Overdosing the Parkinsonian brain

Most people know that patients with Parkinson’s disease are impaired in their movements. But it is less well known that patients also suffer from mental problems: they find it difficult to do multiple things at the same time or to plan ahead for instance. The dopaminergic medication that they take helps them move and think. Unfortunately, in some patients, the same medication can also contribute to worrisome impulsive behavior with respect to reward, such as pathological gambling or compulsive shopping. 

 Pouring water in a glass that is already full. 

Pouring water in a glass that is already full. 

These contradictory effects of medication – on the one hand improving moving and thinking, but on the other hand causing impulsivity – have been attributed to effects of medication on different regions in the Parkinsonian brain. Dopaminergic medication would ‘refill’ regions deep in the brain that have a severe shortage of dopamine due to the disease. Those are the regions that are involved in moving and thinking. However, medication acts on the entire brain, so also on deep brain structures that do not have a dopamine shortage yet. These regions – involved in reward – would get ‘overdosed’, comparable with pouring water in a glass that is already full. The consequence is exaggerated sensitivity to reward and, hence, impulsivity. This theory has been around since the beginning of the century. Yet, actual evidence was lacking that medication improves moving and thinking by acting on the regions with dopamine shortage, and – at the same time, in the same patients – medication ‘overdoses’ more intact regions in the Parkinsonian brain involved in reward processes. 

In our recent study, published in Neuropsychologia, patients performed a computer game (i.e. task) that involved a mental component (i.e. hard and easy parts) and a reward component (i.e. promising 15 cents or only 1 cent reward for correct answers). Concurrently, we looked at patients’ brain activation using functional magnetic resonance imaging (fMRI). Patients came twice to the lab to do the task: once while on their normal medication regime and once when not taking their medication. We found that when the brain region with a shortage of dopamine (called the dorsal striatum) was more active with than without medication, this was accompanied by better mental capabilities with than without medication. However, when – in the same patients, during the same task – the brain region with intact dopamine levels (called the ventral striatum) was more active with than without medication, this was accompanied by worse reward performance (i.e. more ‘impulsivity’) with than without medication. This seems to suggest that mental capabilities improved because the first region (dorsal striatum) got ‘refilled’, whereas impulsivity arised because the latter region (ventral striatum) got ‘overflowed’ by dopaminergic medication.

Interestingly, only a few patients showed this overflowing of their reward region. In most patients, this region was less active with than without medication, and reward performance was better (i.e. less ‘impulsivity’) with than without medication. Thus, it appears important to take individual differences into account, as not every patient responds the same to medication. Our results are in line with the observation that only some patients become impulsive on their anti-Parkinson medication, whereas others do not. Future studies should investigate the cause of these individual differences, as this will create huge potential for more personalized medication treatment in Parkinson’s disease patients.

This blog was written by Esther Aarts, senior researcher of the lab, and accompanies this paper:

Aarts E, Nusselein AAM, Smittenaar P, Helmich RC, Bloem BR, Cools, R (2014). Greater striatal responses to medication in Parkinson's disease are associated with better task-switching but worse reward performance. Neuropsychologia 62: 390-397. (link)