論文 - 野田　賀大

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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