry. 2015年

Neurobiological predictors of response to dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation in depression: a systematic review

野田 賀大

Depression and anxiety 32 (12), 871-891 （Depression and Anxiety）  32 （ 12 ） 871 - 891 2015年

研究論文（学術雑誌）, 査読有り,  ISSN  10914269

　概要を見る

Background A significant proportion of patients with depression fail to respond to psychotherapy and standard pharmacotherapy, leading to treatment-resistant depression (TRD). Due to the significant prevalence of TRD, alternative therapies for depression have emerged as viable treatments in the armamentarium for this disorder. Repetitive transcranial magnetic stimulation (rTMS) is now being offered in clinical practice in broader numbers. Many studies have investigated various different neurobiological predictors of response of rTMS. However, a synthesis of this literature and an understanding of what biological targets predict response is lacking. This review aims to systematically synthesize the literature on the neurobiological predictors of rTMS in patients with depression. Methods Medline (1996-2014), Embase (1980-2014), and PsycINFO (1806-2014) were searched under set terms. 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. Results The search identified 1,673 articles, 41 of which met both inclusion and exclusion criteria. Various biological factors at baseline appear to predict response to rTMS, including levels of certain molecular factors, blood flow in brain regions implicated in depression, electrophysiological findings, and specific genetic polymorphisms. Conclusions Significant methodological variability in rTMS treatment protocols limits the ability to generalize conclusions. However, response to treatment may be predicted by baseline frontal lobe blood flow, and presence of polymorphisms of the 5-hydroxytryptamine (5-HT) -1a gene, the LL genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) gene, and Val/Val homozygotes of the brain-derived neurotrophic factor (BDNF) gene.

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Neurobiological mechanisms of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic review

野田 賀大

Psychological medicine 45 (16), 3411-3432 （Psychological Medicine）  45 （ 16 ） 3411 - 3432 2015年

研究論文（学術雑誌）, 査読有り,  ISSN  00332917

　概要を見る

Depression is one of the most prevalent mental illnesses worldwide and a leading cause of disability, especially in the setting of treatment resistance. In recent years, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative strategy for treatment-resistant depression and its clinical efficacy has been investigated intensively across the world. However, the underlying neurobiological mechanisms of the antidepressant effect of rTMS are still not fully understood. This review aims to systematically synthesize the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996-2014), Embase (1980-2014) and PsycINFO (1806-2014) were searched under set terms. Three 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. Of 1647 articles identified, 66 studies met both inclusion and exclusion criteria. rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limits the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggest that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. More research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

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Acupuncture-induced changes of vagal function in patients with depression: a preliminary sham-controlled study with press needles

野田 賀大

Complementary therapies in clinical practice 21 (3), 193-200 （Complementary Therapies in Clinical Practice）  21 （ 3 ） 193 - 200 2015年

研究論文（学術雑誌）, 査読有り,  ISSN  17443881

　概要を見る

© 2015 Elsevier Ltd. To study the biological effects of acupuncture on depression, we hypothesized that acupuncture will exert its antidepressant effect through a bottom-up neuromodulation of the autonomic dysfunction in depression. The participants received press needle (PN) acupuncture for 72 h continuously in a sham-controlled design. Psychological assessments and Holter electrocardiography were performed before and after PN acupuncture. We evaluated their autonomic functions through the heart rate variability (HRV). As a result, following PN acupuncture participants showed significant improvement in the Beck's Depression Inventory scores (P = 0.031), systolic/diastolic blood pressures (P = 0.002/P = 0.011), and coefficient of variation of the R-R interval (P < 0.0001), compared to sham PN. The present findings showed PN acupuncture induced alterations in vagal function, blood pressure, and Beck's Depression Inventory scores. It was suggested that vagal stabilization effect by acupuncture may be associated with the therapeutic mechanism in depression.

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Clinical Application of the K-Style Acupuncture Score (KSAS): Towards the Establishment of a Novel Rating Scale for Depression in Acupuncture Medicine

Y Noda, K Matsumoto, H Murakami, A Ito, Y Shinse, A Suzuki, Y Sawada, ...

Neuropsychiatry 5 (1), 50-58 2015年

研究論文（学術雑誌）, 査読有り

Magnetic seizure therapy-induced mania: a report of 2 cases

野田 賀大

The journal of ECT 31 (1), e4-e6 2014年

研究論文（学術雑誌）, 査読有り

Magnetic seizure therapy in an adolescent with refractory bipolar depression: a case report

野田 賀大

Neuropsychiatric disease and treatment 10, 2049 （Neuropsychiatric Disease and Treatment）  10   2049 - 2055 2014年

研究論文（学術雑誌）, 査読有り,  ISSN  11766328

　概要を見る

Magnetic seizure therapy (MST) has shown efficacy in adult patients with treatment-resistant depression with limited impairment in memory. To date, the use of MST in adolescent depression has not been reported. Here we describe the first successful use of MST in the treatment of an adolescent patient with refractory bipolar depression. This patient received MST in an ongoing open-label study for treatment-resistant major depression. Treatments employed a twin-coil MST apparatus, with the center of each coil placed over the frontal cortex (ie, each coil centered over F3 and F4). MST was applied at 100 Hz and 100% machine output at progressively increasing train durations. Depressive symptoms were assessed using the 24-item Hamilton Depression Rating Scale and cognitive function was assessed with a comprehensive neuropsychological battery. This adolescent patient achieved full remission of clinical symptoms after an acute course of 18 MST treatments and had no apparent cognitive decline, other than some autobiographical memory impairment that may or may not be related to the MST treatment. This case report suggests that MST may be a safe and well tolerated intervention for adolescents with treatment-resistant bipolar depression. Pilot studies to further evaluate the effectiveness and safety of MST in adolescents warrant consideration.

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Variation in the DRD2 gene affects impulsivity in intertemporal choice

野田 賀大

Scientific Research Publishing 3 （ 1 ） 26 - 31 2013年

研究論文（学術雑誌）, 査読有り

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Potentiation of Quantitative Electroencephalograms Following Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression.

野田 賀大

Neuroscience Research. 2013年

Repetitive transcranial magnetic stimulation to maintain treatment response to electroconvulsive therapy in depression: a case series

野田 賀大

Frontiers in psychiatry 4, 73 （Frontiers in Psychiatry）  4 （ JUL ） 73 - 31 2013年

研究論文（学術雑誌）, 査読有り

　概要を見る

Electroconvulsive therapy (ECT) is the most effective treatment for a refractory major depression in the context of both unipolar and bipolar affective disorders. However, the relapse rate within the first 6 months after a successful course of ECT to treat a depressive episode can be as high 50%. Evidence-based strategies to prevent relapse have partial efficacy and are associated with problematic adverse effects limiting their use as long-term treatments. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in treatment-resistant depression with a favorable adverse effect profile. Herein, we describe six patients, four with unipolar and two with bipolar depression, where rTMS was used to maintain response after a successful course of acute and continuation ECT. rTMS was administered once or twice weekly, at 120% of the resting motor threshold. Patients received sequential bilateral rTMS (low frequency right: 600 pulses, then high frequency left: 3000 pulses). The site of stimulation was 6 cm anterior and 1 cm lateral from the site of maximum stimulation of the abductor pollicis brevis muscle. Depressive symptoms were monitored with the quick inventory of depressive symptoms-self rated. Five of the six patients were able to maintain their response status from 6 to 13 months at the time of last observation. The use of rTMS may be an important relapse prevention strategy following an acute course of ECT. Controlled studies comparing rTMS to current evidence-based relapse prevention strategies are warranted. ©2013 Noda, Daskalakis, Ramos and Blumberger.

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DNA polymorphism in the FKBP5 gene affects impulsivity in intertemporal choice

野田 賀大

Asia‐Pacific Psychiatry 5 (1), 31-38 （Asia-Pacific Psychiatry）  5 （ 1 ） 31 - 38 2013年

研究論文（学術雑誌）, 査読有り,  ISSN  17585864

　概要を見る

Introduction: Impulsivity in intertemporal choice has been operationalized as "delay discounting", referring to the preference for a sooner, smaller reward. FK506 binding protein 5 (FKBP5) is a co-chaperone of the glucocorticoid receptor (GR). FKBP5 overexpression causes GR resistance, resulting in increased plasma cortisol levels. High cortisol levels are associated with low impulsivity in intertemporal choice. The aim of this study was to explore the effect of single nucleotide polymorphisms (SNPs) in FKBP5 on delay discounting. Methods: The participants consisted of 91 healthy Japanese people (66 males and 25 females with a mean age of 40.9±6.9 years). Each participant completed Kirby's monetary choice questionnaire (MCQ) and donated a whole blood sample. Five SNPs in FKBP5 were genotyped using the DigiTag2. SNP linear regression analyses with 100,000 permutations were conducted for the hyperbolic time-discount rate (k). Results: Two SNPs were excluded from analysis because of their low minor allelic frequencies. The SNP rs1360780 showed a significant association; participants with more minor alleles (T) were less impulsive in intertemporal choice for delayed gain (multiplicity-corrected P=0.047). Discussion: The significant SNP rs1360780 is located in the region adjacent to the hormone response element (HRE)-binding sequence where transcription factors bind and alter the transcription of FKBP5. A minor allele (T) of rs1360780, which causes FKBP5 overexpression, may reduce impulsivity in intertemporal choice (i.e. delay discounting) via GR resistance and the subsequent high cortisol levels. This is the first study to demonstrate an association between FKBP5 and impulsivity in intertemporal choice. © 2012 Wiley Publishing Asia Pty Ltd.

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Localized potentiation of sleep slow-wave activity induced by prefrontal repetitive transcranial magnetic stimulation in patients with a major depressive episode

T Saeki, M Nakamura, N Hirai, Y Noda, S Hayasaka, H Iwanari, ...

Brain stimulation 6 (3), 390-396 （Brain Stimulation）  6 （ 3 ） 390 - 396 2013年

研究論文（学術雑誌）, 査読有り,  ISSN  1935861X

　概要を見る

Background: The effects of repetitive transcranial magnetic stimulation (rTMS) on sleep structure in major depression are currently unknown. Objective: To determine the effects of prefrontal rTMS on sleep electroencephalography (EEG) in major depression. Methods: In this open-label pilot study, twelve male patients with relatively mild depression, who had been medication-resistant, underwent 10 daily rTMS sessions over the left dorsolateral prefrontal cortex (DLPFC). Polysomnographic (PSG) data were recorded over four nights: Adaptation, Baseline, Post-1 (after the fifth rTMS session), and Post-2 (after the tenth rTMS session). Discrete Fourier Transform (DFT) band power analyses were performed to quantify delta and sigma band activities during Stages II-IV, and determine time courses of these activities between Baseline and Post-1 (first five sessions) and between Post-1 and Post-2 (last five sessions). Results: Post-hoc tests based on a three-way ANOVA model indicated significant delta power increase at F3 (t11 = -2.762, P = 0.018) during the first five sessions; however, sigma power was unchanged. No significant band power changes were observed during the second half. Stages II-IV (percent total sleep time) increased significantly during the first half (t12 = -2.43, P = 0.033). No other significant changes in sleep parameters or clinical correlations were observed. Conclusions: The first five sessions of high frequency rTMS to the left DLPFC increase slow-wave activity (SWA) at F3, possibly reflecting locally enhanced synaptic plasticity induced by rTMS. This increased activity was not observed during the last half, possibly due to a homeostatic regulation mechanism intrinsic to SWA. © 2013 Elsevier Inc. All rights reserved.

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Potentiation of quantitative electroencephalograms following prefrontal repetitive transcranial magnetic stimulation in patients with major depression

Y Noda, M Nakamura, T Saeki, M Inoue, H Iwanari, K Kasai

Neuroscience Research 77 (1-2), 70-77 （Neuroscience Research）  77 （ 1-2 ） 70 - 77 2013年

研究論文（学術雑誌）, 査読有り,  ISSN  01680102

　概要を見る

The long-lasting effects of repetitive transcranial magnetic stimulation (rTMS) on electroencephalogram (EEG) activity are not clear. We aimed to investigate the cumulative rTMS effects on EEG and clinical outcomes in patients with major depression. Twenty-five patients with medication-resistant depression underwent 10 daily rTMS sessions over the left dorsolateral prefrontal cortex. We measured resting EEG and spectrum-power before and after the rTMS course. Clinical efficacy was evaluated with the Hamilton's Depression Rating Scale (HAM-D) and Wisconsin Card Sorting Test (WCST). In an ANOVA model, including all prefrontal electrodes, post hoc analyses revealed significant time effects on the theta (F1,24=7.89, P=0.010; +43%), delta (F1,24=6.58, P=0.017; +26%), and alpha (F1,24=4.64, P=0.042; 31%) bands without site specificity. Clinical correlations were observed between F4 alpha power increases and improvements in HAM-D retardation, F3 alpha power increases and improvements of the absolute changes in perseveration and error number on the WCST, and C3 and C4 theta power increases and improvements of the percent change in perseveration and error number on the WCST following rTMS. Consecutive prefrontal rTMS could induce long-lasting EEG potentiations beyond the aftereffects, resulting in improved cognitive and depressive symptoms. © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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大うつ病性障害の左背外側前頭前野への反復性高頻度経頭蓋磁気刺激法による定量脳波増強効果についての研究

野田賀大

東京大学  - 31 2012年03月

査読有り

　概要を見る

本研究では薬物治療抵抗性の大うつ病性障害を対象に反復性高頻度経頭蓋磁気刺激法(rTMS)による定量脳波(qEEG)への影響及び臨床効果について調べた。うつ病患者25名に対して、計10回のrTMSセッションを左背外側前頭前野に施行した。その前後で安静覚醒閉眼脳波を計測し、パワースペクトラム解析を行った。rTMSによる臨床効果はハミルトンうつ病評価尺度とウィスコンシンカードソーティングテストで評価した。前頭前野領域を対象としたqEEGパワー変化の分散分析では、rTMS治療後にシータパワーの有意な増加を認めた。F3, Fz, F4を対象とした相関分析では、F3/F4のシータパワーの増高と認知機能改善との間に有意な臨床相関を認めた。本研究結果からは、うつ病に対するrTMS治療により、長期増強様変化を反映したqEEG変化が引き起こされている可能性が示唆された。

Localized potentiation of sleep slow-wave activity induced by prefrontal repetitive transcranial magnetic stimulation in patients with a depressive episode.

野田 賀大

Brain Stimulation. 2012年

P3‐071: SOD1 loss accelerates Aß oligomerization and memory impairment in Tg2576 mice

N Kinoshita, KJ Barnham, H Hatsuta, K Murakami, Y Noda, T Shirasawa, ...

Alzheimer's & Dementia 8 2012年

Six-year stability of affective temperaments as measured by TEMPS-A.

野田 賀大

Psychopathology. （KARGER）  43 （ 4 ） 240 - 247 2010年

査読有り,  ISSN  0254-4962

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Background: A number of psychopathological and neurobiological studies on affective temperament have been conducted based on the assumption that temperament is a stable trait. However, few studies have actually assessed the long-term stability of affective temperament. The objective of this study is to evaluate the 6-year stability of affective temperaments as measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego - Autoquestionnaire version (TEMPS-A) in a non-clinical adult population. Sampling and Methods: Study participants consisted of 178 Japanese white-collar workers (103 males and 75 females; mean age = 38.5 years, SD = 7.8) who completed the Japanese version of TEMPS-A twice over a 6-year interval, and who did not have either past or current DSM-IV affective, anxiety or psychotic disorders, as diagnosed with the Mini-International Neuropsychiatric Interview. The long-term stability of affective temperaments as measured by TEMPS-A was assessed by analyzing Pearson correlation coefficients for temperament scores over a 6-year period. Results: Temperament scores were moderately to highly correlated over the 6-year period (depressive temperament, r = 0.59; cyclothymic temperament, r = 0.68; hyperthymic temperament, r = 0.82; irritable temperament, r = 0.66; anxious temperament, r = 0.74; p &lt; 0.01 for all values). Pearson coefficients were in the range of 0.61-0.83 for males and 0.51-0.79 for females, while they were 0.56-0.85 for younger and 0.63-0.77 for older participants. All correlations were significant at p &lt; 0.01, irrespective of temperament type, gender and age. Conclusions: Affective temperaments as measured by TEMPS-A exhibited good long-term stability and were robust, irrespective of temperament type, gender and age. Affective temperaments as measured by TEMPS-A may be considered to be stable traits, providing a sound basis for psychopathological and neurobiological studies. Limitations of this study include the fact that our sample was not drawn from the general community, it was entirely composed of Japanese participants and the size was not large. Copyright (C) 2010 S. Karger AG, Basel

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