Neuroimaging brainstem circuitry supporting cardiovagal response to pain: a combined heart rate variability/ultrahigh-field (7 T) functional magnetic resonance imaging study

Central autonomic control nuclei in the brainstem have been difficult to evaluate non-invasively in humans. We applied ultrahigh-field (7 T) functional magnetic resonance imaging (fMRI), and the improved spatial resolution it affords (1.2 mm isotropic), to evaluate putative brainstem nuclei that control and/or sense pain-evoked cardiovagal modulation (high-frequency heart rate variability (HF-HRV) instantaneously estimated through a point-process approach). The time-variant HF-HRV signal was used to guide the general linear model analysis of neuroimaging data. Sustained (6 min) pain stimulation reduced cardiovagal modulation, with the most prominent reduction evident in the first 2 min. Brainstem nuclei associated with pain-evoked HF-HRV reduction were previously implicated in both autonomic regulation and pain processing. Specifically, clusters consistent with the rostral ventromedial medulla, ventral nucleus reticularis (Rt)/nucleus ambiguus (NAmb) and pontine nuclei (Pn) were found when contrasting sustained pain versus rest. Analysis of the initial 2-min period identified Rt/NAmb and Pn, in addition to clusters consistent with the dorsal motor nucleus of the vagus/nucleus of the solitary tract and locus coeruleus. Combining high spatial resolution fMRI and high temporal resolution HF-HRV allowed for a non-invasive characterization of brainstem nuclei, suggesting that nociceptive afference induces pain-processing brainstem nuclei to function in concert with known premotor autonomic nuclei in order to affect the cardiovagal response to pain.