Parkinson's disease duration determines effect of dopaminergic therapy on ventral striatum function.

We investigated the hypothesis that variation in endogenous dopamine (DA) across brain regions explains dissimilar effects of dopaminergic therapy on aspects of cognition in early Parkinson's disease (PD). Extensive degeneration of DA-producing cells in the substantia nigra cause dorsal striatum (DS) DA deficiency and movement abnormalities. Particularly in early PD, this contrasts with relative sparing of the dopaminergic cells of the ventral tegmental area (VTA). The hypothesis predicts that DS-mediated cognitive functions are deficient at baseline and improved by DA replacement, whereas functions depending upon VTA-innervated brain regions are normal off medication and worsen with treatment. The latter pattern presumably owes to overdose of relatively DA-replete VTA-supplied brain regions with medication levels titrated to DS-mediated motor symptoms. As PD progresses, however, VTA degeneration increases. Impairment in cognitive operations performed by VTA-innervated brain regions, such as the ventral striatum (VS), is expected. We compared the performance of early and late PD patients, on and off dopaminergic medication, relative to age-matched controls, on reward learning, previously shown to implicate the VS. As expected, in early PD, stimulus-reward learning was normal off medication, but worsened with DA replacement. At more advanced disease stages, PD patients learned stimulus-reward contingencies more poorly than controls and early PD patients off medication. Furthermore, dopaminergic medication did not worsen reward learning in late PD patients, in line with the dopamine overdose hypothesis. Unlike its effect on DS-mediated functions, however, DA-replacement therapy did not improve reward learning in late PD patients.