A circuit-based approach to repair hypersexuality in Parkinson’s disease

Abstract

AbstractOne common neuropsychiatric complication in patients with Parkinson’s disease treated with dopamine replacement therapy is impulse control disorders. A proportion of patients under dopamine agonist exhibit excessive desire towards appetitive cues accompanied by lost control over behaviour in forms of pathological gambling, hypersexuality or binge eating. The balance between enhanced desire towards sexual cues and cognitive control changes has been hypothesized to be biased toward the former in individuals with hypersexuality and impulse control disorders. Yet, some studies report no behavioural differences in cognitive control differences between impulsive patients and general Parkinson’s disease, suggesting possible functional changes along the mesocorticolimbic cortico-subcortical circuitry. Here, we provide evidence for this hypothesis by comparing the neurobiological substrate of sexual disturbance over response inhibition associated to medication states in Parkinson’s disease patients with a specific subtype of impulse control disorders (i.e., hypersexuality).We assessed the impact of sexual cues on response inhibition using a novel erotic stop signal task inside an fMRI. A total of 50 participants were included divided in 16 hypersexual and 17 non-hypersexual Parkinson’s disease patients and 17 healthy controls. Task-related activations, functional and anatomical connectivity models were performed. Additionally, a separate sample of 20 hypersexual Parkinson’s disease patients received excitatory neuromodulation (sham-controlled) over the pre-supplementary motor area (based on fMRI group-based results) aiming to improve response inhibition when exposed to sexual cues.Compared with their non-hypersexual peers, medication perturbed response inhibition upon presentation of sexual cues in patients with hypersexuality, recruiting a network involving caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex. Dynamic causal modelling revealed distinct best models to account for cortico-subcortical interactions with reduced task-related inputs in pre-supplementary motor area and descending connectivity to caudate in hypersexual compared to non- hypersexual Parkinson’s disease patients (while medicated). This was sustained by enhanced fractional anisotropy and reduced mean diffusivity in the pre-supplementary motor area-caudate pathway. Importantly, stimulation over the pre-supplementary motor area improved response inhibition when exposed to sexual cues in hypersexual Parkinson’s disease.We identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual behaviours in Parkinson’s disease induced by medication, with recovery options by applying neuromodulation.