Serotonergic dysfunction in patients with impulse control disorders in Parkinson’s disease

Impulse control disorders (ICDs) are frequent and particularly distressing neuropsychiatric symptoms in patients with Parkinson's disease (PD) which are related to impaired behavioural inhibition. Multiple PET imaging studies indicate that striatal dopaminergic abnormalities contribute to hyperdopaminergic functioning in PD patients with ICD (PDICD+) and to the dysregulation of the limbic fronto-striatal networks which are critical for reward-related decision impulsivity. However, the serotonergic system is central to response inhibition and plays a critical role in neuropsychiatric symptoms in PD, but its role remains undetermined in PDICD. We hypothesized that PDICD+ patients exhibit serotonergic dysfunction within the cortico-striato-pallido-thalamic circuits involved in the inhibitory control of behaviour and decided to investigate the pre- and post-synaptic serotonergic innervation using two highly-specific PET tracers for the serotonin transporter (SERT) using [11C]DASB and the 5-HT2A receptor using [18F]altanserin. In this prospective, case-control, double-tracer PET study, we recruited 15 PDICD+ patients, 15 PDICD- patients and 15 healthy controls, matched for age and sex, and compared the availability of [11C]DASB and [18F]altanserin using permutation-based analysis. PDICD+ patients had one (n=9) or multiple ICDs (n=6), consisting in hypersexuality (n=8), compulsive eating (n=6), compulsive shopping (n=5) and pathological gambling (n=4) and were characterized by greater choice impulsivity (impaired delay discounting for monetary rewards) and greater urgency with more severe depressive and anxious symptoms. We demonstrate that PDICD+ patients had greater [11C]DASB binding in the posterior putamen and pallidum in comparison to PDICD- patients, corresponding to relatively preserved presynaptic SERT availability within the subcortical sensorimotor network involved in response inhibition. In addition, cortical [18F]altanserin binding was greater in PDICD+ patients in the bilateral supplementary motor area, precentral gyrus and right dorsolateral prefrontal cortex, involving the sensorimotor and associative networks which regulate behavioural inhibition. Furthermore, we show that pre- and post-synaptic serotonergic dysfunction subserving action versus decision impulsivity in PD patients specifically followed the distinctive functional organization of the sensorimotor and associative fronto-striatal networks. Altogether, we demonstrate that serotonergic dysfunction related to ICDs in PD specifically involve the sensorimotor and associative cortico-striato-pallido-thalamic circuits involved in inhibitory control. Thus, serotonergic dysfunction contributes to the mechanisms related to the vulnerability and development of ICDs in PD patients, beyond the known dopaminergic abnormalities in the limbic fronto-striatal circuit.