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.

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.

Eligibility Criteria:
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.