Faculty Profiles - HASHIZUME Atsushi

Papers - HASHIZUME Atsushi

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Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA). Invited Reviewed

Hashizume A, Fischbeck KH, Pennuto M, Fratta P, Katsuno M.

J Neurol Neurosurg Psychiatry. Vol. 91 ( 10 ) page： 123 - 130 2020.10

Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. Reviewed

Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M.

J Neurol. Vol. 266 ( 12 ) page： 2952 - 2961 2019.12

Diffuse but Non-homogeneous Brain Atrophy: Identification of Specific Brain Regions and Their Correlation with Clinical Severity in Rett Syndrome Reviewed Open Access

Narita H., Natsume J., Suzuki T., Shiohama T., Kawaguchi M., Okazaki M., Hashizume A., Naganawa S., Ito Y., Yamamoto H., Nakata T., Kidokoro H., Takahashi Y., Takahashi S., Tsujimura K.

Brain and Development Vol. 47 ( 3 ) page： 104348 2025.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Brain and Development

Background: Rett syndrome is a genetic neurodevelopmental disorder that predominantly affects girls. While microcephaly is a common feature, there is limited information on the detailed structural changes in the brain. This study aimed to identify regional brain volume abnormalities and explore the correlation between brain volume and clinical characteristics. Methods: We compared the regional brain volumes of 20 female children with Rett syndrome to those of 25 healthy female children. Additionally, we assessed the correlation between regional brain volume, Clinical Severity Scores, and epilepsy status. Results: Significantly smaller volumes were observed in all brain regions, including the cerebral cortex, cerebral white matter, subcortical gray matter, cerebellum, and brainstem. Within the cortical regions, volume reduction was prominent in the left precentral, right lateral occipital, left precuneus, left inferior parietal, and right medial orbitofrontal cortices. After correcting for intracranial volumes, volume reduction was more prominent in the cerebral cortices than in the cerebral white matter. Small volumes were consistently observed, regardless of age. Negative correlations were observed between the volumes of multiple regions and the Clinical Severity Scores. There were no correlations among regional brain volume, seizure control, or duration of epilepsy. Conclusion: The mechanism underlying the cortical-dominant volume reduction remains unclear; however, it may be caused by altered synapse development associated with methyl-CpG-binding protein 2 gene abnormalities. Characteristic impairments in visual recognition and deterioration of motor function in Rett syndrome may be associated with significant volume reduction in specific cortical regions, such as the lateral occipital cortex, precuneus, and precentral gyrus.

DOI： 10.1016/j.braindev.2025.104348

Open Access

Scopus

PubMed

Re-evaluation of blood culture contamination rates: Discordance between clinical and laboratory assessment Reviewed

Hamada, H; Morioka, H; Okazaki, M; Hashizume, A; Kanda, K; Oka, K; Iguchi, M; Yagi, T

JOURNAL OF INFECTION AND CHEMOTHERAPY Vol. 31 ( 4 ) page： 102628 2025.4

Self-Organized Prediction-Classification-Superposition of Longitudinal Cognitive Decline in Alzheimer's Disease: An Application to Novel Clinical Research Methodology Reviewed

Sato H., Hanazawa R., Suzuki K., Hashizume A., Hirakawa A.

IEEE Journal of Biomedical and Health Informatics 2025

Language：English Publishing type：Research paper (scientific journal) Publisher：IEEE Journal of Biomedical and Health Informatics

Progressive cognitive decline spanning across decades is characteristic of Alzheimer's disease (AD). Various predictive models have been designed to realize its early onset and study the long-term trajectories of cognitive test scores across populations of interest. Research efforts have been geared towards superimposing patients' cognitive test scores with the long-term trajectory denoting gradual cognitive decline, while considering the heterogeneity of AD. Multiple trajectories representing cognitive assessment for the long-term have been developed based on various parameters, highlighting the importance of classifying several groups based on disease progression patterns. In this study, a novel method capable of self-organized prediction, classification, and the overlay of long-term cognitive trajectories based on short-term individual data was developed, based on statistical and differential equation modeling. Here, "self-organized"denotes a data-driven mechanism by which the prediction model adaptively configures its structure and parameters to classify individuals and estimate long-term trajectories. We validated the predictive accuracy of the proposed method on two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Japanese ADNI. We also presented two practical illustrations of the simultaneous evaluation of risk factor associated with both the onset and the longitudinal progression of AD, and an innovative randomized controlled trial design for AD that standardizes the heterogeneity of patients enrolled in a clinical trial. These resources would improve the power of statistical hypothesis testing and help evaluate the therapeutic effect. The application of predicting the trajectory of longitudinal disease progression goes beyond AD, and is especially relevant for progressive and neurodegenerative disorders.

DOI： 10.1109/JBHI.2025.3546020

Scopus

Regulations related to the development of pharmaceuticals and medical devices Reviewed

Hashizume Atsushi

Neurological Therapeutics Vol. 42 ( 1 ) page： 13 - 18 2025

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Neurological Therapeutics

Most medical research is mainly clinical research conducted to gain knowledge that contributes to promoting the public's health, patients' recovery from diseases, or improving the quality of life through understanding the causes of diseases. The establishment of full–fledged ethical guidelines for clinical research was concentrated after 2000. However, the ethical guidelines are not legally binding, nor is administrative guidance for failing to comply. Under such circumstances, the need for a legal system was considered, and the “Clinical Trials Act” was enacted and issued after thorough consideration of the scope of the legal regulations and the content of specific regulations and measures, and came into effect in April 2018.With the enactment of the Clinical Trials Act, clinical research in Japan now includes clinical trials conducted under the “Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices”, clinical trials conducted under the “Clinical Trials Act”, and other clinical researches conducted under the “Ethical Guidelines for Medical and Health Research Involving Human Subjects”. In this manuscript, after mentioning the Declaration of Helsinki, on which these laws and regulations are based, the laws and regulations that must be complied with in the above three types of clinical research are summarized.

DOI： 10.15082/jsnt.42.1_13

CiNii Research

Past and future roles of the Japanese Society of Neurological Therapeutics in therapy development for neurological disorders Reviewed

Katsuno Masahisa, Hashizume Atsushi, Fujimoto Yoko

Neurological Therapeutics Vol. 42 ( 1 ) page： 33 - 37 2025

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Neurological Therapeutics

Research and development for diseases in the field of neurology have dramatically advanced over the past two decades. This owes to the identification of disease causes through advances in genome research, the development of imaging and body fluid biomarkers, the enhancement of academia–led research such as physician–led clinical trials and registries, and the development of new modalities of therapeutic agents such as nucleic acid medicine and antibody therapy. In particular, genomics and biomarkers are undergoing extremely rapid technological innovation and are expected to be further utilized for diagnosis and prognosis prediction of diseases, and for stratification in clinical trials. Biotechnologies such as cell therapy, genome editing, and CAR–T, as well as bioengineering technologies such as robotics and brain–computer interfaces, are also being applied to neurological diseases. Further innovations are expected to emerge in the future, such as the integration of different modalities and the combination of pharmaceuticals and medical devices. The Japanese Society of Neurological Therapeutics established the Drug Discovery Working Group in 2020 with the aim of stimulating the development of treatments for neurological diseases, and in 2022, this working group became the Drug Discovery Promotion Committee, which has been promoting projects including the support for clinical trial execution, initiation of a consultation service for clinical research, and holding symposium. This article introduces the activities of the Drug Discovery Promotion Committee and explains the current status and prospects of drug discovery in the field of neurology, which is the background of the committee's activities.

DOI： 10.15082/jsnt.42.1_33

CiNii Research

Comparison of Early-onset Efficacy of Anti-calcitonin Gene-related Peptide Monoclonal Antibodies for Patients with Migraine in Real-world Clinical Practice: Study Protocol for an Exploratory Clinical Trial. Open Access

Takafumi Tanei, Satoshi Maesawa, Yusuke Nishimura, Tomotaka Ishizaki, Yoshitaka Nagashima, Miki Hashida, Shun Yamamoto, Masahiko Ando, Yachiyo Kuwatsuka, Atsushi Hashizume, Toshihiko Wakabayashi, Ryuta Saito

Neurologia medico-chirurgica Vol. 65 ( 2 ) page： 71 - 80 2024.12

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Neurosurgical Society

Three anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) are available in Japan: galcanezumab, fremanezumab, and erenumab. Early-onset efficacy has been demonstrated for each CGRP-mAb in comparison with placebo, but differences among the drugs are unclear. Only galcanezumab requires 2 doses at the initial injection. This study is a multicenter, open-label, randomized, two-group comparison trial, consisting of the random selection of a CGRP-mAb and 6 consecutive injections, and then discontinuation of the CGRP-mAb after 6 injections. The primary outcome is a comparison of early-onset efficacy between galcanezumab and both fremanezumab and erenumab after the initial injection. The secondary outcomes are comparisons between galcanezumab and both fremanezumab and erenumab, and between fremanezumab and erenumab as follows: weekly number of headache days, migraine days, and acute medication use are compared to baseline during one month after initial injection; time of subjectively perceiving onset of effect after initial injection; monthly changes in headache status from baseline to after third (3rd) injections; effective rates after initial and 3rd injections; improvement rates of depression scores between baseline and after 3rd injections; changes in number of absenteeism and presenteeism days in each month from baseline to after 3rd injections; proportion of ineffective cases after 3rd injections; recurrence rates and time to recurrence after CGRP-mAb discontinuation; effective rates of CGRP-mAb re-injections; detection of clinical factors associated with effectiveness after the initial and 3rd injections. The aim of this study is to investigate differences in early-onset efficacy among the CGRP-mAbs, and when and to what extent headache symptoms recur after discontinuation.

DOI： 10.2176/jns-nmc.2024-0201

Conventional magnetic resonance imaging key features for distinguishing pathologically confirmed corticobasal degeneration from its mimics: a retrospective analysis of the J-VAC study Reviewed Open Access

Sakurai, K; Tokumaru, AM; Yoshida, M; Saito, Y; Wakabayashi, K; Komori, T; Hasegawa, M; Ikeuchi, T; Hayashi, Y; Shimohata, T; Murayama, S; Iwasaki, Y; Uchihara, T; Sakai, M; Yabe, I; Tanikawa, S; Takigawa, H; Adachi, T; Hanajima, R; Fujimura, H; Hayashi, K; Sugaya, K; Hasegawa, K; Sano, T; Takao, M; Yokota, O; Miki, T; Kobayashi, M; Arai, N; Ohkubo, T; Yokota, T; Mori, K; Ito, M; Ishida, C; Idezuka, J; Toyoshima, Y; Kanazawa, M; Aoki, M; Hasegawa, T; Watanabe, H; Hashizume, A; Niwa, H; Yasui, K; Ito, K; Washimi, Y; Kubota, A; Toda, T; Nakashima, K; Aiba, I

NEURORADIOLOGY Vol. 66 ( 11 ) page： 1917 - 1929 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Neuroradiology

Purpose: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. Methods: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. Results: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer’s disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. Conclusion: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

DOI： 10.1007/s00234-024-03432-w

Phase II/III and efficacy confirmation study of aceneuramic acid for GNE myopathy in Japan Reviewed

Suzuki, N; Yoshimura, MM; Katsuno, M; Takahashi, M; Yamashita, S; Oya, Y; Hashizume, A; Yamada, S; Nakamori, M; Izumi, R; Kato, M; Warita, H; Tateyama, M; Kuroda, H; Asada, R; Yamaguchi, T; Nishino, I; Aoki, M

NEUROMUSCULAR DISORDERS Vol. 43 2024.10

脊髄小脳変性症患者に対するHAL腰タイプを用いた在宅運動療法 Reviewed

岸本祥之, 橋詰淳, 山田晋一郎, 伊藤大輔, 小森祥太, 川瀬崇広, 近藤彩乃, 小原一輝, 森悠, 山本宗隆, 阿部友和, 戸田莉恵, 安永好宏, 勝野雅央

神経治療学 Vol. 41 ( 6 ) page： S299 - S299 2024.10

球脊髄性筋萎縮症における骨脆弱性への治療法の検討 Reviewed

川瀬崇広, 橋詰淳, 山田晋一郎, 伊藤大輔, 岸本祥之, 小森祥太, 近藤彩乃, 森悠, 小原一輝, 山本宗隆

神経治療学 Vol. 41 ( 6 ) page： S280 - S280 2024.10

AUTOANTIBODIES AGAINST DIHYDROLIPOAMIDE S-ACETYLTRANSFERASE IN IMMUNE-MEDIATED NEUROPATHIES Reviewed

Fukami, Y; Iijima, M; Koike, H; Yagi, S; Furukawa, S; Mouri, N; Ouchida, J; Murakami, A; Iida, M; Yokoi, S; Hashizume, A; Iguchi, Y; Imagama, S; Katsuno, M

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM Vol. 29 page： S184 - S184 2024.8

Comparing preprocessing strategies for 3D-Gene microarray data of extracellular vesicle-derived miRNAs. Reviewed International journal Open Access

Yuto Takemoto, Daisuke Ito, Shota Komori, Yoshiyuki Kishimoto, Shinichiro Yamada, Atsushi Hashizume, Masahisa Katsuno, Masahiro Nakatochi

BMC bioinformatics Vol. 25 ( 1 ) page： 221 - 221 2024.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology. RESULTS: Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement. CONCLUSIONS: This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.

DOI： 10.1186/s12859-024-05840-4

Safety and efficacy of aceneuramic acid in GNE myopathy: open-label extension study. Reviewed International journal Open Access

Naoki Suzuki, Madoka Mori-Yoshimura, Masahisa Katsuno, Masanori P Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

Journal of neurology, neurosurgery, and psychiatry Vol. 95 ( 11 ) page： 1093 - 1094 2024.6

Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies. Reviewed International journal Open Access

Yuki Fukami, Masahiro Iijima, Haruki H Koike, Satoru Yagi, Soma Furukawa, Naohiro Mouri, Jun Ouchida, Ayuka Murakami, Madoka Iida, Satoshi Yokoi, Atsushi Hashizume, Yohei Iguchi, Shiro Imagama, Masahisa Katsuno

Neurology(R) neuroimmunology & neuroinflammation Vol. 11 ( 2 ) page： e200199 2024.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

DOI： 10.1212/NXI.0000000000200199

PMDA experience and current work ―Clinical research support in academia― Reviewed

Hashizume Atsushi

Neurological Therapeutics Vol. 41 ( 3 ) page： 411 - 414 2024

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Neurological Therapeutics

As a pioneer of investigator–initiated clinical trials in Japan, Nagoya University started a multi–institutional Phase III study (JASMITT trial) to evaluate the efficacy and safety of leuprorelin acetate in the patients with Spinal and Bulbar Muscular Atrophy (SBMA) in 2006. The JASMITT trial is a translational study based on basic research findings on animal models of SBMA. In investigator–initiated new drug developments, academic researchers often need help to prepare a complete clinical data package. Experience with PMDA may lead to better preparation of regulatory filings. The author joined the New Drug Review 2 of the Pharmaceutical and Medical Device Agency (PMDA) in April 2013, during the clinical development of leuprorelin acetate, and learned the actual operations of consultation and new drug reviews. After that, leuprorelin acetate got approval based on the investigator–initiated clinical trials in 2017.In April 2021, the Department of Clinical Research Education (CRE) opened at the Nagoya University Graduate School of Medicine to promote clinical researches at Nagoya University. The two essential missions of CRE are “clinical research education” and “clinical research support”. CRE could be the only department to comprehensively deepen understanding and practice from observational researches to clinical trials.

DOI： 10.15082/jsnt.41.3_411

CiNii Research

球脊髄性筋萎縮症に対するリュープロレリン酢酸塩の薬事承認とその後 Reviewed

橋詰淳

神経治療学 Vol. 41 ( 6 ) page： S225 - S225 2024

Impact of periodic neck ultrasonography on locoregional disease control in surveillance after total thyroidectomy for patients with low- and intermediate-risk papillary thyroid carcinoma: a propensity score-matched study Open Access

Inaishi Takahiro, Takeuchi Dai, Ichikawa Takahiro, Inaguma Gai, Hashizume Atsushi, Okazaki Masaki, Masuda Norikazu, Kikumori Toyone

Endocrine Journal Vol. 71 ( 12 ) page： 1135 - 1143 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Endocrine Society

This study aimed to evaluate the impact of periodic neck ultrasonography (US) on postoperative surveillance for locoregional disease control of patients with low- and intermediate-risk papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. This retrospective cohort study included patients with PTC who underwent total thyroidectomy and central neck dissection at our institution between January, 2000 and December, 2016. The patients were divided into two groups: the physical examination (PE) group (follow-up by PE without periodic US) and the US group (follow-up by PE with periodic US). Serum thyroglobulin levels were measured periodically in both groups. Propensity score matching was used to rigorously balance the significant variables and assess the 10-year postoperative outcomes between the groups. Of the 189 patients, 150 were included after matching (75 in each group). There were no significant differences between the two groups in terms of background characteristics. The median follow-up period was 127.9 months. There was no significant difference in locoregional relapse-free survival between the PE and US groups (97.0 vs. 98.7%, p = 0.541). The overall survival was 96.7% and 98.7% in the PE and US groups, respectively, with no significant difference (p = 0.364). This study demonstrated that the addition of periodic US to PE for postoperative surveillance of patients with low- and intermediate-risk PTC who underwent total thyroidectomy did not significantly affect locoregional control.

DOI： 10.1507/endocrj.ej24-0194

Efficacy of the latest new stimulation patterns of spinal cord stimulation for intractable neuropathic pain compared to conventional stimulation: study protocol for a clinical trial. Reviewed International journal Open Access

Takafumi Tanei, Satoshi Maesawa, Yusuke Nishimura, Yoshitaka Nagashima, Tomotaka Ishizaki, Masahiko Ando, Yachiyo Kuwatsuka, Atsushi Hashizume, Shimon Kurasawa, Ryuta Saito

Trials Vol. 24 ( 1 ) page： 604 - 604 2023.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Spinal cord stimulation (SCS) is one of the neuromodulation therapies for chronic neuropathic pain. The conventional paresthesia-based SCS involves the application of tonic stimulation that induces a sense of paresthesia. Recently, new SCS stimulation patterns without paresthesia have been developed. Differential target multiplexed (DTM) stimulation and fast-acting subperception therapy (FAST) stimulation are the latest paresthesia-free SCS patterns. METHODS: A single-center, open-label, crossover, randomized clinical trial to investigate the superiority of SCS using the latest new stimulation patterns over conventional tonic stimulation for neuropathic pain is planned. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). In the SCS trial, participants will be randomly assigned to 4 groups receiving stimulation, including tonic, DTM, and FAST. Each stimulation will then be performed for 2 days, and a visual analog scale (VAS) for pain will be evaluated before and after each stimulation pattern. A stimulation-off period for 1 day is set between each stimulation pattern to wash out the residual previous stimulation effects. Pain improvement is defined as more than 33% reduction in the pain VAS. The primary analysis will compare pain improvement between the new stimulation patterns and the conventional tonic stimulation pattern in the SCS trial. The secondary outcomes will be evaluated as follows: (1) the relationships between causative disease and improvement rate by each stimulation pattern; (2) comparison of pain improvement between the DTM and FAST stimulation patterns in all cases and by causative disease; (3) changes in assessment items preoperatively to 24 months after the implantation; (4) preoperative factors associated with long-term effects defined as continuing for more than 12 months; and (5) adverse events related to this study 3 months after the implantation. DISCUSSION: This study aims to clarify the effectiveness of the latest new stimulation patterns compared to the conventional tonic stimulation. In addition, which stimulation pattern is most effective for which kind of causative disease will be clarified. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 1,042,220,094. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is an approved member of the Primary Registry Network of WHO ICTRP.

DOI： 10.1186/s13063-023-07637-x

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Papers - HASHIZUME Atsushi