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

Abstract

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.

Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart rate variability

“…In one study, inducing pain both increased LC activity and decreased HF-HRV (Sclocco et al, 2016). In another study (Bosch, et al, 2003), increases in salivary α-amylase (a marker of adrenergic activity; Granger, et al, 2007) were associated with decreases in RMSSD (which as mentioned is a measure of rapid heart rate changes that—like HF-HRV—is predominantly vagally mediated; Sztajzel, 2004).…”

Methods for cleaning the BOLD fMRI signal

“…The low and high frequency components of HRV can be extracted by performing a time-frequency analysis using wavelets (Chang et al, 2013) or the Smoothed Pseudo Wigner Ville Distribution (Gil et al, 2010). Heart rate variability is correlated to regional BOLD signal variations induced by multiple experimental paradigms (Iacovella and Hasson, 2011), such as emotion (Critchley et al, 2005), pain (Sclocco et al, 2016), and cognitive tasks (Basile et al, 2013), as well as when assessing the function of the autonomic nervous system during task performance (Napadow et al, 2008) or at rest (Chang et al, 2013). In that respect, it is relevant to consider that some neuropsychiatric diseases, e.g.…”

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

“…The small number of witnessed cases suggests that most patients who succumb to SUDEP are recovering from a severe seizure and are still not fully responsive when it suddenly comes to a breakdown of the autonomic system that is typically initiated by a disturbance of the respiratory function followed by cardiac failure, and often accompanied by a generalized suppression of the EEG activity (Ryvlin et al, 2013). HRV is a measure of beat-to-beat variability of the heart that results from modulation of the sinoatrial node by the autonomic system and has been shown to be controlled by brainstem structures in neuroimaging studies in humans (Napadow et al, 2008;Sclocco et al, 2016). The possible role of brainstem dysfunction in SUDEP was further supported by a MR imaging study demonstrating brainstem volume loss that was most prominent at the level of the dorsal mesencephalon in patients suffering from drug resistant temporal lobe epilepsy.…”

“…(1) By investigating if atrophy in these regions is associated with reduced heart rate variability (HRV). HRV is a measure of beat-to-beat variability of the heart that results from modulation of the sinoatrial node by the autonomic system and has been shown to be controlled by brainstem structures in neuroimaging studies in humans (Napadow et al, 2008;Sclocco et al, 2016). A reduced HRV has been demonstrated in epilepsy patients and is associated with increased cardiac mortality in nonepilepsy populations (Dlouhy et al, 2015).…”