Cognitive Stress Reduces the Effect of Levodopa on Parkinson's Resting Tremor

Abstract

SummaryAimsResting tremor in Parkinson′s disease (PD) increases markedly during cognitive stress. Dopamine depletion in the basal ganglia is involved in the pathophysiology of resting tremor, but it is unclear whether this contribution is altered under cognitive stress. We test the hypothesis that cognitive stress modulates the levodopa effect on resting tremor.MethodsTremulous PD patients (n = 69) were measured in two treatment conditions (OFF vs. ON levodopa) and in two behavioral contexts (rest vs. cognitive co‐activation). Using accelerometry, we tested the effect of both interventions on tremor intensity and tremor variability.ResultsLevodopa significantly reduced tremor intensity (across behavioral contexts), while cognitive co‐activation increased it (across treatment conditions). Crucially, the levodopa effect was significantly smaller during cognitive co‐activation than during rest. Resting tremor variability increased after levodopa and decreased during cognitive co‐activation.ConclusionCognitive stress reduces the levodopa effect on Parkinson's tremor. This effect may be explained by a stress‐related depletion of dopamine in the basal ganglia motor circuit, by stress‐related involvement of nondopaminergic mechanisms in tremor (e.g., noradrenaline), or both. Targeting these mechanisms may open new windows for treatment. Clinical tremor assessments under evoked cognitive stress (e.g., counting tasks) may avoid overestimation of treatment effects in real life.

The cerebral basis of Parkinsonian tremor: A network perspective

“…We have previously focused on 1 of these modulatory factors: cognitive stress. In a sample of 69 tremor‐dominant PD patients, we measured resting tremor power (using accelerometry) under the following 4 conditions: OFF and ON 200/50 mg levodopa and with and without cognitive stress (subtracting 7 from 100 as fast as possible) . We replicated previous findings that showed that levodopa reduced tremor overall, whereas cognitive stress increased tremor .…”

“…The idea that dopaminergic denervation of thalamic nuclei has a role in the pathophysiology of PD, particularly tremor, requires further validation, for example, in postmortem studies. The finding that dopamine influenced both the pallidum and the VLp may explain why levodopa reduces both the occurrence of tremor (possibly by acting on the pallidum) and the amplitude of the tremor (possibly by acting on the VLp) . It may also explain why dopaminergic dysfunction of the pallidum per se is not sufficient for tremor development.…”

The Impact of the COVID-19 Pandemic on Parkinson’s Disease: Hidden Sorrows and Emerging Opportunities

“…Importantly, increased levels of stress during the COVID-19 pandemic may have several short-term as well as long-term adverse consequences for individuals with PD. First, increased psychological stress can temporarily worsen various motor symptoms, such as tremor, freezing of gait or dyskinesias [6][7][8][9], while it reduces the efficacy of dopaminergic medication [6]. Second, increased stress may unmask a latent hypokinetic rigid syndrome, possibly by depleting compensatory mechanisms [10,11].…”

Pathophysiology and Management of Parkinsonian Tremor

“…Clinically, it is clear that tremor increases during stress. [24][25][26][27] This may suggest that noradrenaline has a role in modulating tremor amplitude, but clear empirical evidence is lacking. Previous work has shown that intravenous injection of adrenaline increases tremor, possibly by activating the cerebral locus coeruleus noradrenaline system.…”

“…27 On the other hand, the antitremor effect of levodopa was smaller for tremor under stress than for tremor at rest. 26 This suggests that nondopaminergic mechanisms (possibly the noradrenergic system) have a context-dependent role in amplifying resting tremor. This may partly explain why tremor appears to be dopamine-resistant in some patients.…”