D₂-Like Receptor Expression in the Hippocampus and Amygdala Informs Performance on the Stop-Signal Task in Parkinson's Disease

Abstract

The stop-signal task is a well-established assessment of response inhibition, and in humans, proficiency is linked to dorsal striatum D₂ receptor availability. Parkinson's disease (PD) is characterized by changes to efficiency of response inhibition. Here, we studied 17 PD patients (6 female and 11 male) using the stop-signal paradigm in a single-blinded d-amphetamine (dAMPH) study. Participants completed [¹⁸F]fallypride positron emission topography (PET) imaging in both placebo and dAMPH conditions. A voxel-wise analysis of the relationship between binding potential (BP_ND) and stop-signal reaction time (SSRT) revealed that faster SSRT is associated with greater D₂-like BP_ND in the amygdala and hippocampus (right cluster q_FDR-corr = 0.026, left cluster q_FDR-corr = 0.002). A region of interest (ROI) examination confirmed this association in both the amygdala (coefficient = −48.26, p = 0.005) and hippocampus (coefficient = −104.94, p = 0.007). As healthy dopaminergic systems in the dorsal striatum appear to regulate response inhibition, we interpret our findings in PD to indicate either nigrostriatal damage unmasking a mesolimbic contribution to response inhibition, or a compensatory adaptation from the limbic and mesial temporal dopamine systems. These novel results expand the conceptualization of action-control networks, whereby limbic and motor loops may be functionally connected.

SIGNIFICANCE STATEMENT While Parkinson's disease (PD) is characteristically recognized for its motor symptoms, some patients develop impulsive and compulsive behaviors (ICBs), manifested as repetitive and excessive participation in reward-driven activities, including sex, gambling, shopping, eating, and hobbyism. Such cognitive alterations compel a consideration of response inhibition in PD. To investigate inhibitory control and assess the brain regions that may participate, we assessed PD patients using a single-blinded d-amphetamine (dAMPH) study, with [¹⁸F]fallypride positron emission topography (PET) imaging, and stop-signal task performance. We find a negative relationship between D₂-like binding in the mesial temporal region and top-signal reaction time (SSRT), with greater BP_ND associated with a faster SSRT. These discoveries indicate a novel role for mesolimbic dopamine in response inhibition, and advocate for limbic regulation of action control in this clinical population.