Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD

Abstract

Objective: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls).

Methods: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H₂(15)O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback.

Results: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity.

Conclusions: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions--outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)--together with restricted access of those areas to executive control (external pallidum)--may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.

Figure 1 Differential effect of medication on brain activity in the 2 patient groups In brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex [OFC], rostral cingulate zone [RCZ], amygdala, external pallidum), controls significantly increased activity in response to dopamine agonist (DA), while gamblers showed a significant DA-induced reduction of activity. Projections of statistical parametric maps superimposed on a standardized MRI template. The bar graphs show regional cerebral blood flow (rCBF) in the peak voxel of the significant cluster. Stereotactic coordinates (x, y, z) are given in mm. *Significant differences in rCBF. CI = confidence interval.

Figure 2 Relationship between regional cerebral blood flow (rCBF) change and changes in gambling symptoms Dopamine agonist (DA)-induced change in gambling severity plotted against DA-induced change in brain activity in gamblers (red) and controls (blue). Only in gamblers, DA-induced rCBF change showed a strong positive relationship with DA-induced change in gambling severity. m = Slope of linear regression (change in gambling severity/change in rCBF). Stereotactic coordinates (x, y, z) are given in mm.