Experimental Physiology

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1 Exp Physiol 97.1 pp Symposium Report Mapping the central neurocircuitry that integrates the cardiovascular response to exercise in humans Shanika D. Basnayake 1,AlexanderL.Green 1,2 and David J. Paterson 1 1 Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK 2 Nuffield Department of Surgery, University of Oxford and Department of Neurosurgery, The West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK Experimental Physiology There are abundant animal data attempting to identify the neural circuitry involved in cardiovascular control. Translating this research into humans has been made possible using functional neurosurgery during which deep brain stimulating electrodes are implanted into various brain nuclei for the treatment of chronic pain and movement disorders. This not only allows stimulation of the human brain, but also presents the opportunity to record neural activity from various brain regions. This symposium review highlights key experiments from the past decade that have endeavoured to identify the neurocircuitry responsible for integrating the cardiovascular response to exercise in humans. Two areas of particular interest are highlighted: the periaqueductal grey and the subthalamic nucleus. Our studies have shown that the periaqueductal grey (particularly the dorsal column) is a key part of the neurocircuitry involved in mediating autonomic changes adapted to ongoing behaviours. Emerging evidence also suggests that the subthalamic nucleus is not only involved in the control of movement, but also in the mediation of cardiovascular responses. Although these sites are unlikely to be the command areas themselves, we have demonstrated that the two nuclei have the properties of being key integrating sites between the feedback signals from exercising muscle and the feedforward signals from higher cortical centres. (Received 26 July 2011; accepted after revision 5 October 2011; first published online 7 October 2011) Corresponding author D. J. Paterson: Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK. david.paterson@dpag.ox.ac.uk It has been hypothesized since the early 19th century that the human cardiovascular system is under the control of the central nervous system (Montastruc et al. 1996), and that this system initiates and sustains the circulatory response depending on the particular physiological conditions being experienced. Exercise provides the greatest physiological challenge to the cardiovascular system, yet the control circuits regulating this response are still poorly defined and understood. Three systems have been proposed to have a role in the origin of the activation signals of the autonomic nervous system during exercise: (1) central command ; (2) the muscle pressor reflex; and (3) the arterial baroreceptor reflex (Rowell, 1993). Central command, a term coined by Goodwin et al. (1972), is a feedforward signal whereby activation of brain regions responsible for skeletal muscle motor unit recruitment results in the parallel activation of medullary neuronal circuits, causing autonomic activation. In contrast, the muscle pressor reflex is a feedback circuit arising from activation of sensory nerve endings innervating contracting skeletal muscle (Coote et al. 1971; McCloskey & Mitchell, 1972; Kaufman & Forster, 1996). The arterial baroreflex originates from baroreceptors located in the walls of the carotid sinus and the aortic arch, which respond to stretch stimuli (Dampney, 1994). This reflex arc provides beat-to-beat information about the pressure of the arterial system, the cardiac chambers and the greater veins, and appropriately influences the activity of cardiovascular autonomic nerves so that resting arterial blood pressure operates around a set point. Both central command and the exercise pressor reflex modulate the resetting of the arterial baroreflex DOI: /expphysiol

2 30 S. D. Basnayake and others Exp Physiol 97.1 pp in order to allow heart rate and arterial blood pressure to increase during exercise (Mitchell, 1990; Williamson, 2010). Established cardiovascular circuits: animal experiments Electrical stimulation of a specific region within the rostral ventrolateral medulla in both the cat (Chai & Wang, 1962) and the rabbit (Dampney & Moon, 1980) elicits a marked rise in arterial blood pressure; lesions within the same area decrease arterial blood pressure. Furthermore, microinjection of glutamate into this region in rabbits causes a significant pressor response (Dampney et al. 1982). Althoughthe medulla is knownto contain the major nuclei that manipulate cardiovascular parameters, the roles of midbrain nuclei and higher cortical circuits in the integration of cardiovascular regulation are less clearly defined. Electrical stimulation of the subthalamic locomotor region of the hypothalamus in decorticate cats drives both locomotion and the associated cardiorespiratory responses that normally accompany volitional exercise (Eldridge et al. 1981, 1985). This response is independent of afferent feedback, as the cardiorespiratory responses persist during stimulation of the subthalamic locomotor region (fictive locomotion) following paralysis with neuromuscular blocking drugs. Electrical stimulation of the periaqueductal grey (PAG) in cats also results in cardiovascular responses that mimic aspects of the exercise response (Abrahams et al. 1960). Similar responses can be evoked by microinjection of glutamate into the PAG of anaesthetized rabbits (Tan & Dampney, 1983). Although research using animal models has identified potential circuits by direct manipulation of relevant central nervous system areas (via both electrical and chemical stimulation), translating these findings into humans has now been made possible by the introduction of functional neurosurgery. Here, deep brain stimulating electrodes are implanted into various midbrain nuclei for the treatment of chronic pain and movement disorders (Fig. 1). This procedure allows stimulation of relevant nuclei, but also presents the unique opportunity to record neural activity (in terms of local field potentials) within the implanted regions. The technique has been described in detail elsewhere (Bittar et al. 2005). The mechanism of deep brain stimulation (DBS) is extremely complex and is not yet fully understood. There is debate that the electrodes could be working through a synaptic mechanism (Anderson et al. 2004), by stimulation of the afferent fibres (Gradinaru et al. 2009) and/or efferent fibres ofthetargetednuclei(zhenget al. 2011), or even by stimulation of passing fibres (Bosch et al. 2011). In this report, we examine how the DBS procedure has allowed identification of some specific central neurocircuitry involved in the integration of the cardiovascular response to exercise in humans. Figure 1. Electrode localization in the periaqueductal grey (PAG) A, postoperative image (postoperative computed tomography scan fused to preoperative magnetic resonance imaging) showing a unilateral electrode in the right PAG (arrow). B, schematic diagram showing a dorsal PAG electrode in the sagittal plane. Abbreviations: AC, anterior commissure; MCP, mid-commissural point; PAG, periaqueductal grey; PC, posterior commissure; PVG, periventricular grey; RN, red nucleus; and SC, superior colliculus. Basnayake et al. (2011) Journal of Applied Physiology; American Physiological Society, used with permission.

3 Exp Physiol 97.1 pp Neurocircuitry and cardiovascular response to exercise 31 Figure 2. Cardiovascular response to subthalamic nucleus (STN) stimulation Raw data trace showing that STN stimulation results in an increase in heart rate [HR; in beats per minute (bpm)] and arterial blood pressure (ABP; in millimetres of mercury) that is maintained for the duration of the stimulation. Modified from Thornton et al. (2002). Cardiovascular effects of midbrain stimulation in humans Amongst the first cardiovascular function studies using DBSpatientsasthesubjectgroupwerethoseconductedby Thornton et al. (2002) and Green et al. (2005). Electrodes were placed using stereotactic co-ordinates aided by pre- and postoperative computed tomgraphy/magnetic resonance imaging scans. Knowing the precise location is not possible without histology; however, distinct regions that were cardiovascular active were isolated in the midbrain. Specifically, Thornton et al. (2002) established that high-frequency electrical stimulation (i.e. >90 Hz) of the thalamus, substantia nigra and subthalamic nucleus (STN) increased heart rate and mean arterial pressure (Fig. 2), whereas high-frequency stimulation of the globus pallidus did not change these cardiovascular variables. Low-frequency stimulation (i.e. <20 Hz) of any of these sites had no effect on cardiovascular parameters. Also in awake humans, Green et al. (2005) showed that stimulation of the dorsal or ventral areas of the periventricular grey (PVG; rostral to and continuous with the PAG) could either increase or decrease arterial blood pressure, respectively (Fig. 3). They found analogous changes in both systolic and diastolic blood pressure, pulse pressure and maximal rate of change of pressure. However, there was no change in heart rate, suggesting that the cardiovascular effects are a result of both altered myocardial contractility and a change in total peripheral resistance. We have revisited three classic human cardiovascular models (Krogh & Lindhard, 1913; Alam & Smirk, 1937; Figure 3. Cardiovascular response to periventricular grey (PVG)/PAG stimulation A and B, mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively, for six patients who had increased arterial blood pressure on stimulation of the dorsal PVG/PAG. C and D, mean changes in SBP and DBP for seven patients who had a reduction in arterial blood pressure on stimulation of the ventral PVG/PAG. Shaded area denotes ± 1 SEM. Data are redrawn from Green et al. (2005).

4 32 S. D. Basnayake and others Exp Physiol 97.1 pp Goodwin et al. 1972), of which the central circuits have thus far remained unidentified. Neurocircuity involved in central command in humans: role of periaqueductal grey and subthalamic nucleus The idea that a centrally generated neural signal could initiate the cardiovascular response to exercise was first proposed by Krogh & Lindhard (1913). They demonstrated that heart rate, arterial blood pressure and pulmonary ventilation could all be modified by altering the subject s perception of exercise. It appeared that the initial cardiorespiratory response anticipated the perceived work rate. Using neuroimaging techniques, Thornton et al. (2001) and Williamson et al. (2001) hypnotically manipulated the subject s sense of exercise effort, in order for the subject to focus on the motor task whilst uncoupling the task from the movement itself. They showed that an increase in perceived effort elevated the cardiorespiratory responses to imagined exercise, especially the ventilatory responses (Thornton et al. 2001). Several neural correlates were identified that are known to be coupled to cardiorespiratory centres. Using the model of Krogh & Lindhard (1913), we tested the hypothesis that neural activity recorded from subcortical structures in humans is directly related to Figure 4. Results of central command study A, raw data trace showing local field potentials recorded from the PAG during activation of the central command signal. B, mean changes in cardiovascular parameters with exercise and anticipation of exercise for all deep brain stimulation patients, showing increased arterial blood pressure and heart rate during anticipation of exercise and exercise itself. The significance is calculated for each condition ( anticipation, exercise and recovery ) compared with rest. C, normalized power spectral changes for the PAG (rest = 1.0) divided into frequency bands, showing increased neural activity in high-frequency bands (12 90 Hz) during both anticipation of exercise and exercise itself. D, normalized power spectral changes for the STN, showing decreased neural activity in the Hz band and increased activity in the Hz bands during both anticipation of exercise and exercise itself. P < 0.05, P < 0.01 and P < Modified from Green et al. (2007).

5 Exp Physiol 97.1 pp Neurocircuitry and cardiovascular response to exercise 33 changes in cardiovascular parameters, such as heart rate and arterial blood pressure, when they are altered by both anticipation of exercise and real exercise (Green et al. 2007). Anticipation of exercise, along with the accompanying increases in cardiovascular parameters, correlated to increased PAG activity (Fig. 4A C). This suggested that the PAG may be directly involved in the neurocircuitry integrating the central command signal before the onset of exercise. During exercise itself, further increases in PAG activity were observed, which were mirrored by increases in heart rate and arterial blood pressure (Fig. 4B). Local field potential recordings from the STN showed a decrease in neural activity during the anticipation of exercise and real exercise in the lower frequency (12 25 Hz) bands; however, there was an increase in neural activity during these same conditions in the higher frequency (25 90 Hz) bands (Fig. 4D). It is possible that this decrease in activity is directly linked to cardiovascular changes. The STN is known to project to a number of nuclei that have been shown to be involved in the parallel activation of the cardiorespiratory system and the locomotor system; for example, the pedunculopontine nucleus (Pahapill & Lozano, 2000). The cardiovascular changes coupled with the motor changes suggest that central command exists and that there is a link from the STN, but is the STN activity simply correlated (due to the motor effect) or is it causal? The STN also projects to the thalamus to facilitate movement. The decrease in STN activity in the Hz band during exercise could suggest that there is a release of inhibitory drive on the cardiovascular nuclei receiving projections from the STN, which could cause the increase in heart rate and arterial blood pressure. It is conceivable that the increase in the Hz band is due to the involvement Figure 5. Preliminary results of central command study using vibration to alter perception of exercise: increased central command A, schematic diagram showing a normal biceps contraction compared with a biceps contraction with vibrations of the triceps tendon (so more central command is required). B, mean power spectral density (PSD) for four STN patients showing reduced neural activity during a normal biceps contraction and a further reduction in neural activity during a biceps contraction with vibration of the triceps tendon. C, mean changes in cardiovascular parameters showing significantly increased arterial blood pressure with a biceps contraction with vibration of the triceps tendon compared with a normal biceps contraction. P < 0.01.

6 34 S. D. Basnayake and others Exp Physiol 97.1 pp of the STN in movement, because this increase is not seen during sustained isometric contractions (see following preliminary experiments). Preliminary case study experiments following the protocol of Goodwin et al. (1972) have been conducted that demonstrate decreased STN activity corresponding to increased central command. Subthalamic nucleus activity in lower frequency bands appears to be decreased in humans performing sustained isometric contractions of the biceps muscle. When a vibration stimulus was applied to the triceps tendon (the antagonist tendon) in order to activate its muscle spindle afferents, reflex inhibition occurred, so that more central command was required to hold the same contraction (Fig. 5). This corresponded to a further decrease in STN activity and a further increase in heart rate and arterial blood pressure. Conversely, on application of the vibration stimulus to the biceps tendon in order to activate its muscle spindle afferents, reflex excitation occurred, so that less central command was required to hold the same contraction (Fig. 6). During these conditions, the decrease in STN activity was not as pronounced, and there was a corresponding fall in heart rate and arterial blood pressure. Neurocircuitry involved in the human exercise pressor reflex Alam & Smirk (1937) produced evidence in humans to support the hypothesis of a reflex pressor response to exercise. They reported maintained elevation in arterial blood pressure during muscle blood flow occlusion following exercise, and suggested that accumulation of byproducts within the muscle resulted in afferent nerve fibre stimulation. Coote et al. (1971) produced direct evidencetosupportthishypothesisinbothanaesthetized and decerebrate cats, and showed that the increase in arterial blood pressure that accompanied hindlimb muscle contraction via ventral root stimulation was abolished by sectioning of the dorsal roots from the muscle. The reflex was mediated by groups III and IV afferent fibres, and was stimulated by the mechanical effects of muscular Figure 6. Preliminary results of central command study using vibration to alter perception of exercise: decreased central command A, schematic diagram showing a normal biceps contraction compared with a biceps contraction with vibration of the biceps tendon (so less central command is required). B, mean power spectral density (PSD) for four STN patients showing reduced neural activity during a normal biceps contraction and a diminished reduction in neural activity during a biceps contraction with vibration of the biceps tendon. C, mean changes in cardiovascular parameters showing significantly decreased arterial blood pressure during a biceps contraction with vibration of the biceps tendon compared with a normal biceps contraction. P < 0.05.

7 Exp Physiol 97.1 pp Neurocircuitry and cardiovascular response to exercise 35 contraction and the metabolic products of muscular contraction, respectively (McCloskey & Mitchell, 1972; Kaufman et al. 1983). Using local field potential recordings from DBS patients, our group investigated the subcortical structures involved in the integration of the exercise pressor reflex (Basnayake et al. 2011). Role of the periaqueductal grey We demonstrated that the exercise pressor reflex was associated with significant increases in dorsal PAG activity (Fig. 7) and, in addition, that this response was graded to exercise intensity and was greater during periods of ischaemic exercise. When exercise drive was increased, neural activity increased and became more widespread across the frequency bands, and also became significantly elevated in terms of absolute power spectral density values. The PAG is a vital neural structure for both autonomic regulation and modulation of the cardiovascular responses accompanying the defence reaction in animals (Bandler & Carrive, 1988). It is known to project to the ventrolateral medullary regions that control blood pressure (Lovick, 1985; Carrive et al. 1988, 1989). It is also known to project to higher cardiac regulatory centres, such as the hypothalamus (Horiuchi et al. 2009). The structure of the PAG, with its functionally distinct columns, is well recognized (Carrive & Bandler, 1991b), as are its responses to stimulation. In animal models, direct activation of Figure 7. Results of exercise pressor reflex study A, raw data trace showing local field potential recorded from the PAG during activation of the exercise pressor reflex. B, mean changes in cardiovascular parameters showing increased arterial blood pressure with both exercise and occlusion, and increased heart rate only during exercise. The significance is calculated for each condition ( exercise, occlusion and recovery ) compared with rest. C, normalized power spectral changes (rest = 1.0) divided into frequency bands, showing increased neural activity in the low-frequency bands (4 25 Hz) during occlusion. Basnayake et al. (2011) Journal of Applied Physiology; American Physiological Society, used with permission. P < 0.01, P <

8 36 S. D. Basnayake and others Exp Physiol 97.1 pp the dorsomedial, dorsolateral and lateral columns of the PAG elicits a fight or flight response, including hypertension and tachycardia (Duggan & Morton, 1983; Lovick, 1985; Carrive & Bandler, 1991a). Likewise, in humans, stimulation of the dorsal PVG/PAG increases arterial blood pressure (Green et al. 2005). Conversely, stimulation of the ventrolateral PAG in animals (Carrive & Bandler, 1991b; Johnson et al. 2004) results in a passive coping response, including hypotension and bradycardia. In humans, stimulation of the ventral PVG/PAG decreases arterial blood pressure (Green et al. 2005), and its destruction prevents the rise in arterial blood pressure that normally accompanies the activation of skeletal muscles (Williams et al. 1990). When the results of the experiments conducted with DBS patients (Green et al. 2007; Basnayake et al. 2011) are taken together with the known effects of stimulation of the dorsal PVG in humans and lateral PAG in animals, there is now compelling evidence that this area of the PAG is a key part of the neurocircuitry involved in mediating autonomic changes adapted to ongoing behaviours. In particular, the integration of the cardiovascular responses to exercise involving the pressor reflex (Basnayake et al. 2011) and central command (Green et al. 2007). Role of the subthalamic nucleus There is evidence to suggest that the STN is involved in the parallel activation of cardiovascular and locomotor systems. Smith et al. (1960) showed that stimulation of the H 2 fields of Forel (which include the dorsal portion of the STN) in dogs resulted in cardiovascular responses similar to those that result from exercise. Eldridge et al. (1981) demonstrated that electrical stimulation of the subthalamic locomotor region drives both locomotion and the accompanying cardiovascular responses that are usually associated with volitional exercise. Likewise, Angyán & Angyán (2003) observed an increase in both arterial blood pressure and heart rate during electrical stimulation of the subthalamic nucleus in conscious, freely moving cats. Taken together with the study by Thornton et al. (2002) and the preliminary results of the central command study representing the Goodwin model described earlier, it appears that the STN is not only involved in the control of movement per se, butis also an important aspect of the circuitry underpinning the cardiovascular responses to exercise. Conclusion The proposal of a link between the central and peripheral nervous systems during exercise has been championed for almost a century, since the classical studies of Krogh & Lindhard (1913), Alam & Smirk (1937), Coote et al. (1971), McCloskey & Mitchell (1972) and Goodwin et al. (1972). Emerging evidence suggests that both the PAG and the STN are major sites of integration of cardiovascular responses to exercise (Fig. 8), in particular the dorsolateral PAG in animals (Lovick, 1985; Bandler & Carrive, 1988; Horiuchi et al. 2009) and the dorsal PVG/PAG in humans (Green et al. 2007; Basnayake et al. 2011). Although they may not be the command areas as such, they have all the properties of being key integrating sites or relay stations. Figure 8. Hypothesized neurocircuitry for the neural control of the cardiovascular system during exercise (highlighting deep brain stimulation studies) Abbreviations: MABP, mean arterial blood pressure; NTS, nucleus of the solitary tract; PAG, periaqueductal grey; and STN, subthalamic nucleus.

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