TremorNCT05512299
Investigating Cerebellar Inhibition and Its Clinical Significance in Parkinsonian Tremor and Intention Tremor
An observational study of Tremor, run by China Medical University Hospital at 1 site in Taiwan.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Tremor
- What is being tested?
- Transcranial Magnetic Stimulation
- How many people
- 84 participants
- Where
- 1 siteTaiwan
- Study dates
- 1 Aug 2022to 31 Jul 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- Patients meet the diagnosis of PD with resting/postural or cerebellar degeneration with intention tremor based on the established consensus criteria.
Who cannot join
- Patients with contraindication to TMS or MRI examination.
- Impairment of cognition that leads unable to fully cooperate with the oral commands during examinations.
- Functional III or above congestive heart failure, or cancer with distant metastasis.
Trial locations and contacts
1 site in 1 country.
Taiwan1 site, 1 recruiting
- Recruiting
Department of Neurology, China Medical University Hospital
Taichung, 40447
Ming-Kuei Lu, MD, PhD, +886-4-22052121 ext. 5039, d4297@mail.cmuh.org.tw
About this study
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.
Read the 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.
- Conditions
- Tremor
- Being tested
- Transcranial Magnetic Stimulation
- Keywords
- cerebellar inhibition, pallidothalamic tractotomy, thalamotomy, Parkinson's disease, MR-guided focused ultrasound
- Medical subject headings
- Tremor, Parkinson Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcranial Magnetic StimulationDiagnostic test
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.
| Study group | Role | What they receive |
|---|---|---|
| PD with resting tremor | Parkinson's disease patient with pure resting tremor. Receives: Diagnostic Test: Transcranial Magnetic Stimulation | |
| PD with postural tremor | Parkinson's disease patient with postural tremor. Receives: Diagnostic Test: Transcranial Magnetic Stimulation | |
| Cerebellar degeneration with intention tremor | Cerebellar degeneration patient with intention tremor. Receives: Diagnostic Test: Transcranial Magnetic Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: baseline (before the MRgFUS), 48-weeks after the MRgFUS
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Aug 2022
- Study start1 Aug 2022
- Primary completion31 Jul 2023 (estimated)
- Study completion31 Jul 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for TremorStudies of the same condition, open and under way.
- More trials run by China Medical University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- China Medical University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Ministry of Science and Technology, Taiwan
- Responsible party
- Sponsor
- Investigators
- Ming-Kuei Lu, MD, PhD, Principal investigator, Department of Neurology, China Medical University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05512299
- Sponsor's protocol ID
- CMUH111-REC3-014
- Status last verified
- Aug 2022
- First submitted
- 19 Aug 2022
- Last updated
- 23 Aug 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigating Cerebellar Inhibition and Its Clinical Significance in Parkinsonian Tremor and Intention Tremor
- ClinicalTrials.gov ID
- NCT05512299
- Acronym / sponsor ID
- CMUH111-REC3-014
- Conditions
- Tremor
- Keywords
- cerebellar inhibition, pallidothalamic tractotomy, thalamotomy, Parkinson's disease, MR-guided focused ultrasound
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- China Medical University HospitalUniversity, hospital or other
- Collaborators
- Ministry of Science and Technology, Taiwan
- Study start
- 1 Aug 2022 (actual)
- Primary completion
- 31 Jul 2023 (estimated)
- Study completion
- 31 Jul 2024 (estimated)
- First posted
- 23 Aug 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| PD with resting tremor | – | Diagnostic Test: Transcranial Magnetic StimulationParkinson's disease patient with pure resting tremor. |
| PD with postural tremor | – | Diagnostic Test: Transcranial Magnetic StimulationParkinson's disease patient with postural tremor. |
| Cerebellar degeneration with intention tremor | – | Diagnostic Test: Transcranial Magnetic StimulationCerebellar degeneration patient with intention tremor. |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (1 listed)
- Patients meet the diagnosis of PD with resting/postural or cerebellar degeneration with intention tremor based on the established consensus criteria.
Key exclusion criteria (3 listed)
- Patients with contraindication to TMS or MRI examination.
- Impairment of cognition that leads unable to fully cooperate with the oral commands during examinations.
- Functional III or above congestive heart failure, or cancer with distant metastasis.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcranial Magnetic StimulationThe 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. | Diagnostic test | Cerebellar degeneration with intention tremor, PD with postural tremor, PD with resting tremor |
Primary outcome
Change from baseline cerebellar inhibition (CBI) input output curve
Time frame: baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
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.
Change from baseline functional magnetic resonance imaging
Time frame: baseline (before the MRgFUS), 48-weeks after the MRgFUS
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.
3 secondary outcomes
Change from baseline clinical evaluations
Time frame: baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Change from baseline gait analysis
Time frame: baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Change from baseline surface electromyography and eye-tracking pattern
Time frame: baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ming-Kuei Lu, MD, PhD principal investigator
Department of Neurology, China Medical University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Tremor, run by China Medical University Hospital at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 23 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ming-Kuei Lu, MD, PhD (8864-22052121 ext. 5039, d4297@mail.cmuh.org.tw), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline cerebellar inhibition (CBI) input output curve (time frame: baseline (before the MRgFUS), 1-day, 24-weeks and 48-weeks after the MRgFUS). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2022.