Nociceptive Responses and Resting-State Functional Connectivity of the Human Midbrain Tegmentum

The rostromedial tegmental nucleus (RMTg) has been shown to inhibit midbrain dopaminergic centers through its GABAergic projections, and to be critical for regulating responses to aversive and rewarding stimuli. This nucleus has primarily been evaluated in rodents and non-human primates, while recent postmortem analysis of human brainstem tissue localized GABergic cell clusters in the putative RMTg. The objectives of this preliminary investigation in healthy controls (HC) were to (i) define RMTg function during evoked thermal stimulation and the resting-state using 7T functional magnetic resonance imaging (fMRI), and (ii) explore the expression of putative RMTg markers, μ-opioid receptors (OPMR1), nociceptin receptors (NOPR), and FOXP1 as well as tyrosine hydroxylase (TH) in the midbrain tegmentum. Relative to 40°C stimuli, greater responses to 46°C (normally noxious) in the putative RMTg as well as raphe nuclei, locus coeruleus, substantia nigra, thalamus, putamen, and anterior cingulate were observed. Resting-state 7T fMRI showed robust RMTg functional connectivity with components of mesocorticolimbic and nigrostriatal circuitry, thalamus, hippocampus, and cerebellar subdivision. In postmortem analyses, neurons immunolabeled for OPMR1, NOPR, and FOXP1 were detected in an area adjacent to the decussation of the superior cerebellar peduncle. These immune-positive neurons in the area of the putative RMTg were adjacent to intense TH immunoreactivity. This investigation provides novel evidence of activation of a distinct area within the human midbrain tegmentum, putatively identified as the RMTg, particularly during nociceptive processing in addition to its resting-state connectivity with the broader central nervous system. Further exploration of the human RMTg is warranted.