Tremor Affects Cognition and Learning Skills in Differing Ways, Study Suggests

Tremor in Parkinson’s patients affects how well levodopa treatment, via dopamine production, affects learning skills in these people — supporting evidence of a link between tremor and cognition, a study found.

Specifically, its researchers showed that levodopa-treated patients without tremor had better reinforced learning skills (learning through rewards, like earning points on a test) than did those with tremor, who did better at avoidance learning (or  learning to avoid a punishment).

The study, “Effects of dopamine on reinforcement learning in Parkinson’s disease depend on motor phenotype,” was published in the journal Brain.

“This study tells us that the dopamine systems of Parkinson’s disease patients with and without tremor are affected in different ways, and that this goes beyond the level of just motor problems, affecting cognition as well,” Rick Helmich, a study co-author and neurologist, said in a press release.

Tremor is a characteristic motor symptom of Parkinson’s disease that most patients experience, although its severity can vary widely.

The minority of patients with non-tremor dominant Parkinson’s exhibit more severe cognitive symptoms, abnormal gait, and balance problems than do people with tremor-dominant disease. The loss of dopamine-producing nerve cells in the brain is also more pronounced in non-tremor patients.

Dopamine, the chemical messenger that is gradually lost to this disease, is a well-established factor for both motor skills and cognition, specifically decision-making and reinforcement learning. Parkinson’s patients are known to lose sensitivity to reward learning due to dopamine’s loss.

Levodopa works by converting to dopamine in the brain, but not all patients show the gains in reinforcement learning ability that might be expected with treatment.

Researchers at Radboud University in The Netherlands sought to determine if the presence of tremor in Parkinson’s patients was associated with levodopa’s effect on reinforcement learning. Specifically, they looked at patients’ ability to discern action-related outcomes and select actions to maximize positive outcomes and minimize negative ones.  

Their study was part of a larger, multi-year Phase 1/2 clinical trial (NL4940) to identify differences between and within tremor and non-tremor patient groups. It recruited 63 people with Parkinson’s disease (median age of 61) — 43 with tremor-dominant disease, and 20 were non-tremor dominant — and 22 healthy people serving as controls (median age 64.3). 

For a first testing session, patients were randomly assigned to either a standard oral dose of 200/50 mg levodopa-benserazide or to a placebo. For the second session, those previously given levodopa moved to a placebo and vice versa.  

All were assessed at two sessions over three months, with motor symptoms measured using the MDS-Unified Parkinson’s Disease Rating Scale while patients were off medication (off state). A second such measure was taken with patients on medication (on state). 

Tests at sessions were given as reinforcement learning tasks — positive “go or no go” cues  in order to win (points) — or as avoidance learning tasks — negative “go or no go” cues to avoid unpleasant situations. The tasks included combinations of motor response requirements (go or no go), and motivational choices (win/avoid). 

“We followed up any patient group effects with a comparison to healthy controls to assess whether medication ‘normalizes’ altered behaviour, or disturbs normal behaviour,” the researchers wrote.

All successfully learned given tasks, and showed motivational bias in their responses to positive and negative cues.

Patients in both the tremor and non-tremor groups showed a significant effect of levodopa’s use on their performance during “win” and “avoid” cues, but in opposite ways.

“The non-tremor group replicated the previous literature: patients ON levodopa exhibited higher accuracy in Win versus Avoid trials than those OFF levodopa,” the researchers wrote.

“In contrast, in the tremor group, those ON levodopa exhibited higher accuracy in the Avoid versus the Win trials relative to those OFF levodopa … but, surprisingly, lower accuracy in Avoid than Win trials OFF levodopa.”

In other words, levodopa’s use improved non-tremor patients’ accuracy in making reward-based choices consistent with results from previous studies. In tremor-dominant patients, levodopa improved learning from punishment.

Non-tremor patients’ performance was closer to that of controls when they were in a medication “on state,” while tremor patients’ performance was closer to controls when in an “off state.”

Computational models were used to evaluate if levodopa’s effects resulted from motivational learning or motivational bias. The best performing model separated learning rates for reward cues and punishment cues. 

Patients without tremor showed significantly lesser motivational bias, with no changes in reward or punishment learning rates. Among those with tremor, patients on levodopa had higher punishment learning rates than patients off medication, with no change in reward learning rate or motivational bias. This supported the previous finding that tremor patients on levodopa perform better when trying to avoid punishment.

“Our results provide evidence for different cognitive effects of dopamine-enhancing medication in tremor-dominant and non-tremor Parkinson’s disease patients,” the researchers wrote.

Specifically, “tremor-dominant patients under levodopa learned faster during trials when punishment needed to be avoided,” suggesting “a novel correspondence, with a dopaminergic basis, between motor and cognitive phenotypes in Parkinson’s disease patients,” they added.

“It is somewhat surprising that until now, studies of cognition in Parkinson’s disease never assessed the distinction between patients who exhibit tremor and those who do not. Our study shows that there is a link between problems with motor skills and problems with cognition in patients with Parkinson’s disease,” Hanneke den Ouden, a brain researcher at Radboud University, said in the release.

The researchers also suggested that these results “may have brought to light a structural testing bias in earlier studies, and underline the importance of increased awareness of interpatient diversity in Parkinson’s disease.”