Dopaminergic modulation of cortical function in patients with Parkinson's disease

Abstract

Patients with idiopathic Parkinson's disease suffer not only from classic motor symptoms, but from deficits in cognitive function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in patients with Parkinson's disease. Ten patients with stage I and II Parkinson's disease were studied with functional magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively correlated with errors in task performance, and the increased activation in the cortical motor regions during the dopamine-replete state was positively correlated with improvement in motor function. These results support evidence from basic research that dopamine modulates cortical networks subserving working memory and motor function via two distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency of this region.

L-DOPA Disrupts Activity in the Nucleus Accumbens during Reversal Learning in Parkinson's Disease

“…The present lack of cortical modulation of reversal-related activity apparently contradicts results from previous imaging studies in PD, which have revealed cortical changes (Cools et al, 2002b;Mattay et al, 2002;Lewis et al, 2003;Monchi et al, 2004). There are three explanations of this discrepancy.…”

“…There are three explanations of this discrepancy. First, the paradigms employed in previous L-DOPA withdrawal imaging studies measured working memory, which strongly implicates dorsolateral PFC (Cools et al, 2002b;Mattay et al, 2002). This concurs with overwhelming evidence for a role of PFC DA in working memory (Goldman-Rakic, 1992;Mattay et al, 2003;Meyer-Lindenberg et al, 2005).…”

“…It was hypothesized that the beneficial effect of L-DOPA on task-switching reflects a remediation of DA levels in severely depleted dorsal fronto-striatal circuitry, while, conversely, the impairing effect of L-DOPA on reversal learning reflects a detrimental 'over-dosing' of intact ventral fronto-striatal circuitry (Gotham et al, 1988;Swainson et al, 2000;Cools et al, 2001). In keeping with this hypothesis, previous functional imaging studies in PD patients have revealed that the beneficial effect of L-DOPA on working memory is accompanied by modulation of the dorsolateral PFC, which is strongly connected with the severely depleted dorsal striatum (Cools et al, 2002b;Mattay et al, 2002). However, no study has yet investigated the neural site at which L-DOPA acts to impair cognitive functioning.…”

Role of the Anterior Cingulate Cortex in the Control of Micturition Reflex in a Rat Model of Parkinson's Disease

“…Previous functional brain imaging studies have shown some overlaps as well as differences in brain activation sites during bladder filling between healthy volunteers and patients with PD who had detrusor overactivity 18 . Moreover, PD patients have decreasing ability to process sensory inputs as the disease progresses 19 , whereas other studies have demonstrated that PD patients require activation of larger cortical areas to manage tasks compared to normal controls 20 . These studies indicate that integrated cortical dysfunctions may play a role in the development of bladder dysfunction in PD.…”

The G72/G30 Gene Complex and Cognitive Abnormalities in Schizophrenia

“…The N Back task was used as a cognitive challenge because it reliably activates a working memory and attentional network that includes prefrontal cortex. Critically, in groups known to have prefrontal cortical pathophysiology (eg schizophrenia, Parkinson's disease), an inefficient response characterized by greater BOLD activation during this version of the Two Back test (vs 0 Back) has been found (Callicott et al, 2000;Mattay et al, 2002). Thus, we predicted that the individuals with the disadvantageous homozygous T,T genotype would show a less efficient neurophysiological response to working memory demands and vigilance in prefrontal cortex than individuals with A,T or A,A genotypes as based on prior studies.…”