Clinical efficacy of Repetitive Deep TMS in Patient with Parkinson’s disease: a pilot study

Clinical efficacy of Repetitive Deep TMS in Patient with Parkinson’s disease: a pilot study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical efficacy of Repetitive Deep TMS in Patient with Parkinson’s disease: a pilot study In-Uk Song, Sonya Young Joo Park, Yong An Chung, Byung Seok Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8071479/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pharmaceutical therapy can provide effective symptomatic relief for Parkinson’s disease (PD) initially, but symptoms become more complex and refractory as the disease progresses, necessitating alternative therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique for brain stimulation, which is recommended as a potential therapeutic tool for various neurological and psychiatric disorders. This study aimed to investigate the effects of deep rTMS using an H-coil on cerebral perfusion and motor function in PD. Five PD patients underwent high-frequency dTMS over the supplementary motor area (SMA) for two weeks. Clinical assessments, including the Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and Timed-Up-Go (TUG) test, were conducted before and three months after dTMS. Brain perfusion was evaluated using single-photon emission computed tomography (SPECT) and analyzed with statistical parametric mapping. There were no statistically significant changes in Hoehn-Yahr scale, TUG, or UPDRS motor scores following dTMS intervention. However, SPECT analysis revealed a significant increase in regional cerebral blood flow (rCBF) in the right cerebellum after dTMS treatment. Although dTMS did not result in significant clinical improvements in motor symptoms, it was associated with increased cerebellar perfusion, suggesting potential neuromodulatory effects. Therefore, we cautiously suggest that rTMS procedure may be a new therapeutic option for PD. Further studies are necessary to investigate associations between changes in rCBF and motor function tests after rTMS application in PD. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Parkinson’s disease deep transcranial magnetic stimulation regional cerebral blood flow Figures Figure 1 Introduction Parkinson disease (PD) is defined as a widespread neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor and postural instability( 1 ). Levodopa therapy can provide effective symptomatic relief for PD initially, but symptoms become more complex and refractory as the disease progresses( 2 ). Therefore, patients with long-standing PD may require additional nonpharmacological therapeutic interventions to preserve independent mobility and function. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique for brain stimulation, which is recommended as a potential therapeutic tool for various neurological and psychiatric disorders( 3 , 4 ). rTMS is a painless, non-invasive, well-tolerated technique of brain stimulation based on the theory of electromagnetic induction( 5 ). It can induce currents in the local areas of cerebral cortex through rapidly changing magnetic fields to depolarize nerve cells of central nervous system and produce activity of the synaptic terminals, which may lead to a series of brain metabolic changes and other physiological functional responses( 6 ). Several clinical studies of rTMS for the treatment of PD have been published, some of which reported moderate improvement of motor symptoms( 3 , 7 ). These studies suggest that rTMS may be effective in improving motor symptoms in patients with PD in the short and long term( 3 , 8 ). The literature investigating the effectiveness of rTMS in PD shows mixed results, possibly owing to low statistical power and wide variation in treatment protocol. Functional neuroimaging such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) has been widely used for diagnosis, evaluation of treatment effect, and monitoring disease progression( 9 ). Moreover, functional neuroimaging has advantages of detecting subtle changes before appearance of behavioral or clinical signs( 10 ). Brain perfusion SPECT is widely available and provides information about alterations of regional cerebral blood flow, which are known to reflect cortical function ( 11 ). However, studies compared the regional cerebral blood flow for evaluation of the effectiveness of non-invasive brain stimulation such as rTMS in PD had rarely been performed yet. Previous studies to date using rTMS have mostly applied using the standard circular or figure-of-8 coils, which act on relatively narrow cortical regions ( 12 ). In contrast, our study applied deep rTMS (dTMS) using Hesed coil (H-coil), which has been designed to stimulate deeper and wider areas of effective cortical stimulation compared with the standard coils ( 13 ). We aimed to further explore the therapeutic effects of dTMS on PD patients through analysis of cerebral blood flow. Therefore, we conducted this study to investigate alteration of perfusion SPECT in PD after dTMS therapy using SPM program. Methods Participants and Clinical Assessment Five patients with PD participated in this study and met the inclusion criteria of a clinical diagnosis of PD defined by the presence of at least two out of three cardinal motor features (resting tremor, rigidity, and bradykinesia). Additionally, we only included PD patients with decreased dopamine transporters (DATs) in the posterior putamen on 123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) PET. Exclusion criteria were significant medical or psychiatric illness, history of seizure, abnormal EEG findings and metal objects or stimulators in the head, which might pose a hazard during dTMS procedure. Additionally, participants were excluded if they had any of the following: remarkable cognitive dysfunction; any signs of atypical Parkinsonism; delirium; amnestic disorders; or cerebrovascular lesions on magnetic resonance imaging. Patients who were taking psychotropic medications were also excluded. A comprehensive clinical assessment, including medical history and neurological examination, was conducted by board certified neurologists. Disease severity was assessed using the Hoehn-Yahr scale, Timed-Up-Go test (TUG) and the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III ( 14 , 15 ). Study procedures included a clinical assessment and SPECT imaging before and three months after the dTMS procedure. To assess clinical efficacy, changes in UPDRS motor score, TUG and Hoehn-Yahr scale from baseline to the 3-month follow-up were analyzed using Wilcoxon signed-rank test. The study was approved by the Institutional Review Board and all participants provided written informed consent. Transcranial magnetic stimulation Within four weeks of baseline clinical evaluation including SPECT imaging, all participants received dTMS procedure three times per week for two weeks over supplementary motor area (SMA). The dTMS was administered using the BrainsWay H1-coil with a Magstim Rapid2 (Magstim Company, Spring Gardens, UK) stimulator or with the BrainsWay stimulator (BrainsWay, Jerusalem, Israel). The H1-coil has been designed to stimulate deep prefrontal cortex areas that include neuronal pathways associated with the brain reward system ( 16 ). The coil is placed in a helmet to allow effective cooling during stimulation, and the frame of the inner rim of the coil is flexible in order to accommodate variability in human skull shape. dTMS procedure protocol is follow as; 18 Hz, 120% intensity related to the resting motor threshold (rMT), 55 trains of 2 sec. duration, inter-train interval (ITI) 20 sec., 1980 pulses per session. Each session lasted for approximately 30 min, of which dTMS delivery lasted 20 min. SPECT Acquisition and Analysis Brain SPECT was performed at baseline and 3-month follow-up using a dual-headed gamma camera (Discovery NM630, GE Healthcare, Milwaukee, WI, USA) equipped with a low energy fan-beam collimator. Images were obtained 40 minutes after the intravenous injection of 555–740 MBq of Tc-99m ECD. Image preprocessing and analyses were performed using Statistical Parametric Mapping 12 (SPM, Wellcome Trust Centre for Neuroimaging, London, UK) implemented inMATLAB R2017b (MathWorks, Natick, MA, USA). For voxel-wise analysis, a paired t-test was performed to assess changes in rCBF between baseline and follow-up. The voxel-wise significance threshold was set at P < 0.001 (uncorrected) with a minimum cluster size of 50 contiguous voxels. Results Five patients with PD received dTMS six times (3 times per week) over two weeks. The clinical characteristics of all patients before and 3-months after the dTMS procedure are shown in Table 1 . There was no significant difference of Hoehn-Yahr scale score (P = 0.76), TUG score (P = 0.323), UPDRS part 4 score (P = 1.0) or UPDRS motor score (P = 0.421) between baseline and follow-up in all participants (Table 1 ). Table 1 Demographic and Clinical Characteristics of the Patients with Parkinson's disease CASE 1 CASE 2 CASE 3 CASE 4 CASE 5 Mean ± SD P-value age 72 65 54 57 68 63.2 ± 7.53 - sex male female male female female - - Levodopa equivalent dose (mg/day) 675 375 225 450 300 405 ± 172.66 - HY before TMS 2 2.5 1 2 2 1.9 ± 0.55 - HY after TMS 2 2 1 2 2 1.8 ± 0.45 0.76 Part 3 of UPDRS before TMS 13 22 7 16 16 14.80 ± 5.45 - Part 3 of UPDRS after TMS 9 16 3 15 16 11.80 ± 5.72 0.421 Part 4 of UPDRS before TMS 3 2 0 2 0 1.40 ± 1.34 - Part 4 of UPDRS after TMS 2 1 0 2 2 1.40 ± 0.89 1 TUG of UPDRS before TMS 8.51 12.5 6.5 11.1 12.5 10.22 ± 2.64 - TUG of UPDRS after TMS 7.18 11 6.84 6.87 11.06 8.59 ± 2.23 0.323 dTMS = deep repetitive Transcranial Magnetic Stmulation UPDRS = United Parkinson’s disease Rating Scale; HY = Hoehn-Yahr scale Regarding the brain perfusion image analysis, there were significant clusters of increased rCBF on the right cerebellar area (Fig. 1 and Table 2 ). Table 2 Brain Regions with Significantly Increased Regional Cerebral Blood Flow in Patients with Parkinson’s Disease After Deep Transcranial Magnetic Stimulation Brain regions Cluster size (voxels) t z p-value Coordinates* Right cerebellar cortex 28 5.96 3.11 < 0.001 22, − 38, −44 *The coordinates refer to the Montreal Neurological Institute coordinate system Discussion As Parkinson's disease progresses, the effectiveness of medications becomes limited, so research into new treatments is needed. Previous studies explored the improvement of symptoms through rTMS therapy on cerebral cortex. However, it is not clear yet whether or not rTMS therapy for Parkinson’s disease is effective. We performed this study to investigate influence on clinical effects as well as perfusion image via high frequency rTMS therapy. Furthermore, the present study conducted research on the effectiveness using the H-coil which is a novel rTMS tool, unlike previous studies conducted with standard coils such as C-type or round-type. H-coil is designed to maximized summation of induced fields around a target and to minimized non-tangential coil elements close to that area( 4 , 16 ). Based on mathematical modeling and on actual phantom brain measurements, it was shown that the H-coil allows safe of large brain tissue volumes and a penetration of the stimulation field to a depth of 3 to 4 cm ( 4 , 17 ). Thus, H-coil is designed to affect extensive neuronal pathways, including deeper cortical regions and fibers targeting subcortical regions, without a significant increase of the electric field induced in superficial cortical layers( 18 ). The current study investigated the change of cerebral function in patients with PD after dTMS procedure. Cerebral function was evaluated via changes in rCBF on cerebral perfusion SPECT, and follow-up images showed significantly increased rCBF in the right cerebellum when compared to baseline images. Previous studies have reported that functional modulations in the cerebellum were related to akinesia/rigidity, tremor, gait disturbance, dyskinesia and some non-motor symptoms ( 19 – 22 ). The cerebellum is believed to play both pathological and compensatory roles in Parkinson’s disease (PD). Previous studies suggested that dopaminergic degeneration, abnormal activation of the basal ganglia, and pathological changes in the cerebellum may be induced by dopaminergic treatment( 23 – 25 ). These findings may help explain some of the clinical symptoms of Parkinson’s disease. Therefore, the compensatory function of cerebellum may contribute to maintaining better motor and non-motor performance ( 22 ). Regarding compensatory effect, together with the hyperactivation or strengthened connectivity in the cerebellum are hypoactivations in some other regions, such as the supplementary motor cortex and striatum, in patients with Parkinson’s disease compared with healthy control subjects( 22 , 26 , 27 ). Lewis et al. also reported that patients with Parkinson’s disease show overall increased activity within the striato-thalamo-cortical and cerebello-thalamo-cortical pathways relative to controls ( 28 ). Therefore, the cerebellum is generally recognized for its compensatory role in Parkinson’s disease, exerting its influence through the cortico-thalamo-cerebellar and striato-thalamo-cortical pathways ( 29 ). However, in this study, the observed cerebellar hyperperfusion is presumed to result not from a compensatory mechanism but rather an effect of deep transcranial magnetic stimulation (dTMS) applied to the left SMA, which influences the cerebellum via the cortico-thalamo-cerebellar pathway. While our study did not demonstrate a significant improvement in motor symptoms, previous studies have reported clinical benefits of motor function, such as gait, balance and UPDRS score, after rTMS procedure in Parkinson’s disease ( 4 , 7 , 8 ). These discrepancies may stem from various factors, such as limited statistical power due to a small sample size of the present study, heterogeneity in patient characteristics, and variability in the targeted brain regions for rTMS application. Interestingly, one of the previous studies showed an improvement in motor functions with only low frequency rTMS procedure over both dorsolateral prefrontal cortex (DLPFC) and brain stem but not high frequency ( 7 ). Conversely, other studies reported that high frequency stimulation over SMA, motor cortex or DLPFC showed clinical improvement in Parkinson’s disease ( 8 , 30 ). Previous research found that significant clinical benefits can be obtained in patients with Parkinson’s disease (PD) by stimulating different cortical regions with rTMS at low (inhibitory) or high (excitatory) frequency. These effects were thought to result from plastic changes in motor cortical networks. In our study, high-frequency dTMS was applied over the left SMA, leading to increased regional cerebral blood flow (rCBF) in the right cerebellum. Although no statistically significant improvements in motor symptoms were observed, motor function test scores showed improved results following dTMS application. A few limitations of our study need to be addressed. This study was conducted in a small number of patients, and we did not perform any neuropathological investigations to confirm the presence of Lewy bodies because the patients were still living. We tried to reduce this confounder by only including patients with decreased DAT uptake in the striatum based on the FP-CIT PET. Despite the small sample size, this study is the first to investigate the effects of rTMS on cerebral blood flow in patients with Parkinson’s disease. Furthermore, we conducted this study using the H-coil for dTMS, which is not the conventional standard type for rTMS used in previous studies and clinical practice. In conclusion, this study showed that the application of high frequency rTMS to the SMA may enhance cerebellar CBF. Although the improvement in motor function after rTMS was not statistically significant, there was a trend towards improvement in motor function tests after rTMS application. Therefore, we cautiously suggest that rTMS procedure may be a new therapeutic option for PD. Further studies are necessary to investigate associations between changes in rCBF and those in motor function tests after rTMS application in PD. Declarations Conflict of interests Declaration of any potential financial and non-financial conflict of interest, or declaration of no conflict of interest Funding information This research was supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2025-02216889) Author Contribution IU Song, Sonya YJ Park, and YA Chung wrote the main manuscript text.BS Kim prepared table and figure.All authors reviewed the manuscript. Acknowledgments None. Data Availability The datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request. 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Neuroscience 166 , 712–719 (2010). Hanoglu, L. et al. Preliminary findings on the role of high-frequency (5Hz) rTMS stimulation on M1 and pre-SMA regions in Parkinson's disease. Neurosci. Lett. 724 , 134837 (2020). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8071479","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":543825047,"identity":"a5198425-5d0d-4d6a-8a06-2dc708cfab78","order_by":0,"name":"In-Uk Song","email":"","orcid":"","institution":"Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea","correspondingAuthor":false,"prefix":"","firstName":"In-Uk","middleName":"","lastName":"Song","suffix":""},{"id":543825048,"identity":"2ce34b4e-e99e-4ec7-992c-3914a489d0ea","order_by":1,"name":"Sonya Young Joo Park","email":"","orcid":"","institution":"Yeouido St. 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1","display":"","copyAsset":false,"role":"figure","size":140746,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in relative regional cerebral blood flow (rCBF) at follow-up. Increment of rCBF at follow-up compared with baseline are presented on right cerebellum. The color bar represents voxel-level t-values. L = left; R = right.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8071479/v1/27cbcb09938786d19509e151.jpeg"},{"id":97664624,"identity":"cd23affa-9924-4d51-8026-ee8977022e1c","added_by":"auto","created_at":"2025-12-08 09:11:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":660008,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8071479/v1/8ac65c1e-b402-4758-b957-88400d6761c9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical efficacy of Repetitive Deep TMS in Patient with Parkinson’s disease: a pilot study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson disease (PD) is defined as a widespread neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor and postural instability(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Levodopa therapy can provide effective symptomatic relief for PD initially, but symptoms become more complex and refractory as the disease progresses(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Therefore, patients with long-standing PD may require additional nonpharmacological therapeutic interventions to preserve independent mobility and function. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique for brain stimulation, which is recommended as a potential therapeutic tool for various neurological and psychiatric disorders(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). rTMS is a painless, non-invasive, well-tolerated technique of brain stimulation based on the theory of electromagnetic induction(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). It can induce currents in the local areas of cerebral cortex through rapidly changing magnetic fields to depolarize nerve cells of central nervous system and produce activity of the synaptic terminals, which may lead to a series of brain metabolic changes and other physiological functional responses(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Several clinical studies of rTMS for the treatment of PD have been published, some of which reported moderate improvement of motor symptoms(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). These studies suggest that rTMS may be effective in improving motor symptoms in patients with PD in the short and long term(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The literature investigating the effectiveness of rTMS in PD shows mixed results, possibly owing to low statistical power and wide variation in treatment protocol.\u003c/p\u003e\u003cp\u003eFunctional neuroimaging such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) has been widely used for diagnosis, evaluation of treatment effect, and monitoring disease progression(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Moreover, functional neuroimaging has advantages of detecting subtle changes before appearance of behavioral or clinical signs(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Brain perfusion SPECT is widely available and provides information about alterations of regional cerebral blood flow, which are known to reflect cortical function (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHowever, studies compared the regional cerebral blood flow for evaluation of the effectiveness of non-invasive brain stimulation such as rTMS in PD had rarely been performed yet. Previous studies to date using rTMS have mostly applied using the standard circular or figure-of-8 coils, which act on relatively narrow cortical regions (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In contrast, our study applied deep rTMS (dTMS) using Hesed coil (H-coil), which has been designed to stimulate deeper and wider areas of effective cortical stimulation compared with the standard coils (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). We aimed to further explore the therapeutic effects of dTMS on PD patients through analysis of cerebral blood flow. Therefore, we conducted this study to investigate alteration of perfusion SPECT in PD after dTMS therapy using SPM program.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eParticipants and Clinical Assessment\u003c/h2\u003e\u003cp\u003eFive patients with PD participated in this study and met the inclusion criteria of a clinical diagnosis of PD defined by the presence of at least two out of three cardinal motor features (resting tremor, rigidity, and bradykinesia). Additionally, we only included PD patients with decreased dopamine transporters (DATs) in the posterior putamen on 123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) PET. Exclusion criteria were significant medical or psychiatric illness, history of seizure, abnormal EEG findings and metal objects or stimulators in the head, which might pose a hazard during dTMS procedure.\u003c/p\u003e\u003cp\u003eAdditionally, participants were excluded if they had any of the following: remarkable cognitive dysfunction; any signs of atypical Parkinsonism; delirium; amnestic disorders; or cerebrovascular lesions on magnetic resonance imaging. Patients who were taking psychotropic medications were also excluded.\u003c/p\u003e\u003cp\u003eA comprehensive clinical assessment, including medical history and neurological examination, was conducted by board certified neurologists. Disease severity was assessed using the Hoehn-Yahr scale, Timed-Up-Go test (TUG) and the Unified Parkinson\u0026rsquo;s Disease Rating Scale (UPDRS) Part III (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Study procedures included a clinical assessment and SPECT imaging before and three months after the dTMS procedure. To assess clinical efficacy, changes in UPDRS motor score, TUG and Hoehn-Yahr scale from baseline to the 3-month follow-up were analyzed using Wilcoxon signed-rank test. The study was approved by the Institutional Review Board and all participants provided written informed consent.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTranscranial magnetic stimulation\u003c/h3\u003e\n\u003cp\u003eWithin four weeks of baseline clinical evaluation including SPECT imaging, all participants received dTMS procedure three times per week for two weeks over supplementary motor area (SMA). The dTMS was administered using the BrainsWay H1-coil with a Magstim Rapid2 (Magstim Company, Spring Gardens, UK) stimulator or with the BrainsWay stimulator (BrainsWay, Jerusalem, Israel). The H1-coil has been designed to stimulate deep prefrontal cortex areas that include neuronal pathways associated with the brain reward system (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The coil is placed in a helmet to allow effective cooling during stimulation, and the frame of the inner rim of the coil is flexible in order to accommodate variability in human skull shape.\u003c/p\u003e\u003cp\u003edTMS procedure protocol is follow as; 18 Hz, 120% intensity related to the resting motor threshold (rMT), 55 trains of 2 sec. duration, inter-train interval (ITI) 20 sec., 1980 pulses per session. Each session lasted for approximately 30 min, of which dTMS delivery lasted 20 min.\u003c/p\u003e\n\u003ch3\u003eSPECT Acquisition and Analysis\u003c/h3\u003e\n\u003cp\u003eBrain SPECT was performed at baseline and 3-month follow-up using a dual-headed gamma camera (Discovery NM630, GE Healthcare, Milwaukee, WI, USA) equipped with a low energy fan-beam collimator. Images were obtained 40 minutes after the intravenous injection of 555\u0026ndash;740 MBq of Tc-99m ECD.\u003c/p\u003e\u003cp\u003eImage preprocessing and analyses were performed using Statistical Parametric Mapping 12 (SPM, Wellcome Trust Centre for Neuroimaging, London, UK) implemented inMATLAB R2017b (MathWorks, Natick, MA, USA). For voxel-wise analysis, a paired t-test was performed to assess changes in rCBF between baseline and follow-up. The voxel-wise significance threshold was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 (uncorrected) with a minimum cluster size of 50 contiguous voxels.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFive patients with PD received dTMS six times (3 times per week) over two weeks. The clinical characteristics of all patients before and 3-months after the dTMS procedure are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There was no significant difference of Hoehn-Yahr scale score (P\u0026thinsp;=\u0026thinsp;0.76), TUG score (P\u0026thinsp;=\u0026thinsp;0.323), UPDRS part 4 score (P\u0026thinsp;=\u0026thinsp;1.0) or UPDRS motor score (P\u0026thinsp;=\u0026thinsp;0.421) between baseline and follow-up in all participants (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic and Clinical Characteristics of the Patients with Parkinson's disease\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCASE 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCASE 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCASE 3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCASE 4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCASE 5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e63.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevodopa equivalent dose\u003c/p\u003e\u003cp\u003e(mg/day)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e675\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e375\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e225\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e450\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e300\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e405\u0026thinsp;\u0026plusmn;\u0026thinsp;172.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHY \u003c/p\u003e\u003cp\u003ebefore TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHY \u003c/p\u003e\u003cp\u003eafter TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePart 3 of UPDRS \u003c/p\u003e\u003cp\u003ebefore TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.80\u0026thinsp;\u0026plusmn;\u0026thinsp;5.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePart 3 of UPDRS \u003c/p\u003e\u003cp\u003eafter TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e11.80\u0026thinsp;\u0026plusmn;\u0026thinsp;5.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.421\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePart 4 of UPDRS \u003c/p\u003e\u003cp\u003ebefore TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.40\u0026thinsp;\u0026plusmn;\u0026thinsp;1.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePart 4 of UPDRS \u003c/p\u003e\u003cp\u003eafter TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTUG of UPDRS \u003c/p\u003e\u003cp\u003ebefore TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10.22\u0026thinsp;\u0026plusmn;\u0026thinsp;2.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTUG of UPDRS \u003c/p\u003e\u003cp\u003eafter TMS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8.59\u0026thinsp;\u0026plusmn;\u0026thinsp;2.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.323\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003edTMS\u0026thinsp;=\u0026thinsp;deep repetitive Transcranial Magnetic Stmulation\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eUPDRS\u0026thinsp;=\u0026thinsp;United Parkinson\u0026rsquo;s disease Rating Scale; HY\u0026thinsp;=\u0026thinsp;Hoehn-Yahr scale\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eRegarding the brain perfusion image analysis, there were significant clusters of increased rCBF on the right cerebellar area (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBrain Regions with Significantly Increased Regional Cerebral Blood Flow in Patients with Parkinson\u0026rsquo;s Disease After Deep Transcranial Magnetic Stimulation\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrain regions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCluster size (voxels)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003et\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ez\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCoordinates*\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRight cerebellar cortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e22, \u0026minus;\u0026thinsp;38, \u0026minus;44\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e*The coordinates refer to the Montreal Neurological Institute coordinate system\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs Parkinson's disease progresses, the effectiveness of medications becomes limited, so research into new treatments is needed. Previous studies explored the improvement of symptoms through rTMS therapy on cerebral cortex. However, it is not clear yet whether or not rTMS therapy for Parkinson\u0026rsquo;s disease is effective. We performed this study to investigate influence on clinical effects as well as perfusion image via high frequency rTMS therapy. Furthermore, the present study conducted research on the effectiveness using the H-coil which is a novel rTMS tool, unlike previous studies conducted with standard coils such as C-type or round-type. H-coil is designed to maximized summation of induced fields around a target and to minimized non-tangential coil elements close to that area(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Based on mathematical modeling and on actual phantom brain measurements, it was shown that the H-coil allows safe of large brain tissue volumes and a penetration of the stimulation field to a depth of 3 to 4 cm (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Thus, H-coil is designed to affect extensive neuronal pathways, including deeper cortical regions and fibers targeting subcortical regions, without a significant increase of the electric field induced in superficial cortical layers(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe current study investigated the change of cerebral function in patients with PD after dTMS procedure. Cerebral function was evaluated via changes in rCBF on cerebral perfusion SPECT, and follow-up images showed significantly increased rCBF in the right cerebellum when compared to baseline images. Previous studies have reported that functional modulations in the cerebellum were related to akinesia/rigidity, tremor, gait disturbance, dyskinesia and some non-motor symptoms (\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe cerebellum is believed to play both pathological and compensatory roles in Parkinson\u0026rsquo;s disease (PD). Previous studies suggested that dopaminergic degeneration, abnormal activation of the basal ganglia, and pathological changes in the cerebellum may be induced by dopaminergic treatment(\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). These findings may help explain some of the clinical symptoms of Parkinson\u0026rsquo;s disease. Therefore, the compensatory function of cerebellum may contribute to maintaining better motor and non-motor performance (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Regarding compensatory effect, together with the hyperactivation or strengthened connectivity in the cerebellum are hypoactivations in some other regions, such as the supplementary motor cortex and striatum, in patients with Parkinson\u0026rsquo;s disease compared with healthy control subjects(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Lewis et al. also reported that patients with Parkinson\u0026rsquo;s disease show overall increased activity within the striato-thalamo-cortical and cerebello-thalamo-cortical pathways relative to controls (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Therefore, the cerebellum is generally recognized for its compensatory role in Parkinson\u0026rsquo;s disease, exerting its influence through the cortico-thalamo-cerebellar and striato-thalamo-cortical pathways (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). However, in this study, the observed cerebellar hyperperfusion is presumed to result not from a compensatory mechanism but rather an effect of deep transcranial magnetic stimulation (dTMS) applied to the left SMA, which influences the cerebellum via the cortico-thalamo-cerebellar pathway.\u003c/p\u003e\u003cp\u003eWhile our study did not demonstrate a significant improvement in motor symptoms, previous studies have reported clinical benefits of motor function, such as gait, balance and UPDRS score, after rTMS procedure in Parkinson\u0026rsquo;s disease (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). These discrepancies may stem from various factors, such as limited statistical power due to a small sample size of the present study, heterogeneity in patient characteristics, and variability in the targeted brain regions for rTMS application. Interestingly, one of the previous studies showed an improvement in motor functions with only low frequency rTMS procedure over both dorsolateral prefrontal cortex (DLPFC) and brain stem but not high frequency (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Conversely, other studies reported that high frequency stimulation over SMA, motor cortex or DLPFC showed clinical improvement in Parkinson\u0026rsquo;s disease (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Previous research found that significant clinical benefits can be obtained in patients with Parkinson\u0026rsquo;s disease (PD) by stimulating different cortical regions with rTMS at low (inhibitory) or high (excitatory) frequency. These effects were thought to result from plastic changes in motor cortical networks. In our study, high-frequency dTMS was applied over the left SMA, leading to increased regional cerebral blood flow (rCBF) in the right cerebellum. Although no statistically significant improvements in motor symptoms were observed, motor function test scores showed improved results following dTMS application.\u003c/p\u003e\u003cp\u003eA few limitations of our study need to be addressed. This study was conducted in a small number of patients, and we did not perform any neuropathological investigations to confirm the presence of Lewy bodies because the patients were still living. We tried to reduce this confounder by only including patients with decreased DAT uptake in the striatum based on the FP-CIT PET. Despite the small sample size, this study is the first to investigate the effects of rTMS on cerebral blood flow in patients with Parkinson\u0026rsquo;s disease. Furthermore, we conducted this study using the H-coil for dTMS, which is not the conventional standard type for rTMS used in previous studies and clinical practice.\u003c/p\u003e\u003cp\u003eIn conclusion, this study showed that the application of high frequency rTMS to the SMA may enhance cerebellar CBF. Although the improvement in motor function after rTMS was not statistically significant, there was a trend towards improvement in motor function tests after rTMS application. Therefore, we cautiously suggest that rTMS procedure may be a new therapeutic option for PD. Further studies are necessary to investigate associations between changes in rCBF and those in motor function tests after rTMS application in PD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflict of interests\u003c/h2\u003e\u003cp\u003eDeclaration of any potential financial and non-financial conflict of interest, or declaration of no conflict of interest\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding information\u003c/h2\u003e\u003cp\u003eThis research was supported by the Bio\u0026amp;Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2025-02216889)\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eIU Song, Sonya YJ Park, and YA Chung wrote the main manuscript text.BS Kim prepared table and figure.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBroeder, S. et al. 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Lett.\u003c/em\u003e \u003cb\u003e724\u003c/b\u003e, 134837 (2020).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, deep transcranial magnetic stimulation, regional cerebral blood flow","lastPublishedDoi":"10.21203/rs.3.rs-8071479/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8071479/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePharmaceutical therapy can provide effective symptomatic relief for Parkinson\u0026rsquo;s disease (PD) initially, but symptoms become more complex and refractory as the disease progresses, necessitating alternative therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique for brain stimulation, which is recommended as a potential therapeutic tool for various neurological and psychiatric disorders. This study aimed to investigate the effects of deep rTMS using an H-coil on cerebral perfusion and motor function in PD. Five PD patients underwent high-frequency dTMS over the supplementary motor area (SMA) for two weeks. Clinical assessments, including the Unified Parkinson\u0026rsquo;s Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and Timed-Up-Go (TUG) test, were conducted before and three months after dTMS. Brain perfusion was evaluated using single-photon emission computed tomography (SPECT) and analyzed with statistical parametric mapping. There were no statistically significant changes in Hoehn-Yahr scale, TUG, or UPDRS motor scores following dTMS intervention. However, SPECT analysis revealed a significant increase in regional cerebral blood flow (rCBF) in the right cerebellum after dTMS treatment. Although dTMS did not result in significant clinical improvements in motor symptoms, it was associated with increased cerebellar perfusion, suggesting potential neuromodulatory effects. Therefore, we cautiously suggest that rTMS procedure may be a new therapeutic option for PD. Further studies are necessary to investigate associations between changes in rCBF and motor function tests after rTMS application in PD.\u003c/p\u003e","manuscriptTitle":"Clinical efficacy of Repetitive Deep TMS in Patient with Parkinson’s disease: a pilot study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 08:33:39","doi":"10.21203/rs.3.rs-8071479/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d8ff9c9b-a42c-4a5b-809f-c7fba79c399c","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57858103,"name":"Health sciences/Diseases"},{"id":57858104,"name":"Health sciences/Medical research"},{"id":57858105,"name":"Health sciences/Neurology"},{"id":57858106,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2025-12-03T09:09:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-13 08:33:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8071479","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8071479","identity":"rs-8071479","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}