We have previously reported that there are inter-individual differences in the cardiovascular responses to experimental muscle pain, which are consistent over time: intramuscular infusion of hypertonic saline, causing pain lasting ~60 min, increases muscle sympathetic nerve activity (MSNA)—as well as blood pressure and heart rate—in certain subjects, but decrease it in others. Here, we tested the hypothesis that baseline physiological parameters (resting MSNA, heart rate, blood pressure, heart rate variability) determine the cardiovascular responses to long-lasting muscle pain. MSNA was recorded from the common peroneal nerve, together with heart rate and blood pressure, during a 45-min intramuscular infusion of hypertonic saline solution into the tibialis anterior of 50 awake human subjects (25 females and 25 males). Twenty-four subjects showed a sustained increase in mean amplitude of MSNA (160.9 ± 7.3%), while 26 showed a sustained decrease (55.1 ± 3.5%). Between the increasing and decreasing groups there were no differences in baseline MSNA (19.0 ± 1.5 vs. 18.9 ± 1.2 bursts/min), mean BP (88.1 ± 5.2 vs. 88.0 ± 3.8 mmHg), HR (74.7 ± 2.0 vs. 72.8 ± 1.8 beats/min) or heart rate variability (LF/HF 1.8 ± 0.2 vs. 2.2 ± 0.3). Furthermore, neither sex nor body mass index had any effect on whether MSNA increased or decreased during tonic muscle pain. We conclude that the measured baseline physiological parameters cannot account for the divergent sympathetic responses during tonic muscle pain.

Experimentally induced tonic muscle pain evokes divergent muscle vasoconstrictor responses, with some individuals exhibiting a sustained increase in muscle sympathetic nerve activity (MSNA), and others a sustained decrease. These patterns cannot be predicted from an individual's baseline physiological or psychological measures. The aim of this study was to investigate whether the different muscle sympathetic responses to tonic muscle pain were associated with differential changes in regional brain activity. Functional magnetic resonance imaging (fMRI) of the brain was performed concurrently with microelectrode recording of MSNA from the peroneal nerve during a 40-min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle. MSNA increased in 26 and decreased in 11 of 37 subjects during tonic muscle pain. Within the prefrontal and cingulate cortices, precuneus, nucleus accumbens, caudate nucleus, and dorsomedial hypothalamus, blood oxygen level dependent (BOLD) signal intensity increased in the increasing-MSNA group and remained at baseline or decreased in the decreasing-MSNA group. Similar responses occurred in the dorsolateral pons and in the region of the rostral ventrolateral medulla. By contrast, within the region of the dorsolateral periaqueductal gray (dlPAG) signal intensity initially increased in both groups but returned to baseline levels only in the increasing-MSNA group. These results suggest that the divergent sympathetic responses to muscle pain result from activation of a neural pathway that includes the dlPAG, an area thought to be responsible for the behavioral and cardiovascular responses to psychological rather than physical stressors. Hum Brain Mapp 38:869-881, 2017. © 2016 Wiley Periodicals, Inc.

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IntroductionLong‐lasting experimental muscle pain elicits divergent muscle sympathetic responses, with some individuals exhibiting a persistent increase in muscle sympathetic nerve activity (MSNA), and others a decrease. These divergent responses are thought to result from sustained functional changes in specific brain regions that modulate the cardiovascular responses to pain.AimThe aim of this study was to investigate brain regions that are functionally coupled to the generation of an MSNA burst at rest and to determine their behavior during tonic muscle pain.MethodsFunctional magnetic resonance imaging of the brain was performed concurrently with microelectrode recording of MSNA from the common peroneal nerve during a 40 min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle of 37 healthy human subjects.ResultsAt rest, blood oxygen level‐dependent signal intensity coupled to bursts of MSNA increased in the rostral ventrolateral medulla, insula, dorsolateral prefrontal cortex, posterior cingulate cortex, and precuneus and decreased in the region of the midbrain periaqueductal gray. During pain, MSNA‐coupled signal intensity was greater in the region of the nucleus tractus solitarius, midbrain periaqueductal gray, dorsolateral prefrontal, medial prefrontal, and anterior cingulate cortices, than at rest. Conversely, MSNA‐coupled signal intensity decreased during pain in parts of the prefrontal cortex.ConclusionsThese results suggest that multiple brain regions are recruited in a burst‐to‐burst manner, and the magnitude of these signal changes is correlated to the overall change in MSNA amplitude during tonic muscle pain.

Blood pressure is tightly controlled by the central nervous system, particularly the brainstem. The aim of this study was to investigate the relationship between mean blood pressure (MBP), muscle sympathetic nerve activity (MSNA) and resting regional brain activity in healthy human subjects. Pseudocontinuous arterial spin labeling and functional magnetic resonance imaging of the brain were performed immediately following a laboratory microneurography recording of MSNA and BP measurement in 31 young, healthy normotensive subjects. Regional cerebral blood flow (CBF) correlated significantly with resting MBP levels in the region encompassing the rostroventrolateral medulla (RVLM), dorsolateral pons, and insular, prefrontal and cingulate cortices. Functional connectivity analysis revealed that the ventrolateral prefrontal cortex displayed greater resting connectivity strength within the RVLM in the lower compared with the higher MBP group. No significant differences in CBF were found when subjects were divided based on their MSNA levels. These results suggest that even subtle differences in resting MBP are associated with significant differences in resting activity in brain regions, which are well known to play a role in cardiovascular function. These data raise the question of the potential long-term consequences of differences in regional brain activity levels and their relationship with systemic blood pressure.