Rapid relief of severe freezing of gait after accelerated high-dose magnetic stimulations

Freezing of gait (FOG), defined as an episodic inability to generate effective stepping despite the intention to walk [[1]Giladi N. Nieuwboer A. Understanding and treating freezing of gait in parkinsonism, proposed working definition, and setting the stage.Mov Disord Off J Mov Disord Soc. 2008; 23: S423-S425Crossref PubMed Scopus (262) Google Scholar], is associated with a high risk of falling, limitation of activities and poor quality of life. FOG is one of the most disabling symptoms of Parkinson's disease (PD) and there is currently no effective therapy. Alternative therapies, such as repetitive transcranial magnetic stimulation (rTMS), have been used in an attempt to alleviate FOG, but the clinical benefit is limited [[2]Kim Y.W. Shin I.S. Moon H.I. Lee S.C. Yoon S.Y. Effects of non-invasive brain stimulation on freezing of gait in parkinsonism: a systematic review with meta-analysis.Park Relat Disord. 2019; 64: 82-89Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. A recent study indicated that accelerated theta-burst stimulation (TBS) for patients with depression, with 18000 pulses per day, significantly increased the remission ratio [[3]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177 (appiajp201919070720): 716-726Crossref PubMed Scopus (88) Google Scholar]. Here, we examined the efficacy of this accelerated high-dose TBS (ahTBS) protocol in the treatment of FOG. PD patients were prospectively recruited in the First Affiliated Hospital of Anhui Medical University from April 2020 to August 2021 [[4]Ji G.J. Liu T. Li Y. Liu P. Sun J. Chen X. et al.Structural correlates underlying accelerated magnetic stimulation in Parkinson's disease.Human Brain Mapp. 2020; Google Scholar]. The inclusion criteria were as follows: (a) diagnosis of idiopathic PD according to the UK Brain Bank Criteria, confirmed by a neurologist (author K.W. or P.H.) with expertise in movement disorders; (b) ongoing treatment with a stable dose of any medication for 2 months; (c) 40 years of age or older; and (d) Mini-Mental State Examination (MMSE) score >24. Exclusion criteria were as follows: (a) a history of addiction, psychiatric disorders, or neurological diseases other than PD; (b) focal brain lesions on T1-/T2-weighted fluid-attenuated inversion recovery images; (c) anti-PD medication adjustments during rTMS treatment; (d) history of substance abuse within the past 6 months; (e) nonremovable metal objects in or around the head; (f) previously received rTMS treatment; and (g) prior history of seizure or history in first-degree relatives. FOG was diagnosed by two experienced experts (P.H. and K.W.) using objective tests (e.g., step-over obstacles), and unresponsive to drug treatment. The protocol was approved by the Ethics Committee of Anhui Medical University and all participants provided written consent. TMS was performed using a Magstim Rapid2 transcranial magnetic stimulator (Magstim Company, Whitland, UK) with a 70-mm air cooled figure-of-eight coil. All stimulations were guided by the participant's anatomical image (1 × 1 × 1 mm3) and a frameless neuronavigation system (Brainsight; Rogue Research, Montreal, QC, Canada). Treatment comprised ahTBS, targeted to the primary motor cortex of the right lower leg. The target in Montreal Neurological Institute space (coordinates: −10, −24, 75) was transformed into individual high-resolution structural images by applying an inverse matrix produced during brain structure segmentation using SPM12 (www.fil.ion.ucl.ac.uk/spm). Fifty intermittent TBS sessions (1800 pulses per session, 50 minute inter-session interval [[3]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177 (appiajp201919070720): 716-726Crossref PubMed Scopus (88) Google Scholar]) were delivered as ten daily sessions over five consecutive days at 80% resting motor threshold (RMT). RMT was determined on the first day of the experiment by a five-step procedure. Briefly, the electromyography (EMG) signal of the abductor pollicis brevis muscle was recorded using Ag/AgCl surface electrodes, and displayed with the Rogue EMG device when the left “hand knob” area was activated by a single pulse stimulation. The RMT was defined as the lowest intensity evoking a small response (>50 μV) in more than 5 of 10 consecutive trials. The turning time in Standing Start 180° Turning Test (SS-180) [[5]Kim M.S. Chang W.H. Cho J.W. Youn J. Kim Y.K. Kim S.W. et al.Efficacy of cumulative high-frequency rTMS on freezing of gait in Parkinson's disease.Restor Neurol Neurosci. 2015; 33: 521-530PubMed Google Scholar] was selected as the primary outcome because of its objectivity and importance in daily life. The test, which was repeated four times on each test occasion, was videotaped and was carried out before and one day after the intervention. The Freezing of Gait Questionnaire (FOGQ) was used as a secondary outcome. All assessments took place in the medication “on” state at the same time of the day for each patient. Dopaminergic therapy was stable from two months before the study until the end of the study. Twenty PD patients were initially estimated, and 12 of them (mean age = 72, Table 1) with severe FOG (see attached videos) were included in this study. All the patients found the treatment tolerable and eleven out of twelve (91.7%) showed a dramatic improvement in the SS-180 turning test after treatment, as can be easily seen in the attached videos.Table 1Patient demographics and treatment response to accelerated high-dose magnetic stimulations.Sex/age (y)/education (y)Duration (y)/H–Y/LEDD (mg)Measures before and after treatment (pre/post)Measures at follow upTurning timeaThe SS-180 test was repeated four times on each test occasion, twice from left to right and twice from right to left. Average scores were used to calculate percentage improvement relative to baseline.Turning stepsFOGQTurning timeaThe SS-180 test was repeated four times on each test occasion, twice from left to right and twice from right to left. Average scores were used to calculate percentage improvement relative to baseline.Turning stepsFOGQF/69/05/2/60016.3/5.132.3/13.021/184.09.719M/79/165/1/43828.0/6.129.0/11.322/136.812.321F/70/03/3/50022.3/10.956.8/33.322/1910.727.319M/62/128/2/75045.2/5.083.3/9.520/164.910.321F/64/124/3/40012.6/12.632.8/33.320/176.113.519F/68/54/4/57593.9/66.685.0/76.522/1423.439.018M/82/59/4/375131.6/75.9133.5/92.021/21103.8112.823M/76/12/3/200202/76255/12122/2255.3111.520F/76/52/3/010.1/6.426/11.518/117.31218M/77/95/2.5/66323.6/13.388.25/40.321/2114.55423M/76/93/2.5/65073.77/6.1113/15.521/2114.63017F/69/91/3/57521/4.551.8/10.322/316.332.522Mean4/2.8/44056.7/24.082.2/39.021/1622.338.720F = female, H–Y = Hoehn and Yahr stage, LEED = levodopa equivalent daily dose, M = male.a The SS-180 test was repeated four times on each test occasion, twice from left to right and twice from right to left. Average scores were used to calculate percentage improvement relative to baseline. Open table in a new tab F = female, H–Y = Hoehn and Yahr stage, LEED = levodopa equivalent daily dose, M = male. There was a significant improvement in turning time (paired t = 3.1, P = 0.009), number of steps (paired t = 3.7, P = 0.003), and FOGQ (paired t = 2.9, P = 0.014) after treatment (Table 1). After one-month, these remarkable improvements remained well both in time (paired t = 2.86, P = 0.0155), steps (paired t = 3.9, P = 0.0025), and FOGQ (paired t = 1.7, P = 0.126). The improvement ratio (relative to baseline) in time, number of steps, and FOGQ were 55.9%, 51.6%, and 22.1% after treatment respectively, and remained in one-month follow up (56.8%, 54.6%, and 4.6%, respectively). This study reveals that ahTBS provides remarkable relief from FOG in 91.7% of PD patients after five days treatment without adverse events. To the best of our knowledge, this high efficacy is unprecedented in the literature describing treatment of FOG [[2]Kim Y.W. Shin I.S. Moon H.I. Lee S.C. Yoon S.Y. Effects of non-invasive brain stimulation on freezing of gait in parkinsonism: a systematic review with meta-analysis.Park Relat Disord. 2019; 64: 82-89Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. It suggests that ahTBS is an effective therapy for FOG in PD patients. Optimally-spaced high dose may contribute to this high efficacy. Conventional rTMS studies usually applied thousands of pulses per day, which was extremely less than other effective clinical therapy, such as deep brain stimulation (∼500,000 pluses per day) [[6]Williams N.R. Okun M.S. Deep brain stimulation (DBS) at the interface of neurology and psychiatry.J Clin Invest. 2013; 123: 4546-4556Crossref PubMed Scopus (77) Google Scholar]. However, continuously adding the rTMS dose may increase the side effect but not necessarily enhance the treatment effects. According to previous neuroplasticity and clinical studies [[3]Cole E.J. Stimpson K.H. Bentzley B.S. Gulser M. Cherian K. Tischler C. et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression.Am J Psychiatr. 2020; 177 (appiajp201919070720): 716-726Crossref PubMed Scopus (88) Google Scholar,[7]Kramar E.A. Babayan A.H. Gavin C.F. Cox C.D. Jafari M. Gall C.M. et al.Synaptic evidence for the efficacy of spaced learning.Proc Natl Acad Sci U S A. 2012; 109: 5121-5126Crossref PubMed Scopus (96) Google Scholar], we used a long inter-session interval (i.e., 1 hour) to produce cumulative effects. With this setting, the FOG symptoms were rapidly alleviated and the treatment effect sustained for at least one month without relapse trend. Our sample size is relatively small because this study has focused on PD patients with severe FOG and excluded patients with mild FOG. Nevertheless, our findings strongly suggest the clinical efficacy of hdTBS, thus a randomized clinical trial is warranted in the future. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This study was funded by the National Key R&D Program of China (No. 2018YFC1314200 to P.H.); the National Natural Science Foundation of China (Nos. 81971689 to G.-J. J., 31970979 , 91432301 , 31571149 , 82090034 and 2016YFC1300604 to K. W.; No. 82171917 to P.P. H., No. 81971072 to X.C.; No. 81790652 to H. L.; No. 81803130 to X.C.; No. 32071054 to Y.T.); Doctoral Foundation of Anhui Medical University (No. XJ201532 to G.-J. J.); and Collaborative Innovation Center of Neuropsychiatric Disorder and Mental Health of Anhui Province . The following are the Supplementary data to this article:https://www.brainstimjrnl.com/cms/asset/1578b511-0f7e-4b57-93d6-b3a35393dfb4/mmc1.mp4Loading ... 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