Cerebello‐Cortical Control of Tremor Rhythm and Amplitude in Parkinson's Disease

Abstract

The pathophysiology of Parkinson's disease (PD) tremor involves both the basal ganglia and a cerebello-thalamo-cortical circuit.1, 2 It remains unclear how tremor rhythm and amplitude emerge from these circuits and whether these mechanisms depend on tremor phenotype. Previous data suggest that the cerebellum is specifically involved in PD postural tremor.3 However, different postural tremor types (re-emergent or pure postural tremor)4 were included, and region-specific effects on tremor amplitude were not assessed. Here, we investigated the role of the motor cortex (M1) and cerebellum in generating rhythm versus amplitude of PD rest tremor compared with re-emergent tremor. We tested the effect of single-pulse transcranial magnetic stimulation (TMS) on tremor rhythm (tremor reset index [TRI]) and tremor power (electromyography) in 14 patients with PD (Table S1; Appendix S1). All patients had rest tremor and electrophysiologically proven re-emergent tremor: wrist extension suppressed tremor amplitude for up to 3000 milliseconds (F1,20 = 11.7, P < 0.001; part.η2 = 0.47; Fig. 1A,B). Cerebellum-TMS reset re-emergent tremor, but not rest tremor (t13 = 2.1, P = 0.026; Cohen's d = 0.57; TRI vs. 0 [re-emergent tremor: t13 = 3.0, P = 0.010; rest tremor: t13 = 1.0, P = 0.33]; Fig. 1C–E). In re-emergent tremor, the TRI after cerebellum-TMS decreased with subsequent tremor bursts (1–5 after TMS), indicating transient resetting (time: F4,52 = 3.61, P = 0.011; part.η2 = 0.22; Table S2). M1-TMS, but not cerebellum-TMS, reduced tremor power for both rest tremor and re-emergent tremor (site × time interaction: F8,104 = 8.77, P < 0.001; part.η2 = 0.40; Fig. 1F,G [no 3-way interaction with tremor type]). Specifically, M1-TMS reduced tremor power up to 1500 milliseconds in both tremor types (rest tremor, time: F8,104 = 8.17, P < 0.001; part.η2 = 0.39; re-emergent tremor, time: F8,104 = 13.24, P < 0.001, part.η2 = 0.50), whereas cerebellum-TMS did not influence tremor power (F < 1.4). Our findings suggest that the cerebellum is part of the oscillator controlling the rhythm of re-emergent tremor, but not rest tremor. Compared with previous data, the TRI after cerebellum-TMS was smaller (0.1 vs. 0.5), and tremor reset was transient instead of permanent.3 This may relate to the postural tremor types included (here, re-emergent tremor; previously, all postural tremors),3 to the stimulation intensity (here, 56% stimulator output; previously, 68%),3 or both. Re-emergent tremor and resting tremor have been hypothesized to be a continuum (“tremor of stability”),2 and they share clinical features.5 However, re-emergent tremor has as smaller dopamine response and slightly higher frequency than rest tremor.4 Our data suggest that these differences may be explained by the cerebellum, which comes in with voluntary movement and transiently modulates the tremor oscillator and possibly tremor frequency, while the fundamental character of the tremor remains unchanged. Our data further suggest that M1, but not the cerebellum, controls tremor amplitude, independent of tremor phenotype. This finding is in line with previous data.6 M1-TMS effects on tremor power were shorter compared to wrist extension (1500 vs. 3000 milliseconds), suggesting that mechanisms involved in voluntary actions may have an additional role in tremor suppression. TMS pulses were given at intensities that produce motor-evoked potentials, so the effects may be driven in part by somatosensory afferents related to small muscle twitches. Intriguingly, thalamus interventions effectively reduce PD tremor amplitude,7 while cerebellum-TMS did not. This may suggest that the effects of thalamus interventions are not (only) explained by the interruption of cerebello-thalamo-cortical projections, but potentially also by the interruption of cortico-thalamo-cortical projections.8 R.C.H. is supported by the Netherlands Organization for Scientific Research (VENI Grant 9167077) and by The Michael J. Fox Foundation (Grant 15581). He received honoraria (for scientific lectures) from the International Parkinson and Movement Disorder Society. He is handling editor at Neuroimage: Clinical and serves on the Clinical Advisory Board of Cadent Therapeutics. K.R.E.v.d.B., P.P., H.J.C., T.O., P.M., and T.P. have nothing to disclose. E.A.S. is principal investigator on multiple studies, including the PROSPECT study funded by Cala Health Inc, the ADVANCE study funded by Allergan, Inc, and GP2 funded by The Michael J. Fox Foundation. All funding was awarded to The Mid-Atlantic Permanente Research Institute. He is also part of the National Institute of Neurological Disorders and Stroke Intramural Research Program as a special volunteer. D.H. is a full-time employee of Neurocrine Biosciences. The work outlined in this article has been performed in the capacity of Dr. Haubenberger's prior employment at the National Institute of Neurological Disorders and Stroke Intramural Research Program and is unrelated to his current employment. M.H. is an inventor of patents held by the National Institutes of Health (NIH) for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he has received license fee payments from the NIH (from Brainsway). He is on the medical advisory boards of CALA Health and Brainsway (both unpaid positions). He is on the editorial boards of approximately 15 journals and receives royalties and/or honoraria from publishing from Cambridge University Press, Oxford University Press, Springer, and Elsevier. He has research grants from Medtronic, Inc. for a study of deep brain stimulation for dystonia and CALA Health for studies of a device to suppress tremor. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. R.C.H.: 1A, 1B, 1C, 2A, 2B, 3A K.R.E.v.d.B.: 1B, 1C, 2B, 3A P.P.: 1A, 1B, 1C, 3B H.J.C.: 1A, 1B, 1C, 3B T.O.: 1A, 1B, 1C, 3B P.M.: 1A, 1B, 1C, 3B E.A.S.: 1A, 1B, 3B T.P.: 1A, 1B, 1C, 3B D.H.: 1A, 1B, 3B M.H.: 1A, 1B, 2C, 3B Appendix S1. Supporting Information. 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