Dopamine controls Parkinson’s tremor by inhibiting the cerebellar thalamus

Abstract

Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello-thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude-related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self-inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role in Parkinson's tremor.aww331media15307619934001.

Changing views of the pathophysiology of Parkinsonism

“…The basal ganglia–receiving portion of the ventral motor thalamus is also innervated by dopaminergic fibers, arising from several dopaminergic cell groups in the midbrain . There appears to be a substantial loss of the thalamic dopaminergic innervation in MPTP‐induced parkinsonism in monkeys, which could be related to the emergence of tremor (see also below) …”

“…The pathophysiology of parkinsonian tremor thus likely differs from that of bradykinesia or akinesia (which do not respond to such interventions). Imaging and modeling studies have suggested that dopaminergic denervation of the cerebellar receiving territory of the thalamus may contribute to tremor, and that dopaminergic drugs could act directly in the thalamus in such patients . STN‐DBS also affects cerebellar function, perhaps through the pathways shown in Figure , which may account for some of its antiparkinsonian effects, specifically its effects on parkinsonian tremor .…”

“…[190][191][192] There appears to be a substantial loss of the thalamic dopaminergic innervation in MPTPinduced parkinsonism in monkeys, 189 which could be related to the emergence of tremor (see also below). 193,194 Activation of extrastriatal dopamine receptors may contribute to the antiparkinsonian efficacy of systemically administered dopamine receptor agonists, specifically to that of D2LR agonists such as ropinirole or pramipexole. Conceivably, activation of extrastriatal D2LRs by these agents could lower firing irregularities through actions in the STN, while reducing the overall basal ganglia output through actions in SNr and GPi.…”

“…Imaging and modeling studies have suggested that dopaminergic denervation of the cerebellar receiving territory of the thalamus may contribute to tremor, and that dopaminergic drugs could act directly in the thalamus in such patients. 193 STN-DBS also affects cerebellar function, 239,240 perhaps through the pathways shown in Figure 1, which may account for some of its antiparkinsonian effects, 240 specifically its effects on parkinsonian tremor. 241 Although there is mounting evidence that parkinsonian tremor involves the cerebello-thalamocortical system in some way, details of the pathophysiology of parkinsonian tremor remain entirely speculative.…”

Prelemniscal Lesion for Selective Improvement of Parkinson Disease Tremor

“…In the studied cases, 3 fiber components were identified: cerebellar-thalamic-cortical fibers, globus pallidus (Gp)-pedunculopontine fibers, and frontal orbitofrontal cortex-mesencephalic tegmental fibers. Cerebellar thalamic fibers have been implicated in the physiopathology of tremor [4] since a large component enters the nucleus ventralis intermedius (Vim) connecting with the primary motor cortex. Recently it has been described that, with deep brain stimulation (DBS), the achievement of optimum results for tremor control in Vim depends on the proximity of active contacts to the cerebellar fibers ending in the Vim [5].…”