Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease

Abstract

Patients with Parkinson's disease (PD) may experience impulse control disorders (ICDs) when on dopamine agonist therapy for their motor symptoms. In the last few years, a rapid growth of interest for the recognition of these aberrant behaviors and their neurobiological correlates has occurred. Recent advances in neuroimaging are helping to identify the neuroanatomical networks responsible for these ICDs, and together with psychopharmacological assessments are providing new insights into the brain status of impulsive behavior. The genetic associations that may be unique to ICDs in PD are also being identified. Complementing human studies, electrophysiological and biochemical studies in animal models are providing insights into neuropathological mechanisms associated with these disorders. New animal models of ICDs in PD patients are being implemented that should provide critical means to identify efficacious therapies for PD-related motor deficits while avoiding ICD side effects. Here, we provide an overview of these recent advances, with a particular emphasis on the neurobiological correlates reported in animal models and patients along with their genetic underpinnings.

Keywords: 6-OHDA; PET; basal ganglia; dopamine agonists; fMRI; imaging; l-dopa; pramipexole; prefrontal cortex.

Figure 1

A diagram showing the primary excitatory drives of the ventral striatum and its modulation by dopamine. The ventral hippocampal input arising from the hippocampal subiculum is believed to be involved in context dependency. As such, this drive should function to maintain focus on the context of the current task to the exclusion of competing stimuli. In contrast, evidence indicates that one function of the medial prefrontal cortex is to facilitate behavioral flexibility, or the propensity to deviate from a task that is no longer rewarding. The dopamine system exerts differential inputs on these pathways, with increased dopamine input facilitating the hippocampal input via a D1-dependent process, whereas D2 stimulation attenuates prefrontal cortical drive. A model of functioning of this system (Sesack & Grace, 2010) suggests that when a task is rewarding, there is an increase in dopamine input, facilitating the hippocampal drive to maintain focus on the currently-rewarded task while preventing the medial prefrontal cortex from deviating from this task. Lower Left. A diagram showing that the hippocampal drive maintains this dopamine input via disinhibition of the VTA via striatal-ventral pallidal circuits. However, if a behavior fails to produce a reward, there would be an attenuation of dopamine neuron activity (negative reward prediction error, decreasing hippocampal drive and disinhibiting the prefrontal cortex. This would enable the prefrontal cortex to shift focus to a different responses. When a response is encountered that produces reward, the resultant increase in dopamine drive would lock the system into the new state by facilitating focus on the new task by the hippocampus while disabling prefrontal behavioral flexibility. Lower Right. A diagram showing disruption of normal ventral striatal function in the event of overactive dopaminergic drive mediated by dopamine agonists, as proposed to occur during ICDs. These agonists have a high affinity for the D2 family of dopamine receptors which reduce excitatory influences from the prefrontal cortex. Thus, an abnormally high and persistent activation of D2 receptors is proposed to circumvent the normal efficient functioning of this gated system, and the balance of influences by inputs from the prefrontal cortex and hippocampus is disrupted. In such conditions, there would be a continued potentiation of hippocampal focus independent of the rewarding nature of the stimuli, causing the organism to perseverate an impulsive task. Because of the high levels of D2 receptor activation, the prefrontal cortex would not be capable of shifting behaviors toward a more goal-oriented condition, thereby locking the system in this behaviorally ineffective state.