Pathological Gambling in Parkinson's Disease: New Insights from Functional Neuroimaging

Abstract & Commentary

By Melissa J. Nirenberg, MD, PhD, Assistant Professor, Neurology and Neuroscience, Weill Cornell Medical College, New York, NY. Dr. Nirenberg has done consulting for Biovail and participated in clinical research trials sponsored by Boehringer-Ingleheim.

Synopsis: Pathological gambling related to dopamine replacement therapy in Parkinson's disease is associated with overactivity of a right hemisphere network that includes regions involved in impulse control, reward, motivation, and memory.

Source: Cilia R, Siri C, Marotta G, et al. Functional abnormalities underlying pathological gambling in Parkinson disease. Arch Neurology 2008;65:1604-1611.

The use of dopamine replacement therapy (DRT) in Parkinson's disease (PD), and dopamine agonists in particular, has been associated with the development of uncontrolled behaviors, including pathological gambling, hypersexuality, compulsive eating, and compulsive buying. These impulse control disorders (ICDs) are thought to be behavioral addictions, and share many similarities with other addiction disorders, including the potential for devastating psychosocial consequences. Pathological gambling is one of the most common ICDs that occurs in PD, but little is known about its underlying physiological substrates.

In this study, the authors used functional neuroimaging with single-photon emission computed tomography (SPECT) to test the hypothesis that the pattern of brain activity in PD patients with pathological gambling differs from that of controls. Using a case-control study design, they compared resting-state brain perfusion patterns in: 1) PD subjects who currently met DSM-IV criteria for pathological gambling that began after initiation of DRT (n = 11); 2) PD controls with similar demographic features and DRT use but no history of pathological gambling (n = 40); and 3) age-matched healthy controls (n = 29). Subjects were excluded if they had a history of cognitive impairment, prior neurosurgery, or use of psychoactive medications other than DRT. None of the subjects had a history of excessive self-medication with dopaminergic medications (dopamine dysregulation syndrome). All subjects with PD were taking dopaminergic medications at the time of the study.

In comparison with PD controls, PD pathological gamblers in this study had resting state overactivity in a right hemisphere network that included the lateral orbitofrontal cortex extending to the insula; hippocampus extending to the parahippocampal gyrus and amygdala; and ventral pallidum. No areas of reduced cerebral blood flow were seen in PD subjects with pathological gambling compared with PD controls. The authors postulate that DRT-related pathological gambling in PD may be the result of excessive dopaminergic stimulation of relatively preserved mesocorticolimbic pathways, rather than a neurodegenerative process.

Commentary

Pathological gambling is one of the most common and well-studied ICDs in PD. Apparent risk factors include the use of dopaminergic medications (particularly dopamine agonists), male gender, personal or family history of addiction disorders, and high impulsivity and novelty-seeking traits. The biological basis of pathological gambling and other ICDs in PD is poorly understood, but may be related to non-physiological stimulation of postsynaptic dopamine receptors (particularly the D3 subtype) in the mesocorticolimbic dopaminergic system, and/or a tendency for dopaminergic medications to produce impulsivity and increased sensitivity to reward.

In this study, the authors used functional neuroimaging to demonstrate a correlation between DRT-related pathological gambling and increased activity in a right hemisphere network that included areas involved in impulse control, reward, reward-based learning, motivation, and memory. Strengths of the study include the use of two sets of control subjects (PD and non-PD) and the biological plausibility of the findings. Limitations include the relatively small number of subjects with pathological gambling (all but one of whom was male), and the lack of comparison of subjects on versus off of dopaminergic medications. Further studies are warranted to confirm and expand the observed findings, and to determine whether the observed network changes persist in the absence of DRT.

The brain regions that were overactive in PD patients with pathological gambling were similar to those implicated in the pathophysiology of ICDs in non-PD patients. The findings support the concept of pathological gambling in PD as a behavioral addiction, and provide new insights about potential mechanisms of this and other compulsive, reward-seeking behaviors in the general population.