Neurovascular coupling of striatal dopamine D2/3 receptor availability and perfusion using simultaneous PET/MR in humans

Abstract

The midbrain dopamine system contributes to important neural functions in the basal ganglia, and is involved in aspects of pathological processes in schizophrenia. In preclinical and clinical studies, pharmacological blockade or stimulation of brain dopamine receptors alters cerebral perfusion, which is a surrogate marker of metabolic activity. However, there is scant documentation of this neurofunctional coupling in relation to individual differences in the dopamine system of healthy humans. We therefore tested the hypothesis that baseline dopamine D_2/3 receptor availability predicts individual blood flow responses to challenge with a dopamine agonist. We used [¹⁸F]fallypride positron emission tomography (PET) imaging to quantify dopamine D_2/3 receptor availability as binding potential (BP_ND) in nine healthy subjects. Using simultaneous perfusion-weighted functional magnetic resonance imaging (fMRI), we measured perfusion at baseline and after challenge with the dopamine agonist apomorphine. Results of this multimodal imaging study revealed a strong negative association between baseline D_2/3 dopamine receptor availability and apomorphine-induced perfusion changes in the human basal ganglia. There was considerable intra-individual variation in the neurovascular response to the apomorphine challenge, which may call for further investigation of the dopaminergic regulation of cerebral perfusion in patients with schizophrenia. This study describes a novel paradigm for assessing dopamine sensitivity, facilitating an exploration of the dopamine supersensitivity hypothesis.

Keywords: Dopamine; Human; PET; Perfusion; fMRI; pcASL.

Fig. 1

A) Experimental design: Representative time activity curves of the PET acquisition for the bilateral regions: putamen (Put), caudate nucleus (CN), thalamus, inferior temporal cortex (ITC) and cerebellum (Cer). The start of each time frame of the PET acquisition is denoted as tick on the horizontal axis. The time point of the administration of the dopamine agonist apomorphine is depicted as vertical dotted line. Periods of the perfusion weighted image acquisitions (ASL) are marked in dark grey. Inter-session pauses of PET-acquisition are marked in light grey, the signal of the inter-session pauses is based on linear interpolation. b) Representative parametric maps fused with a structural T1-weighted MR MNI152 NLIN 6th generation template (1), fusion parametric map of the dopamine receptor D_2/3 binding potential combined with the structural T1-weighted MR MNI152 template (2) and fusion parametric map of cerebral blood flow combined with the structural T1-weighted MR MNI152 template (3).

Fig. 2

Change in cerebrovascular blood flow (ΔrCBF) in the bilateral striatum upon administration of the dopamine D_2/3R agonist apomorphine as a function of the mean [¹⁸F]FP BP_ND in the group of nine healthy participants.