Autonomic responses to exercise: cortical and subcortical responses during post-exercise ischaemia and muscle pain.

AUTNEU-01708; No of Pages 9 Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx

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Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu

Autonomic responses to exercise: Cortical and subcortical responses during post-exercise ischaemia and muscle pain Vaughan G. Macefield a,b,⁎, Luke A. Henderson c a b c

School of Medicine, University of Western Sydney, NSW, Australia Neuroscience Research Australia, Sydney, NSW, Australia Department of Anatomy and Histology, University of Sydney, Sydney, NSW, Australia

a r t i c l e

i n f o

Article history: Received 28 June 2014 Received in revised form 27 August 2014 Accepted 13 October 2014 Available online xxxx Keywords: Central command fMRI Metaboreflex Microneurography Muscle pain

a b s t r a c t Sustained isometric contraction of skeletal muscle causes an increase in blood pressure, due to an increase in cardiac output and an increase in total peripheral resistance—brought about by an increase in sympatheticallymediated vasoconstriction. Both central command and reflex inputs from metaboreceptors in the contracting muscles have been shown to contribute to this sympathetically mediated increase in blood pressure. Occluding the blood supply and trapping the metabolites in the contracted muscle (post-exercise ischaemia) has shown that, while heart rate returns to baseline following exercise, the increase in MSNA and blood pressure persists in the absence of central command—sustained by peripheral inputs. Post-exercise ischaemia activates group III and IV muscle afferents, which are also activated during noxious stimulation. Indeed, post-exercise ischaemia is painful, so what is the role of pain in the increase in blood pressure? Intramuscular injection of hypertonic saline causes a deep dull ache, not unlike that produced by post-exercise ischaemia, and we have shown that this can cause a sustained increase in MSNA and blood pressure. We have used functional Magnetic Resonance Imaging (fMRI) of the brain to identify the cortical and subcortical sites involved in the sensory processing of muscle pain, and in the generation of the autonomic responses to muscle pain, produced either by post-exercise ischaemia or intramuscular injection of hypertonic saline. During static hand-grip exercise there were parallel increases in signal intensity in the contralateral primary motor cortex, deep cerebellar nuclei and cerebellar cortex that ceased at the end of the exercise, reflecting the start and end of central command. Progressive increases during the contraction phase occurred in the contralateral insula, as well as the contralateral primary somatosensory cortex, and continued during the period of post-exercise ischaemia. Decreases in signal intensity occurred in the perigenual anterior cingulate cortex during the contraction phase; these too were sustained during post-exercise ischaemia. That similar changes occurred with intramuscular injection of hypertonic saline suggests that much of the cortical and subcortical changes seen during post-exercise ischaemia reflect the sensory and affective attributes of the muscle pain, rather than in furnishing the cardiovascular responses per se. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Unlike the rapid vasodilatation and fall in blood pressure seen during intermittent contractions of skeletal muscle (Reeder and Green, 2012), sustained isometric contractions cause an increase in blood pressure through an increase in cardiac output and sympathetically-mediated vasoconstriction (Mitchell, 1990). Indeed, it is well known that fatiguing isometric exercise is associated with increases in sympathetic outflow

⁎ Corresponding author at: School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith NSW 2751, Australia. Tel.: +61 2 94620 3779; fax: +61 2 94620 3890. E-mail address: v.macefi[email protected] (V.G. Macefield).

to the heart and the vascular beds of muscles not engaged in the exercise, resulting in increases in heart rate, cardiac contractility and systemic arterial pressure. What happens to sympathetic outflow to contracting muscle is less well-understood, with decreases (Wallin et al., 1992) or no change (Hansen et al., 1994) in muscle sympathetic nerve activity (MSNA) having been reported; differences in experimental paradigm and analytical approach may account for these disparate findings. We recently showed that, during static isometric contractions of tibialis anterior, MSNA actually increases in an intensity-dependent manner, which—together with the increase in intramuscular pressure —would tend to counteract the effects of local vasodilatory mechanisms (Boulton et al., 2014). Experimental records from one subject, performing a static dorsiflexion of the ankle at ~10% of maximum, are shown in Fig. 1. It can be seen that both burst amplitude and incidence increase during the contraction.

http://dx.doi.org/10.1016/j.autneu.2014.10.021 1566-0702/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Macefield, V.G., Henderson, L.A., Autonomic responses to exercise: Cortical and subcortical responses during postexercise ischaemia and muscle pain, Auton. Neurosci. (2014), http://dx.doi.org/10.1016/j.autneu.2014.10.021

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V.G. Macefield, L.A. Henderson / Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx

Fig. 1. Experimental records from one subject during an isometric control contraction of the ipsilateral tibialis anterior muscle at ~10%MVC. Note that an increase in muscle afferent activity occurs during the contraction, resulting in a baseline shift in the RMS-processed nerve signal. Despite this, bursts of MSNA remained clearly identifiable and increased in amplitude. (A) Raw recordings of the neurogram (top) and root-mean-square processed version of this recording (RMS nerve) which shows spontaneous bursts of MSNA. (B) Expanded view of the selected area in A prior to the contraction. (C) Expanded view of the selected area in A during the contraction, highlighting the increased amplitude of each burst compared with resting activity in (B). Reproduced from Boulton et al (2014).

It is generally accepted that both central and peripheral mechanisms contribute to the physiological changes in exercise: increases in MSNA, heart rate and blood pressure can occur in conscious humans trying to contract muscles which have been pharmacologically paralysed (Victor et al., 1989; Gandevia et al., 1993), while the increase in MSNA and blood pressure can be sustained at the conclusion of exercise by trapping metabolites in the contracted muscles (Victor et al., 1987). It is known that thinly myelinated (group III) and unmyelinated (group IV) muscle afferents respond to mechanical and metabolic events in the muscle (Kniffki et al., 1981; Kaufman et al., 1983; Hayes et al., 2005). These muscle afferents have been shown to excite neurones in nucleus tractus solitarius (NTS) in the medulla (Potts et al., 2000). A subset of the NTS neurones activated by muscle afferents is thought to directly excite neurones of the rostral ventrolateral medulla (RVLM)—the primary output nucleus for MSNA (Dampney et al., 2003)—while another subset of the activated NTS neurones are thought to be interneurones acting within the NTS to inhibit the baroreceptorsensitive neurones of the NTS, which normally inhibit RVLM via the caudal ventrolateral medulla (CVLM) and hence bring about disinhibition of RVLM neurones (Potts, 2005). Both of these mechanisms would lead to increases in activity within RVLM, producing an increase in sympathetic outflow to muscle and the gut and blood pressure. This peripherally derived sympathoexcitatory reflex can occur independent of neuronal circuitry rostral to the brainstem: in decerebrate animals increases in sympathetic traffic, heart rate and blood pressure occur when muscle contraction is produced electrically (Smith et al., 2001); in humans, increases in blood pressure and heart rate can occur during evoked contractions in the absence of motor command (Coote et al., 1971; McCloskey and Mitchell, 1972; Mark et al., 1985; Gandevia and Hobbs, 1990), and during post-exercise ischemia sympathetic activity and blood pressure remain elevated (Victor et al. 1987).

1.1. Cortical and subcortical changes during exercise and post-exercise ischaemia Over the last few years we have been using functional magnetic resonance imaging (fMRI) to identify brainstem nuclei involved in the control of muscle sympathetic nerve activity during manouevres known to cause a sustained increase in MSNA. One such manouevre is a maximal inspiratory breath-hold. This manoeuevre caused significant changes in BOLD (Blood Oxygen Level Dependent) signal intensity in three discrete regions of the medulla: increases in RVLM and decreases in CVLM and NTS (Macefield et al., 2006). These changes in neuronal activity were expected, given that the increase in MSNA during this manouevre is believed to be due to unloading of the low-pressure baroreceptors (Macefield et al., 2006) Moreover, by recording MSNA concurrently with fMRI of the brainstem we recently showed that activities within these three medullary nuclei covaried with the spontaneous bursts of MSNA at rest: increases in signal intensity occurring in RVLM, and deceases in NTS and CVLM, when bursts of MSNA were present (Macefield and Henderson, 2010). Sustained activation of RVLM could also be seen during static handgrip exercise and post-exercise ischaemia (Sander et al., 2010). In this experiment we asked subjects to squeeze a pneumatic bulb at 40% of maximum pressure for 2 min with their right hand, and then inflated a sphygmomanometer cuff around the upper arm for 6 min immediately prior to the conclusion of the static exercise. It can be seen in Fig. 2 that, in addition to the progressive increase in BOLD signal intensity in RVLM during the contraction phase there was a parallel increase in the region of the medulla encompassing NTS. The time-course of activation in these two medullary nuclei mimics the progressive increase in MSNA during static handgrip and the subsequent steady state increase in MSNA during the period of post-exercise ischemia. The increase in NTS activity can be explained by several sources of input:



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Fig. 2. Significant changes in blood oxygen level-dependent (BOLD) signal intensity in the brainstem and cerebellum correlated to mean arterial pressure changes during static handgrip and post-exercise ischaemia overlaid onto an average T2-weighted anatomical image set. The colour scale (coded for t-value) indicates the magnitude of the increases in regional signal intensity. Reproduced from Sander et al. (2010).

(i) mechanosensitive afferent input to the NTS, which would be constant during the isometric contraction but disappear during the post-exercise ischaemia, (ii) metabosensitive afferent input to the NTS would increase progressively as metabolites build up during the contraction and persist during post-exercise ischaemia, and (iii) the sympathetically-mediated increase in blood pressure during the contraction and following cuff inflation would cause a sustained input from the arterial baroreceptors into NTS. In addition to these brainstem changes there were significant changes in BOLD signal intensity within the cortex. Fig. 3 shows a rapid rise in signal intensity in the contralateral primary motor cortex at the onset of the contraction which, despite maintenance of a constant grip pressure, continued to increase linearly at a lower rate during the contraction. This reflected the increase in central command required to overcome the developing muscle fatigue; although not shown, EMG from the forearm flexors increased linearly during the course of the contraction. At the end of the contraction, signal intensity returned towards baseline levels, though there was a slight but insignificant increase after about

2 min; this may well be related to the increase in sensory input during the 6 min of post-exercise ischaemia. Increases in signal intensity in a lateral area of the primary sensorimotor cortex, corresponding to the somatotopic representation of the forearm and hand, presumably reflect the increase in sensory input during the contraction. This progressive increase in signal intensity may reflect an increase in nociceptor activation during the contraction—the accumulation of metabolites would activate metaboreceptors within the intrinsic flexors of the hand and forearm. Moreover, the increase in signal intensity in the somatosensory cortex continued to develop during the period of postexercise ischaemia, essentially paralleling the development of pain. Indeed, subjects did rate the 6 min of post-exercise ischaemia as painful: 5.7 ± 0.6 out of 10 (Sander et al., 2010). Robust increases in signal intensity also occurred in the contralateral (left) insular cortex and ipsilateral (right) parietal association cortex; activity in both regions remained elevated throughout the post-exercise ischaemia, with the largest changes in BOLD signal intensity being exhibited by the entire left insula. Of course, it should be reiterated that heart rate and blood


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pressure increased during the contraction phase, and blood pressure remained elevated during the period of post-exercise ischaemia, so afferent feedback related to these physiological changes may contribute to the increase in signal intensity within the insula. It has also been shown that activity within the insula increases during brief (30 s) periods of handgrip exercise, when heart rate and blood pressure increase yet MSNA remains at baseline levels (Wong et al., 2007b). The insula is a well-known player in autonomic control. Previous neuroimaging studies have shown that the insula is activated during physiological manouevres that increase MSNA, including the Valsalva manoeuvre (Henderson et al., 2002; Macey et al., 2012)), inspiratorycapacity apnoea (Macefield et al., 2006), cold-pressor test (Harper et al., 2003; Macey et al., 2012), hand-grip exercise (Wong et al., 2007a, 2007b; Sander et al., 2010; Macey et al., 2012) and lower-body negative pressure (Kimmerly et al., 2005). Moreover, there is evidence for regional specialization of the insula for different autonomic challenges (Macey et al., 2012). It is known from work in experimental animals that the insula does not project directly to the RVLM but does project to the lateral posterior hypothalamus (Cechetto and Chen, 1990), so may mediate its cardiovascular effects via indirect projections to the hypothalamus. However, if the insula is involved in mediating the autonomic responses to handgrip and post-exercise ischaemia then we may have expected to have seen activation of the hypothalamus. However, while we had previously seen bilateral activation of the lateral hypothalamus during the sustained increases in MSNA produced by an inspiratory-capacity apnoea (Macefield et al., 2006), and recently showed temporal coupling between spontaneous bursts of MSNA at rest and activity bilaterally in the ventromedial hypothalamus and unilaterally in the dorsomedial hypothalamus (James et al., 2013), we saw no changes in the hypothalamus during either the contraction phase or the period of post-exercise ischaemia. Moreover, it has also been shown that the lateral hypothalamus is not activated during the Valsalva manouevre—a forced expiratory effort against resistance that also causes a marked increase in MSNA and blood pressure (Henderson et al., 2002). Of course, it may well be that the insula acts to increase MSNA during handgrip exercise and post-exercise ischaemia via pathways that do not involve the hypothalamus. Indeed, it is known that the rat insula has reciprocal connections with many cortical and subcortical regions, including the medial prefrontal cortex, thalamus, parabrachial nucleus and amygdala, as well as the lateral hypothalamus (Allen et al, 1991). Nevertheless, as noted above, that activity within the insula increases during brief periods of handgrip exercise, despite there being no increase in MSNA (Wong et al., 2007a, 2007b), would argue against a role of the insula in generating the increase in MSNA during the contraction phase; this is not to say that the insula is not involved in longer (fatiguing) isometric contractions or in the period of postexercise ischaemia. In addition to these increases in signal intensity during the contraction that were sustained during post-exercise ischaemia, large decreases in activity occurred in the mid-cingulate cortex and perigenual anterior cingulate cortex, as shown in Fig. 3. Given that the anterior cingulate cortex has been linked to parasympathetic activation, a decrease in activity in this region could contribute to the withdrawal of cardiac vagal outflow at the onset of exercise, as observed by Wong et al. (2007a,b), and contribute to the increase in heart rate during exercise. However, the decrease in BOLD signal intensity we observed during the contraction persisted during the period of post-exercise ischaemia, when heart rate had returned to control levels. Accordingly, we do not attribute the sustained decrease in activity of this region to generation of the cardiac responses. Nevertheless, it is clear that the anterior

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cingulate cortex and adjacent medial prefrontal cortex have roles in autonomic regulation: lesions limited to the anterior cingulate cortex cause an attenuation of cardiovascular arousals in humans, while in the rat stimulation of the medial prefrontal cortex can cause inhibition of sympathetic outflow in the anaesthetized rat (Verberne, 1996; Verberne and Owens, 1998) yet excitatory cardiovascular responses in awake rats (Resstel et al., 2004).

1.2. Cortical and subcortical changes during muscle pain We have been using fMRI to explore the differential processing of deep and superficial pain, induced by intramuscular or subcutaneous injection of hypertonic saline (Henderson et al., 2006, 2007, 2008, 2011; Macefield et al., 2007). A 0.5 ml bolus injection into muscle—we have used tibialis anterior, deltoid, flexor carpi radialis or the first dorsal interosseous—or a 0.2 ml injection into the overlying skin, induces pain lasting about 8 min. Both forms of acute pain cause an increase in MSNA, blood pressure and heart rate that follows the pain profile (Burton et al., 2009). As shown in Fig. 4, significant changes in BOLD signal intensity were observed in multiple brain regions comprising the “pain neuromatrix”—the insular, somatosensory and cingulate cortices—during both muscle and cutaneous pain. A number of areas displayed similar changes in signal intensity during both types of pain. Bilaterally within the cingulate cortex, two regions displayed significant signal increases during both deep and superficial pain: the anterior midcingulate and the posterior mid-cingulate, immediately dorsal to the body of the corpus callosum. Much of the contralateral insular cortex also displayed increases in signal intensity during both muscle and cutaneous pain, with the changes in the anterior and posterior midcingulate regions and insula following the time-course of the pain profile. Similar changes during muscle pain, as measured by regional cerebral blood flow (arterial spin labelling), have been observed during intramuscular infusion of hypertonic saline, with the increase in blood flow within the contralateral posterior insula being strongly correlated to pain intensity (Owen et al., 2010). There were also cortical areas in which differences were apparent according to the type of pain. Within the cingulate cortex, two discrete regions of signal difference emerged (Fig. 5). The first was immediately rostral to the genu of the corpus callosum in the perigenual cingulate region. In contrast to cutaneous pain, which failed to evoke a significant change in signal intensity, muscle pain evoked a profound fall in signal intensity. The second was located in the posterior mid-cingulate region and extended posteriorly and superiorly to include cortex within the cingulate sulcus, the cingulate motor area: again, cutaneous pain had no effect but muscle pain caused a large increase in activity (Fig. 5). There were also differences in the primary somatosensory cortex, with cutaneous pain evoking an increase in the area restricted to the cortical representation of the leg, but muscle pain also activating the cortical representation of the ankle and foot. The latter reflects the larger perceived area of muscle pain, that the pain often refers distally—into the foot for injections into tibialis anterior and into the hand for injections into flexor carpi radialis (Macefield et al., 2007). Unlike the primary somatosensory cortex, electrical stimulation of which never induces perceptions of pain, noxious sensations can be evoked from the insula (Ostrowsky et al., 2002; Mazzola et al., 2006). Moreover, lesions of the insula can lead to asymbolia for pain, in which patients can recognize both superficial and deep painful stimuli and distinguish their quality but cannot generate appropriate motor or emotional responses to noxious stimuli (Berthier et al, 1988). Given

Fig. 3. Significant BOLD signal intensity (SI) changes in the human brain correlated to mean arterial pressure changes during static handgrip (contraction) and post-exercise ischemia, overlaid onto an average T1-weighted anatomical image set. The hot and cold colour scales (coded for t-value) indicate regional signal intensity increases and decreases, respectively. Left M1, primary motor cortex; Left S1, primary sensory cortex; PAC, parietal association cortex; MCC, mid-cingulate cortex; periACC, perigenual anterior cingulate cortex. Reproduced from Sander et al. (2010).


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Fig. 4. Significant BOLD signal intensity changes correlated to the mean profile of pain intensity during muscle and cutaneous pain, produced respectively by intramuscular injection of hypertonic saline into the right tibialis anterior muscle or into the overlying skin, overlaid onto an average T1-weighted anatomical image set. The hot and cold colour scales (coded for t-value) indicate regional signal intensity increases and decreases, respectively. Slice positions are indicated by MNI co-ordinates at the top right of each image. MCC: mid-cingulate cortex; periACC: perigenual anterior cingulate cortex; SI: primary somatosensory cortex; SII: secondary somatosensory cortex. Reproduced from Henderson et al. (2008).

the important role of insula in the processing of pain, it is worth comparing the changes we observed during post-exercise ischaemia with those produced by noxious stimulation. During experimental muscle pain, induced by injection of hypertonic saline into a muscle in the forearm or leg, we showed robust activation of the contralateral posterior insula, the time-course of which matched that of the development of pain; the same was true for cutaneous pain, produced by subcutaneous injection of hypertonic saline (Henderson et al., 2006, 2007, 2011; Macefield et al., 2007). The representation of pain in the posterior insula is arranged somatotopically, both with respect to muscle or cutaneous pain from the forearm, leg or face, and also with respect to pain originating in different muscles in the same limb (Henderson et al., 2006, 2007, 2011). As shown in Fig. 6, muscle pain—but not cutaneous pain—also activates the right anterior insula (Henderson et al., 2006, 2007; Macefield et al., 2007). The anterior insula is activated by negative emotional states such as sadness, anger, fear, frustration and disgust, and fMRI studies have shown that changes in signal intensity within this region are significantly correlated with the level of unpleasantness associated

with visceral and muscle pain (Dunckley et al, 2005; Phan et al, 2004; Schreckenberger et al, 2005). Interestingly, Phan et al. (2004) report that during the appraisal of both intensity and self-relatedness of emotionally charged stimuli, fMRI signal intensity increases in the same region of the right anterior insula to that we had observed during muscle pain. The right anterior insula may integrate somatotopically organized information from muscle nociceptors with the personal relevance of this emotionally charged stimulus, helping to “decide” on an appropriate course of action; according to the “somatic marker” hypothesis, the anterior insula may integrate somatic and external cues of emotional relevance (Damasio, 1996). It is in this context that we favour the interpretation that robust activation of the insula during the metaboreflex is not related to generating the sustained increase in MSNA but is engaged by the increased sensory input during post-exercise ischaemia and is registering unpleasantness and pain. Like the changes occurring during post-exercise ischaemia, muscle (but not cutaneous) pain causes a decrease in BOLD signal intensity within the perigenual anterior cingulate cortex (Henderson et al., 2006, 2007, 2011; Macefield et al., 2007). Such falls in activity have



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Fig. 5. Cortical regions displaying significant differences or similarities in BOLD signal intensity during deep and superficial pain, produced by intramuscular injection of hypertonic saline into the right tibialis anterior muscle or into the overlying skin. Significant differences are colour-coded for t-value and overlaid onto the average T1-weighted anatomical image set. The hot colour scale indicates regions in which signal intensity increased during deep pain and either decreased or remained unchanged during superficial pain. Regions in which BOLD signal intensity increased significantly during both superficial and deep pain are indicated by white shading. Slice positions are indicated on the superior brain view on the bottom left of the figure and by MNI co-ordinates at the bottom left of each image. Percent changes in signal intensity over time during superficial (blue) and deep (red) pain stimuli are shown for the ipsilateral (right) insula and anterior insula. Vertical dashed lines indicate the start of each hypertonic saline injection. Reproduced from Henderson et al. (2006).

been reported previously during visceral or muscle pain (Dunckley et al, 2005; Henderson et al, 2006), and we have speculated that the decreases seen in this region during muscle pain may reflect the negative affect associated with pain; the perigenual anterior cingulate (pACC) is part of the affective division of the cingulate cortex (Bush et al., 2000; Devinsky et al., 1995). Lesions of the pACC result in emotional lability (Hornak et al., 2003) and patients with depression often display decreased metabolism in the pACC (Drevets et al, 1997; Mayberg et al., 1997). Moreover, subjects reporting a larger area of referred

pain exhibited decreases in signal intensity over a larger area than those subjects who reported little referral; it may well be that subjects who reported larger areas of referred pain also found the stimuli to be more unpleasant, particularly given that there were no differences in the reported intensity of pain in subjects with and without referred pain (Macefield et al., 2007). Indeed, the sensation of unpleasantness has been ascribed largely to the insula and the unpleasantness of visceral as well as muscle stimuli involves signal intensity reductions in the pACC and increases in the right insula (Dunckley et al., 2005;


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anxiety-induced increases in pain ratings are associated with increases in signal intensity within the pACC (Ploghaus et al., 2001).

2. Conclusions

Fig. 6. Significant differences in BOLD signal intensity differences and similarities in the insula during deep and superficial pain, produced respectively by intramuscular injection of hypertonic saline into the right tibialis anterior muscle or into the overlying skin. Significant differences are colour-coded for t-value and overlaid onto the average T1-weighted anatomical image set. The hot colour scale indicates regions in which signal intensity increased during deep pain and either decreased or remained unchanged during superficial pain. Regions in which BOLD signal intensity increased significantly during both superficial and deep pain are indicated by white shading. Slice positions are indicated on the superior brain view on the bottom left of the figure and by MNI co-ordinates at the bottom left of each image. Percent changes in signal intensity over time during superficial (blue) and deep (red) pain stimuli are shown for the ipsilateral (right) insula and anterior insula. Vertical dashed lines indicate the start of each hypertonic saline injection. Reproduced from Henderson et al. (2006).

Schreckenberger et al., 2005). Based on this, we argue that the fall in signal intensity in pACC, and increase in activity in the insula, during the static handgrip and post-exercise ischaemia reflect the emotional response to pain. Alternatively, the decrease in pACC may reflect an apparent failure of top-down processing to reduce the pain: it has been shown that cognitive tasks that distract subjects from a painful cutaneous stimulus, leading to reductions in pain ratings, are associated with increases in signal intensity within the pACC yet decreases in areas related to encoding stimulus intensity, such as the thalamus and insula (Bantick et al., 2002). Moreover, an increase in activity within the pACC also features in placebo analgesia, which involves the same circuitry as that engaged during opioid analgesia (Petrovic et al., 2002), and

Our fMRI data have shown that certain areas of the brain exhibit an increase in activity, as judged by regional increases in BOLD signal intensity, while others show a decrease, during static handgrip exercise and post-exercise ischaemia. It is accepted that the increase in heart rate at the beginning of exercise is mediated by central command, returning as it does to baseline levels during post-exercise ischaemia, but the underlying neural processes during the post-exercise ischaemia are less well understood. Studies in experimental animals have found direct projections from the sensorimotor cortex to the NTS and the RVLM (M'hamed et al., 1993; Verberne and Owens, 1998), so central command could cause an increase in muscle sympathetic nerve activity. However, one would expect that if this were to occur the increase in MSNA to non-contracting muscles would commence at the beginning of the contraction phase. Rather, there is no increase at the beginning (Wong et al., 2007a, 2007b), but a progressive increase during the course of the contraction. While central command may contribute to this increase it is clear that metaboreceptor activity will increase progressively during the contraction phase, and remain essentially constant during post-exercise ischaemia. Nevertheless, our recent data on sympathetic outflow to the contracting muscle do show that MSNA increases at the onset of the contraction, in an intensity-dependent manner; this, we believe, is due to central command (Boulton et al., 2014). Based on the evidence we have presented in this review, we conclude that the metaboreflex is mediated via the medulla: projection of group III/IV muscle afferents to NTS, excitation of neurones in RVLM, an increase in muscle sympathetic outflow to non-contracting muscles and hence an increase in blood pressure. Furthermore, we speculate that the increase in activity in the contralateral insula and the decrease in perigenual anterior cingulate cortex—rather than causing the increase in MSNA—may be related more to the unpleasantness and pain subjects experience during post-exercise ischaemia, though the posterior insula may also be activated by the increase in baroreceptor input during the resultant increase in blood pressure. Of course, such an interpretation is problematic, given that both isometric exercise and pain can cause increases in blood pressure. Interestingly, our recent work has shown that long-lasting muscle pain, induced by infusion of hypertonic saline, causes sustained increases in MSNA, blood pressure and heart rate in some individuals but sustained decreases in others (Fazalbhoy et al., 2012, 2014); we are currently undertaking concurrent fMRI and recordings of MSNA using this paradigm in an attempt to disambiguate cortical and subcortical changes related to the sensory input and the generation of the autonomic changes.

References Allen, G.V., Saper, C.B., Hurley, K.M., Cechetto, D.F., 1991. Organization of visceral and limbic connections in the insular cortex of the rat. J. Comp. Neurol. 311, 1–16. Bantick, S.J., Wise, R.G., Ploghaus, A., Clare, S., Smith, S.M., Tracey, I., 2002. Imaging how attention modulates pain in humans using functional MRI. Brain 125, 310–319. Berthier, M., Starkstein, S., Leiguarda, R., 1988. Asymbolia for pain: a sensory-limbic disconnection syndrome. Ann. Neurol. 24, 41–49. Boulton, D., Taylor, C.E., Macefield, V.G., Green, S., 2014. Effect of contraction intensity on sympathetic nerve activity to active human skeletal muscle. Front. Physiol. 5, 194. Burton, A.R., Birznieks, I., Bolton, P.S., Henderson, L.A., Macefield, V.G., 2009. The effects of deep and superficial experimentally-induced acute pain on muscle sympathetic nerve activity in human subjects. J. Physiol. 587, 183–193. Bush, G., Luu, P., Posner, M.I., 2000. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 4, 215–222. Cechetto, D.F., Chen, S.J., 1990. Subcortical sites mediating sympathetic responses from insular cortex in rats. Am. J. Physiol. 258, R245–R255. Coote, J.H., Hilton, S.M., Perez-Gonzalez, J.F., 1971. The reflex nature of the pressor response to muscular exercise. J. Physiol. 215, 789–804. Damasio, A.R., 1996. The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 351, 1413–1420.


V.G. Macefield, L.A. Henderson / Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx Dampney, R.A., Horiuchi, J., Tagawa, T., Fontes, M.A., Potts, P.D., Polson, J.W., 2003. Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone. Acta Physiol. Scand. 177, 209–218. Devinsky, O., Morrell, M.J., Vogt, B.A., 1995. Contributions of anterior cingulate cortex to behaviour. Brain 118, 279–306. Drevets, W.C., Price, J.L., Simpson Jr., J.R., Todd, R.D., Reich, T., Vannier, M., Raichle, M.E., 1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824–827. Dunckley, P., Wise, R.G., Aziz, Q., Painter, D., Brooks, J., Tracey, I., Chang, L., 2005. Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness. Neuroscience 133, 533–542. Fazalbhoy, A., Birznieks, I., Macefield, V.G., 2012. Individual differences in the cardiovascular responses to tonic muscle pain: parallel increases or decreases in muscle sympathetic nerve activity, blood pressure, and heart rate. Exp. Physiol. 97, 1084–1092. Fazalbhoy, A., Birznieks, I., Macefield, V.G., 2014. Consistent interindividual increases or decreases in muscle sympathetic nerve activity during experimental muscle pain. Exp. Brain Res. 232, 1309–1315. Gandevia, S.C., Hobbs, S.F., 1990. Cardiovascular responses to static exercise in man: central and reflex contributions. J. Physiol. 430, 105–117. Gandevia, S.C., Killian, K., McKenzie, D.K., Crawford, M., Allen, G.M., Gorman, R.B., Hales, J.P., 1993. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J. Physiol. 470, 85–107. Hansen, J., Thomas, G.D., Jacobsen, T.N., Victor, R.G., 1994. Muscle metaboreflex triggers parallel sympathetic activation in exercising and resting human skeletal muscle. Am. J. Physiol. 266, H2508–H2514. Harper, R.M., Macey, P.M., Henderson, L.A., Woo, M.A., Macey, K.E., Frysinger, R.C., Alger, J.R., Nguyen, K.P., Yan-Go, F.L., 2003. fMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects. J. Appl. Physiol. 94, 1583–1595. Hayes, S.G., Kindig, A.E., Kaufman, M.P., 2005. A comparison between the effect of static contraction and tendon stretch on the discharge of group III and IV muscle afferents. J. Appl. Physiol. 99, 1891–1896. Henderson, L.A., Macey, P.M., Macey, K.E., Frysinger, R.C., Woo, M.A., Harper, R.K., Alger, J.R., Yan-Go, F.L., Harper, R.M., 2002. Brain responses associated with the Valsalva manouevre revealed by functional magnetic resonance imaging. J. Neurophysiol. 88, 3477–3486. Henderson, L.A., Bandler, R., Gandevia, S.C., Macefield, V.G., 2006. Distinct forebrain activity patterns during deep versus superficial pain. Pain 120, 286–296. Henderson, L.A., Gandevia, S.C., Macefield, V.G., 2007. Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: a single-trial fMRI study. Pain 128, 20–30. Henderson, L.A., Gandevia, S.C., Macefield, V.G., 2008. Gender differences in brain activity evoked by muscle and cutaneous pain: a retrospective study of single-trial fMRI data. NeuroImage 39, 1867–1876. Henderson, L.A., Rubin, T.K., Macefield, V.G., 2011. Within-limb somatotopic representation of acute muscle pain in the human contralateral dorsal posterior insula. Hum. Brain Mapp. 32, 1592–1601. Hornak, J., Bramham, J., Rolls, E.T., Morris, R.G., O'Doherty, J., Bullock, P.R., Polkey, C.E., 2003. Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain 126, 1691–1712. James, C., Macefield, V.G., Henderson, L.A., 2013. Real-time imaging of cortical and subcortical control of muscle sympathetic nerve activity in awake human subjects. NeuroImage 70, 59–65. Kaufman, M.P., Longhurst, J.C., Rybicki, K.J., Wallach, J.H., Mitchell, J.H., 1983. Effects of static muscular contraction on impulse activity of groups III and IV afferents in cats. J. Appl. Physiol. 55, 105–112. Kimmerley, D.S., O'Leary, D.D., Menon, R.S., Gati, J.S., Shoemaker, J.K., 2005. Cortical regions associated with autonomic cardiovascular regulation during lower-body negative pressure in humans. J. Physiol. 569, 331–345. Kniffki, K.-D., Mense, S., Schmidt, R.F., 1981. Muscle receptors with fine afferent fibers which may evoke circulatory reflexes. Circ. Res. 48 (Suppl. 1), 25a–31a. Macefield, V.G., Henderson, L.A., 2010. Real-time imaging of the medullary circuitry involved in the generation of spontaneous muscle sympathetic nerve activity in awake subjects. Hum. Brain Mapp. 31, 539–549. Macefield, V.G., Gandevia, S.C., Henderson, L.A., 2006. Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory capacity apnea: a fMRI study. J. Appl. Physiol. 10, 266–273. Macefield, V.G., Gandevia, S.C., Henderson, L.A., 2007. Discrete changes in cortical activation during experimentally induced referred muscle pain: a single-trial fMRI study. Cereb. Cortex 17, 2050–2059. Macey, P.M1., Wu, P., Kumar, R., Ogren, J.A., Richardson, H.L., Woo, M.A., Harper, R.M., 2012. Differential responses of the insular cortex gyri to autonomic challenges. Auton. Neurosci. 168, 72–81.

9

Mark, A.L., Victor, R.G., Nerhed, C., Wallin, B.G., 1985. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ. Res. 57, 461–469. Mayberg, H.S., Brannan, S.K., Mahurin, R.K., Jerabek, P.A., Brickman, J.S., Tekell, J.L., Silva, J.A., McGinnis, S., Glass, T.G., Martin, C.C., Fox, P.T., 1997. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8, 1057–1061. Mazzola, L., Isnard, J., Mauguiere, F., 2006. Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses. Cereb. Cortex 16, 960–968. McCloskey, D.I., Mitchell, J.H., 1972. Reflex cardiovascular and respiratory responses originating in exercising muscle. J. Physiol. 224, 173–186. M'hamed, S.B., Sequeira, H., Poulain, P., Bennis, M., Roy, J.C., 1993. Sensorimotor cortex projections to the ventrolateral and the dorsomedial medulla oblongata in the rat. Neurosci. Lett. 164, 195–198. Mitchell, J.H., 1990. Neural control of the circulation during exercise. Med. Sci. Sports Exerc. 22, 141–154. Ostrowsky, K., Magnin, M., Ryvlin, P., Isnard, J., Guenot, M., Mauguiere, F., 2002. Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. Cereb. Cortex 12, 376–385. Owen, D.G., Clarke, C.F., Ganapathy, S., Prato, F.S., St Lawrence, K.S., 2010. Using perfusion MRI to measure the dynamic changes in neural activation associated with tonic muscular pain. Pain 148, 375–386. Petrovic, P1., Kalso, E., Petersson, K.M., Ingvar, M., 2002. Placebo and opioid analgesia— imaging a shared neuronal network. Science 295, 1737–1740. Phan, K.L., Taylor, S.F., Welsh, R.C., Ho, S.H., Britton, J.C., Liberzon, I., 2004. Neural correlates of individual ratings of emotional salience: a trial-related f MRI study. Neuroimage 21, 768–780. Ploghaus, A1., Narain, C., Beckmann, C.F., Clare, S., Bantick, S., Wise, R., Matthews, P.M., Rawlins, J.N., Tracey, I., 2001. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J. Neurosci. 21, 9896–9903. Potts, J.T., Mitchell, J.H., 2005. Rapid resetting of carotid baroreceptor reflex by afferent input from skeletal muscle receptors. Am. J. Physiol. 275, H2000–H2008. Potts, J.T., Spyer, K.M., Paton, J.F., 2000. Somatosympathetic reflex in a working heartbrainstem preparation of the rat. Brain Res. Bull. 53, 59–67. Reeder, E., Green, S., 2012. Dynamic response characteristics of muscle hyperaemia: effect of exercise intensity and relation to electromyographic activity. Eur. J. Appl. Physiol. 112, 3997–4013. Resstel, L.B., Fernandes, K.B., Correa, F.M., 2004. Medial prefrontal cortex modulation of the baroreflex parasympathetic component in the rat. Brain Res. 1015, 136–144. Sander, M., Macefield, V.G., Henderson, L.A., 2010. Cortical and brainstem changes in neural activity during static handgrip and post-exercise ischemia in humans. J. Appl. Physiol. 108, 1691–1700. Schreckenberger, M., Siessmeier, T., Viertmann, A., Landvogt, C., Buchholz, H.G., Rolke, R., Treede, R.D., Bartenstein, P., Birklein, F., 2005. The unpleasantness of tonic pain is encoded by the insular cortex. Neurology 64, 1175–1183. Smith, S.A., Mitchell, J.H., Garry, M.A., 2001. The mammalian exercise pressor reflex in health and disease. Exp. Physiol. 91, 89–102. Verberne, A.J., 1996. Medullary sympathoexcitatory neurons are inhibited by activation of the medial prefrontal cortex in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 270, R713–R719. Verberne, A.J., Owens, N.C., 1998. Cortical modulation of the cardiovascular system. Prog. Neurobiol. 54, 149–168. Victor, R.G., Seals, D.R., Mark, A.L., 1987. Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans. J. Clin. Invest. 79, 508–516. Victor, R.G., Pryor, S.L., Secher, N.H., Mitchell, J.H., 1989. Effects of partial neuromuscular blockade on sympathetic nerve responses to static exercise in humans. Circ. Res. 65, 468–476. Wallin, B.G., Burke, D., Gandevia, S.C., 1992. Coherence between the sympathetic drives to relaxed and contracting muscles of different limbs of human subjects. J. Physiol. Lond. 455, 219–233. Wong, S.W., Kimmerly, D.S., Massé, N., Menon, N., Cechetto, D.F., Shoemaker, J.K., 2007a. Sex differences in forebrain and cardiovagal responses at the onset of isometric handgrip exercise: a retrospective fMRI study. J. Appl. Physiol. 103, 1402–1411. Wong, S.W., Massé, N., Kimmerly, D.S., Menon, N., Shoemaker, J.K., 2007b. Ventral medial prefrontal cortex and cardiovagal control in conscious humans. NeuroImage 35, 698–708.


Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly.

inactivity.

Autonomic and skeletal muscle responses to nonelectrical cutaneous stimulation.

Autonomic responses to exercise: where is central command?

Pain Catastrophising Affects Cortical Responses to Viewing Pain in Others.

Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia.

Personality traits modulate subcortical and cortical vestibular and anxiety responses to sound-evoked otolithic receptor stimulation.

Effects of the expression of pain on autonomic and pain tolerance responses to subject-controlled pain.

Autonomic, Behavioral, and Subjective Pain Responses in Alzheimer's Disease.

Topographic recordings of auditory evoked potentials to speech: subcortical and cortical responses.

Physiological responses to glycerol ingestion during exercise.

Cardiac Autonomic Responses during Exercise and Post-exercise Recovery Using Heart Rate Variability and Systolic Time Intervals-A Review.

Muscle pain and blood pressure responses during isometric handgrip exercise in healthy African American and non-Hispanic White adults.

Ventilatory responses to transient and steady state hypoxia during exercise.

Influence of endurance and resistance exercise order on the postexercise hemodynamic responses in hypertensive women.

Experimental Sleep Restriction Facilitates Pain and Electrically Induced Cortical Responses.

Responses of the splanchnic circulation to ischaemia.

Muscle and liver glycogen utilization during prolonged lift and carry exercise: male and female responses.

Muscle sympathetic nerve responses to static leg exercise.

Autophagic cellular responses to physical exercise in skeletal muscle.

Cardiac autonomic responses during upper versus lower limb resistance exercise in healthy elderly men.

Cardiac Autonomic and Blood Pressure Responses to an Acute Bout of Kettlebell Exercise.

Autonomic and cardio-respiratory responses to exercise in Brugada Syndrome patients.

Cardiac pacemakers in absence of the SA node: responses to exercise and autonomic blockade.