Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

Abstract

This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [ 11 C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer.he neural basis of functional magnetic resonance imaging (fMRI) signals has been a topic of extensive investigation. Experimental correlations of fMRI signals or cerebral blood flow with relative changes in glucose or oxygen utilization (1-3) have been performed to determine whether hemodynamic responses reflect a coupling with metabolism-a hypothesis with a long history (4). To relate hemodynamic responses more directly to neural circuitry, fMRI or optical imaging signals have been correlated with electrophysiology, using graded levels of stimulation in preclinical models (5-7). These results generally demonstrate a monotonic coupling between electrical activity and evoked cortical hemodynamic responses, using sensory stimuli. However, the methodology is not readily extensible to human subjects, and the implications of such studies are difficult to generalize to pharmacotherapies or other drug stimuli that target specific neurotransmitter systems.Recent technological advances in multimodal imaging have enabled the simultaneous acquisition of MRI and positron emission tomography (PET) data (8). One of the motivations for conjoining these modalities was the potential for new insights into neural function based upon the complementary natures of PET and fMRI. In activation paradigms, fMRI provides excellent spatio-temporal resolution for localizing changes in brain activity but offers little insight into the underlying neurotransmission. Conversely, although PET has more limited temporal and spati...

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…Using relevant PET radiotracers, it has been established that clinically effective doses are often between 70–90% of D2 receptor occupancy 48 . Figure 1 provides an example of [ 11 C]raclopride binding that results in dose-dependent binding of an injected D2/D3 agonist drug (quinpirole) in competition with the radiotracer 49,50 .…”

“…In a series of studies, the effects of D2/D3 specific agonist and antagonist challenges were tested to characterize receptor function with PET/fMRI in non-human primates: Simultaneous measurement of D2/D3 receptor occupancy and fMRI signal due to D2/D3 blocking or stimulation revealed correlations in anatomical space and with dose 49,50 . For D2/D3 antagonist binding, a direct neurovascular coupling mechanisms to occupancy was shown in time.…”

“…The example shows dose-dependent D2/D3 receptor binding of an agonist with PET and correlated fMRI responses due to D2/D3 agonist and antagonist action. (Displayed images are modified with permission from previously published work by Sander et al 49,50 ). Overall, various types of PET receptor and fMRI measurements can be compared to understand correlations or discrepancies in functional signals.…”

Brain activation and neurochemistry

“…Thus, alternative imaging modalities that overcome these limitations could expand their utilization in clinical research and would bring us closer to a more accessible biomarker for assessing brain DA activity in the clinical setting. In PNAS, Sander et al (1) demonstrate a dynamic coupling between DA D2 receptor (D2R) occupancy level, a marker of DA neurotransmission, and the concomitant regional cerebral blood volume (rCBV) changes in the primate brain.…”

“…Using simultaneous PET and MRI with pharmacological doses of a DA D2/D3 antagonist (raclopride), Sander et al (1) demonstrate that MRI can provide a good surrogate for the D2R measures traditionally obtained with PET. From a technical perspective, the authors' findings help clarify the nature of the coupling between striatal D2R blockade and the consequent cerebrovascular responses that presumably reflect changes in neuronal/glial activity, which has been an area of intense investigation in the functional MRI (fMRI) literature (2).…”