Investigating Cerebellar Inhibition and Its Clinical Significance in Parkinsonian Tremor and Intention Tremor

Cerebellocerebral connection plays an important function in motor control. Nowadays it can be investigated with neuroimaging and physiological methods in humans. Cerebellar inhibition (CBI) is a phenomenon showing a physiological suppression of the motor evoked potential (MEP) evoked from the motor cortex (M1) by delivering a preceding transcranial magnetic stimulation (TMS) on the contralateral cerebellum. Despite the mediated pathway is supposed to be the cerebello-dentato-thalamo-cortical (CDTC) circuit, there is no conclusive evidence. In addition, the clinical significant of CBI remains unclear. Based on our previous studies, we found that the patients with advanced tremor show an impaired Bereitschaftspotential. The findings support a notion that the patients with tremor bear dysfunction of the CDTC circuit. Intriguingly, the pathogenesis of the parkinsonian tremor is highly associated with the CDTC circuit. The "dimmer-switch" model suggests that the basal ganglia-thalamo-cortical circuit dysfunction may initiate the resting tremor, and the following CDTC circuit dysfunction will lead to the large-amplitude resting and postural tremor in Parkinson's disease (PD). The intention tremor is usually found in the patients with cerebellar degeneration, which is also relevant to the CDTC circuit dysfunction. We expect that the clinical significance of CBI and the mediated pathway of CBI will be clarified by this study.

Study Overview

• Status: Recruiting
• Conditions: Tremor
• Intervention / Treatment: Diagnostic test: Transcranial Magnetic Stimulation

Detailed Description

The patients with hereditary cerebellar degeneration usually present intention tremor. Whether the intention tremor and the other cerebellar signs are correlated with their CBI finding remains unclear. By measuring the excitability curve (or input-output curve) of the CBI, we will be able to clarify this issue.

We will first examine the relationship between CBI and clinical manifestations, particularly the different tremor types. Any CBI change following the PTT intervention in the PD patients will provide an excellent opportunity to investigate the relevance of the basal ganglia-thalamo-cortical circuit with CBI. The DTI findings will provide additional support to our hypothesis.

In the first part of the study, we will recruit twenty age-matched patients into the three groups: PD with pure resting tremor, PD with postural tremor and cerebellar degeneration with intention tremor. They will receive clinical assessments, deep phenotyping with eye tracking, tremor recording and gait analysis. Diffusion tensor imaging focusing on pallidothalamic and dentatothalamic tractography will be done. The excitability curve of CBI will be examined with five TMS intensity steps. We suppose that there will be a gradient correlation of the CBI with the three tremor groups and the two diffusion tensor imaging tracts. In the second part of the study, we will follow up the PD patients who receive the pallidothalamic tractotomy via magnetic resonance imaging-guided focus ultrasound (MRg-FUS). Twelve PD patients with pure resting tremor and twelve PD patients with postural tremor will be monitored for one year. The pallidothalamic tractotomy provides an excellent opportunity to verify our findings in the first part. We suppose that the CBI change will occur in the patients with postural tremor instead of those with pure resting tremor. In summary, we expect that the clinical significance of CBI and the mediated pathway of CBI will be clarified by this study.

• Study Type: Observational
• Enrollment (Anticipated): 84

Contacts and Locations

• Study Contact: Name: Ming-Kuei Lu, MD, PhD; Phone Number: 5039 8864-22052121; Email: d4297@mail.cmuh.org.tw

Study Locations

• Taiwan
  • Taichung, Taiwan, 40447
    • Recruiting
    • Department of Neurology, China Medical University Hospital
    • Contact: Ming-Kuei Lu, MD, PhD; Phone Number: 5039 +886-4-22052121; Email: d4297@mail.cmuh.org.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult PD patients with pure resting tremor or mixed resting and postural tremor will be studied. Some of them are the patients receiving MR-guided focus ultrasound (MRgFUS). In addition, patients with cerebellar degeneration with intention tremor will be also recruited. Those patients with contraindication to TMS or MRI examination will be excluded.

Description

Inclusion Criteria:

Patients meet the diagnosis of PD with resting/postural or cerebellar degeneration with intention tremor based on the established consensus criteria.

Exclusion Criteria:

1. Patients with contraindication to TMS or MRI examination.
2. Impairment of cognition that leads unable to fully cooperate with the oral commands during examinations.
3. Functional III or above congestive heart failure, or cancer with distant metastasis.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PD with resting tremor; Parkinson's disease patient with pure resting tremor.	Diagnostic test: Transcranial Magnetic Stimulation; The CBI is recorded with two different TMS coils. The figure-of-eight coil (2X90 mm) is used for the motor cortex stimulation and the double cone coil (2X126 mm) is used for the cerebellar stimulation. The target recording muscle is first dorsal interosseous (FDI). The TMS intensity used to induce an average MEP amplitude of 0.5 mV is also determined. CBI is measured by a paired TMS with an inter-stimulus interval of 6 ms. That is, the test TMS at M1 is delivered 6 ms following the conditional TMS at contralateral cerebellum.
PD with postural tremor; Parkinson's disease patient with postural tremor.	Diagnostic test: Transcranial Magnetic Stimulation; The CBI is recorded with two different TMS coils. The figure-of-eight coil (2X90 mm) is used for the motor cortex stimulation and the double cone coil (2X126 mm) is used for the cerebellar stimulation. The target recording muscle is first dorsal interosseous (FDI). The TMS intensity used to induce an average MEP amplitude of 0.5 mV is also determined. CBI is measured by a paired TMS with an inter-stimulus interval of 6 ms. That is, the test TMS at M1 is delivered 6 ms following the conditional TMS at contralateral cerebellum.
Cerebellar degeneration with intention tremor; Cerebellar degeneration patient with intention tremor.	Diagnostic test: Transcranial Magnetic Stimulation; The CBI is recorded with two different TMS coils. The figure-of-eight coil (2X90 mm) is used for the motor cortex stimulation and the double cone coil (2X126 mm) is used for the cerebellar stimulation. The target recording muscle is first dorsal interosseous (FDI). The TMS intensity used to induce an average MEP amplitude of 0.5 mV is also determined. CBI is measured by a paired TMS with an inter-stimulus interval of 6 ms. That is, the test TMS at M1 is delivered 6 ms following the conditional TMS at contralateral cerebellum.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline cerebellar inhibition (CBI) input output curve	The CBI is recorded with two different TMS coils. The figure-of-eight coil (2X90 mm) is used for the motor cortex stimulation and the double cone coil (2X126 mm) is used for the cerebellar stimulation. The target recording muscle is first dorsal interosseous (FDI). The TMS intensity used to induce an average MEP amplitude of 0.5 mV is also determined. CBI is measured by a paired TMS with an inter-stimulus interval of 6 ms. That is, the test TMS at M1 is delivered 6 ms following the conditional TMS at contralateral cerebellum. There are five TMS intensities used for the conditional cerebellar stimulation: 80%, 90%, 100%, 110% and 120% inion active motor threshold. Ten trials are recorded for each TMS intensity with a pseudorandomized order. The interval between two cerebellum-M1 TMS pairs is 8-seconds with 25% variability (i.e. 6-10 s) to reduce the prediction bias.	baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Change from baseline functional magnetic resonance imaging	In this study we mainly adopt diffusion tensor imaging (DTI) to quantify two interested projections: the pallidothalamic pathway and the dentatothalamic pathway. Diffusion tensor imaging of fifty gradient directions is acquired with five non-gradient (B0) images. The B-value is 1500 s/mm2, FOV = 240mm x 240mm, image matrix = 96 x 96, slice thickness = 2.5mm with zero gap. The voxel size is 2.5 x 2.5 x 2.5 mm3 isotopically. The TR was approximately 10000ms which is adjusted to match the slice number of requirements. Image acquired with axial direction, 56 slices to cover the whole brain.	baseline (before the MRgFUS), 48-weeks after the MRgFUS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline clinical evaluations	In addition to a detailed history and neurological examinations, the clinical assessment also includes International Parkinson and Movement Disorder Society-sponsored UPDRS (MDS-UPDRS) and clinical rating scale for tremor (CRST)for the PD patients. The Scale for the Assessment and Rating of Ataxia (SARA) and CRST are adopted for the patients with cerebellar degeneration.	baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Change from baseline gait analysis	The gait analysis system (Zeno Walkway System with PKMAS) provides detailed gait parameters including velocity, cadence, pressure and cyclogram. Variables in gait analysis: 1.Gait initiation, 2.Level walking, 3.Gait termination.	baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Change from baseline surface electromyography and eye-tracking pattern	The pattern of eye-tracking and surface electromyography (SEMG) with accelerometer will be recorded to monitor the therapy outcome. The eye-tracking system (EyeLink 1000 Plus) will track eye movements regarding the target fixation, saccade, smooth pursuit and image stimuli. The multiple SEMG recording (CED Power1401) will focus on the arm and hand muscles relevant to the tremor (e.g. first dorsal interosseous, abductor pollicis brevis, extensor carpi radialis and flexor carpi radialis). The accelerometer can also reveal the mechanical information of the tremor oscillation.	baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS

Collaborators and Investigators

• Sponsor: China Medical University Hospital
• Collaborators: Ministry of Science and Technology, Taiwan
• Investigators: Principal Investigator: Ming-Kuei Lu, MD, PhD, Department of Neurology, China Medical University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2022
• Primary Completion (Anticipated): July 31, 2023
• Study Completion (Anticipated): July 31, 2024

Study Registration Dates

• First Submitted: August 19, 2022
• First Submitted That Met QC Criteria: August 21, 2022
• First Posted (Actual): August 23, 2022

Study Record Updates

• Last Update Posted (Actual): August 23, 2022
• Last Update Submitted That Met QC Criteria: August 21, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Parkinson's disease; cerebellar inhibition; pallidothalamic tractotomy; thalamotomy; MR-guided focused ultrasound
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Tremor
• Other Study ID Numbers: CMUH111-REC3-014

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No