A new scenario for negative functional magnetic resonance imaging signals: endogenous neurotransmission

Functional magnetic resonance imaging (fMRI) has revolutionized investigations of brain functions. Increases in fMRI signals are usually correlated with neuronal activation, but diverse explanations have been proposed for negative fMRI responses, including decreases in neuronal activity, the vascular-steal effect, and large increases in oxygen consumption. These possible scenarios, although encompassing a wide range of potential neurovascular responses, cannot yet be used to interpret certain types of negative fMRI signals. Recent studies have found that intravenous injection of dopamine D(2) receptor (D2DR) agonist reduced the hemodynamic responses in the caudate-putamen (CPu); however, whether endogenous dopaminergic neurotransmission contributes to fMRI signals remains obscure. Since it has been suggested that the D2DR is involved in pain modulation, and the CPu shows equivocal fMRI signals during noxious stimulation, the present study established an animal model based on graded electrical stimulation to elicit different levels of nociception, and aimed to determine whether nociception-induced endogenous dopaminergic neurotransmission is sufficient to generate negative fMRI responses. Our results from cerebral blood volume (CBV)-weighted fMRI, Fos immunohistochemistry, and electrophysiological recording demonstrated a salient bilateral CBV decreases associated with heightened neuronal activity in the CPu induced by unilateral noxious electrical stimulation. In addition, preinjection of D2DR antagonist reduced the observed CBV decreases. Our findings reveal the role of the D2DR in regulating striatal vascular responses and suggest that endogenous neurotransmission-induced CBV decreases underlie negative fMRI signals. Hence, the influence of endogenous neurotransmission should be considered when interpreting fMRI data, especially in an area involved in strong vasoactive neurotransmission.