Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor

Area of Science:

• Neuroscience
• Neurology
• Movement Disorders

Background:

• Parkinson disease (PD) involves striatal dopamine depletion, explaining motor symptoms like bradykinesia and rigidity.
• Resting tremor in PD is linked to increased activity in the cerebellothalamic circuit, distinct from striatal dopamine depletion.
• The precise interplay between the basal ganglia and cerebellothalamic circuit in generating resting tremor remains unclear.

Purpose of the Study:

• To investigate the functional connectivity and activity patterns within the basal ganglia and cerebellothalamic circuit in PD patients with and without tremor.
• To determine the relationship between dopamine depletion, basal ganglia activity, cerebellothalamic circuit function, and tremor severity in PD.

Main Methods:

• Functional magnetic resonance imaging (fMRI) assessed functional connectivity between basal ganglia nuclei (globus pallidus internus [GPi], globus pallidus externus [GPe], putamen, caudate) and the cerebellothalamic circuit in 21 tremor-dominant PD patients, 23 non-tremor PD patients, and 36 controls.
• Electromyography (EMG) measured tremor-related activity in these circuits during fMRI.
• Iodine-123-N-omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([I-123]FP-CIT) single photon emission computed tomography (SPECT) quantified striatopallidal dopamine depletion.

Main Results:

• Pallidal dopamine depletion, not striatal, correlated with clinical tremor severity.
• The GPi, GPe, and putamen showed transient activation at tremor onset, while cerebellothalamic circuit activity correlated with tremor amplitude.
• Tremor-dominant PD patients exhibited increased functional connectivity between the GPi/putamen and the cerebellothalamic circuit, mediated via the motor cortex.

Conclusions:

• Resting tremor in PD may arise from pathological interactions between the basal ganglia and the cerebellothalamic circuit.
• Dopamine-depleted basal ganglia transmit signals that drive the cerebellothalamic circuit into tremor generation, explaining tremor amplitude control.
• This model accounts for why basal ganglia dysfunction is necessary for resting tremor, even though the cerebellothalamic circuit produces it, and why interventions targeting either circuit can alleviate tremor.