Parkinson’s Disease Duration Determines Effect of Dopaminergic Therapy on Ventral Striatum Function Alex A. MacDonald, BSc, 1 Oury Monchi, PhD, 2,3 Ken N. Seergobin, MSc, 4 Hooman Ganjavi, MD, PhD, 5 Ruzbeh Tamjeedi, BA, 6 and Penny A. MacDonald, MD, PhD 7,8 * 1 Department of Psychology, McGill University, Montreal, Quebec, Canada 2 Functional Neuroimaging Unit, Centre de Recherche, Institut Universitaire de G eriatrie de Montr eal, Montreal, Quebec, Canada 3 Department of Radiology, University of Montreal, Montreal, Quebec, Canada 4 Centre for Biological Timing and Cognition, University of Toronto, Toronto, Ontario, Canada 5 Department of Psychiatry, The University of Western Ontario, London, Ontario, Canada 6 Department of Philosophy, McGill University, Montreal, Quebec, Canada 7 The Brain and Mind Institute, The University of Western Ontario, London, Ontario, Canada 8 Department of Clinical Neurological Sciences, The University of Western Ontario, London, Ontario, Canada ABSTRACT: We investigated the hypothesis that variation in endogenous dopamine (DA) across brain regions explains dissimilar effects of dopaminergic ther- apy 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 defi- ciency and movement abnormalities. Particularly in early PD, this contrasts with relative sparing of the dopaminer- gic cells of the ventral tegmental area (VTA). 1 The hy- pothesis predicts that DS-mediated cognitive functions are deficient at baseline and improved by DA replace- ment, whereas functions depending upon VTA-innervated brain regions are normal off medication and worsen with treatment. The latter pattern presumably owes to over- dose of relatively DA-replete VTA-supplied brain regions with medication levels titrated to DS-mediated motor symptoms. 2,3 As PD progresses, however, VTA degener- ation increases. Impairment in cognitive operations per- formed by VTA-innervated brain regions, such as the ventral striatum (VS), is expected. We compared the per- formance of early and late PD patients, on and off dopa- minergic 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 medica- tion. Furthermore, dopaminergic medication did not wor- sen reward learning in late PD patients, in line with the dopamine overdose hypothesis. Unlike its effect on DS-mediated functions, however, DA-replacement ther- apy did not improve reward learning in late PD patients. V C 2012 Movement Disorder Society Key Words: Parkinson’s disease; cognition; striatum; dopamine; basal ganglia Parkinson’s disease (PD) is characterized by differen- tial degeneration of dopamine (DA)-producing cells in the substantia nigra (SN) and the ventral tegmental area (VTA), particularly early in the disease course. 1 Motor symptoms of tremor, bradykinesia, and rigidity appear when degeneration in the SN is sufficient to seriously restrict DA to its efferent, the dorsal striatum (DS). 4,5 The VTA is relatively spared, 4,6–8 and early in disease, the ventral striatum (VS), as well as the pre- frontal and limbic cortices that it innervates, remain well supplied of DA. 5 As PD progresses, VTA degener- ation and DA deficiency of its efferents increase. Dopaminergic medications, such as L-3,4-dihydroxy- phenylalanine (levodopa) and DA agonists (DAAs), are highly effective in addressing the motor symptoms of ------------------------------------------------------------ *Correspondence to: Dr. Penny A. MacDonald, The Brain and Mind Institute, Natural Sciences Centre, Room 235, The University of Western Ontario London, Ontario, Canada; penny.macdonald@gmail.com Funding agencies: This research was funded by a Canadian Institutes of Health Research Clinician-Scientist Phase I Scholarship. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 9 April 2012; Revised: 22 June 2012; Accepted: 28 June 2012 Published online 19 November 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25152 RESEARCH ARTICLE Movement Disorders, Vol. 28, No. 2, 2013 153