A Century of Exercise Physiology: Key Concepts in Neural Control of the Circulation PDF

European Journal of Applied Physiology https://doi.org/10.1007/s00421-024-05451-0 INVITED REVIEW A century of exercise physiology: key concepts in neural control of the circulation J. Kevin Shoemaker1,2 · Robert Gros2,3 Received: 18 October 2023 / Accepted: 26 February 2024 © The Auth...

European Journal of Applied Physiology https://doi.org/10.1007/s00421-024-05451-0 INVITED REVIEW A century of exercise physiology: key concepts in neural control of the circulation J. Kevin Shoemaker1,2 · Robert Gros2,3 Received: 18 October 2023 / Accepted: 26 February 2024 © The Author(s) 2024 Abstract Early in the twentieth century, Walter B. Cannon (1871–1945) introduced his overarching hypothesis of “homeostasis” (Cannon 1932)—the ability to sustain physiological values within a narrow range necessary for life during periods of stress. Physical exercise represents a stress in which motor, respiratory and cardiovascular systems must be integrated across a range of metabolic stress to match oxygen delivery to oxygen need at the cellular level, together with appropriate thermoregulatory control, blood pressure adjustments and energy provision. Of these, blood pressure regulation is a complex but controlled variable, being the function of cardiac output and vascular resistance (or conductance). Key in understanding blood pressure control during exercise is the coordinating role of the autonomic nervous system. A long history outlines the development of these concepts and how they are integrated within the exercise context. This review focuses on the renaissance observa- tions and thinking generated in the first three decades of the twentieth century that opened the doorway to new concepts of inquiry in cardiovascular regulation during exercise. The concepts addressed here include the following: (1) exercise and blood pressure, (2) central command, (3) neurovascular transduction with emphasis on the sympathetic nerve activity and the vascular end organ response, and (4) tonic neurovascular integration. Keywords Sympathetic nerve activity · Central command · Neurovascular transduction Overview (Adrian et al. 1932) that highlighted their work in direct electrical recordings of sympathetic postganglionic sym- Landmark studies in the 1903–1932 period emerged along pathetic nerves in mammals, providing a pathway to study three disparate lines of inquiry and led to the current under- signals with direct inference to events in the brain. Third, in standing of how the autonomic nervous system modifies the 1933, W.B. Cannon first defined circulating catecholamines cardiovascular system in moments of exercise stress. These (Cannon 1933) as neurotransmitters linking sympathetic papers include Krogh and Lindhard’s (Krogh and Lindhard neurotransmission with vascular cellular responses (what we 1913) suggestion of a central cerebral cortex neural mecha- refer to as sympathetic neurovascular transduction) that had nism that coordinates cardiovascular control with motor been introduced by Langley (1907, 1908) who was study- function, a concept we now call central command. A second ing the concept of a cellular receptor that binds adrenergic paper was published in 1932 by E.D. Adrian and his group chemicals (or drugs) to affect vascular cell function. The concept of neurovascular transduction has become a critical element in understanding muscle blood flow during exercise. Communicated by Michael I Lindinger. These landmark studies, emerging along disparate path- * J. Kevin Shoemaker ways, were establishing the framework to understand how [email protected] the autonomic nervous system interacts with the cardiovas- cular system to form a highly integrated system that enables 1 School of Kinesiology, The University of Western Ontario, cardiovascular adjustments and adaptations to the stress of London, ON N6A 3K7, Canada physical exercise. Figure 1 illustrates the integrated and con- 2 Department of Physiology and Pharmacology, The University nected nature of the brain, autonomic nervous system and of Western Ontario, London, ON N6A 3K7, Canada cardiac or vascular end organs that are captured in the over- 3 Department of Medicine, The University of Western Ontario, all concept of Neural Control of the Circulation. London, ON N6A 3K7, Canada Vol.:(0123456789) Content courtesy of Springer Nature, terms of use apply. Rights reserved.  European Journal of Applied Physiology the original literature). One of the first reported record- ings of blood pressure as a function of prolonged exer- cise was reported in 1907 (Gordon 1907). These early studies provided the consistent observation that the BP response to long-term submaximal whole-body exercise is small (e.g. ~ 10 mmHg). Figure 2 presents an example of the earliest data on blood pressure responses to whole- body dynamic exercise. However, in contrast to moder- ate intensity exercise, blood pressure increases markedly by ~ 50 mmHg during the latter moments of incremental whole-body exercise (Mortensen et al. 2005) (Fig. 3, lower panel) or sustained isometric contractions (Mitch- ell 1990), shown for a single individual in Fig. 4. Notable Fig. 1  Major anatomical segments contributing to neural control of the circulation as depicted in discharge patterns in the postganglionic in Fig. 4 is the role of volitional effort to sustain the heart sympathetic neural signal. This figure expresses the ideas that central rate responses to exercise whereas peripheral sensors in projections from the cortex merge with nuclei in the brainstem and, fatigued muscle are critical for the sympathetic response, through variations discharge patterns affect a titrated regulation of as indicated by the persistence of elevated sympathetic vascular resistance. Missing from this figure are the vagal projections to the heart. Reproduced from (Shoemaker et al. 2018) nerve activity during a period of post-exercise circulatory occlusion when volitional effort is stopped but the reflex drive continues. Concept 1: exercise and blood pressure This concept of the exercise pressor response to fatigu- ing exercise is firmly entrenched in our current under- The reporting of changes in blood pressure during exer- standing of exercise physiology. The mechanisms medi- cise emerged in the 1880s (see (Otis 1911) for review of ating this response, however, are multifactorial and have been debated, addressing important questions regarding Fig. 2  Systolic (A), diastolic (B) and mean (C) blood pressure (Pi), respiration rate (R), systolic (B) and diastolic (P) pressure. From together with ventilation rate (D) before, during and after exercise. (Lambert 1918) with permission Raw values are provided in the bottom four rows for pulse interval Content courtesy of Springer Nature, terms of use apply. Rights reserved. European Journal of Applied Physiology dog model of flow-restricted exercise (O'Leary and Wood- bury 1996). In contrast to isometric models, blood pres- sure regulation during dynamic or whole-body exercise is more complex. For example, sympathetic nerve activity, as measured by microneurography techniques, may decrease during the early moments of moderate intensity cycling or knee extension exercise, and then increase markedly at exercise intensities above 40–50% of maximal strength (Ichinose et al. 2008; Katayama and Saito 2019). These patterns align with a reduced rate of increase (or even reversal) in vascular conductance as one approaches maxi- mal workload (Mortensen et al. 2005) (see Fig. 3, upper panel). Regulation of cardiac output during exercise involves, in part, a specific role for regional variations in alpha- adrenergic sympathetic vascular and venular constriction in the gut that reduce vascular capacitance in this region (Rowell 1986) so that more blood is directed back to the heart to support total cardiac output. However, the role of sympathetic activation towards both active (Boulton et al. 2021) and quiescent (Shoemaker et al. 2000) skeletal muscle, remains poorly understood, particularly when the leg vascular response can be accounted for by a myogenic constrictor effect secondary to the rise in blood pressure (Shoemaker et al. 2000). In addition, the larger release of epinephrine, together with heightened sympathetic nerve activity, observed during fatiguing exercise compared to other sympathetic stressors (Dyson et al. 2006) suggests Fig. 3  Systemic vascular conductance and arterial blood pressure at that the balance between beta adrenergic receptor-induced rest, during submaximal and maximal exercise and 10 min of recov- ery performed during incremental ( ) and constant load (○) exer- dilation and alpha-adrenergic vasoconstriction may be cise. Notice the plateau and reversal of vascular conductance dur- altered in favour of dilation. ing final minutes of maximal exercise. Data are means ± S.E.M. for An additional and incompletely understood question 7–8 subjects, ∗ Lower than the value after 22 min when cycling at regarding the exercise pressor response relates to the 80% of peak power, P < 0.05. ‡Lower than the peak values observed after 20–24 min of constant load maximal cycling, P < 0.05. From underlying peripheral and central neural mechanisms. (Mortensen et al. 2005) with permission Sensory receptors in skeletal muscle that detect altered metabolism and tension contribute reflex-mediated cardio- vascular adjustments (Kaufman et al. 1983). However, the the role of the heart versus vasoconstriction in the blood additional observations that heart rate and blood pressure pressure increase as well as the role of reflex-mediated increase together has led to the concept that the barore- effects (Kaufman and Forster 1996; Kaufman et al. 1983) flex set point can shift, essentially “requesting” a rise in that interact with central perceptual features of “effort- blood pressure. A detailed exploration of this concept has ful” work (Mitchell et al. 1983). Of these factors, the been provided earlier (Raven et al. 2002). Mechanistically, potential role of cardiac function in exercise blood pres- direct electrophysiological and experimental approaches in sure regulation is often overlooked. For example, because anesthetized or decerebrate models indicate that descend- efferent sympathetic nerve activity increases concurrently ing neural inputs from the mesencephalic locomotor region with blood pressure during intense exercise, it has been converge with ascending thin muscle afferents (Type III assumed that peripheral vasoconstriction largely accounts afferents) and baroreceptor afferents in the nucleus tractus for the increased blood pressure. However, during fatigu- solitarius that modify baroreflex sensitivity (Degtyarenko ing isometric handgrip exercise in human models (Shoe- and Kaufman 2006; McIlveen et al. 2001; Potts 2002). In maker et al. 2000; Shoemaker et al. 2007), sympathetic humans, functional neuroimaging data point to involve- nerve activity rises but cardiac output accounts for the ment of higher cortical centres such as the medial pre- bulk of the Ohmic rise in blood pressure rather than sys- frontal cortex and insula cortex (Williamson 2015) (see temic vascular resistance, a conclusion also reported in a Central Command section below). Content courtesy of Springer Nature, terms of use apply. Rights reserved.  European Journal of Applied Physiology Fig. 4  Representative data from a single subject illustrating the car- muscle sympathetic nerve activity; AP, action potential. *Denotes diac, hemodynamic and sympathetic responses at baseline (BSL), noise spikes not included in analysis. From (Badrov et al. 2016b) with during static handgrip exercise and a period of postexercise circula- permission tory occlusion (PECO).. HR, heart rate; BP, blood pressure; MSNA, Concept 2: central command of autonomic function. For example, Walter B. Cannon’s characterization of “voodoo death” in 1942 illustrated the In 1913, Krogh and Lindhard (1913) observed in a small important and sometimes fatal role that psychologic stress sample of healthy individuals a rapid respiratory and tachy- can have on cardiovascular function (Cannon 1932). Clini- cardia response immediately at the onset of, and sometimes cal observations made in the 1980’s indicated that fatali- in anticipation of, whole-body exercise, particularly heavy ties following cerebral stroke often were due to catastrophic exercise. Figure 5 provides the original observation. Hav- cardiac arrhythmias (Cheung and Hachinski 2003; Myers ing ruled out options for a metabolic cause, they interpreted et al. 1982), particularly when that stroke involved the insula the rapidity of the responses to be caused by neural factors. cortex due to its ability to influence cardiopathologic out- They proposed this neural mechanism “irradiated” from the comes from hyperadrenergic activation (Yoon et al. 1997; motor cortex to include respiratory and cardiovascular con- Yasui et al. 1991; Oppenheimer et al. 1991). Additionally, trol. This study led to a continuing search for brain actions studies on individuals with cortical lesions demonstrate the and anatomy that coordinate neural control of the circula- role of the medial prefrontal cortex in modulating cardiovas- tion with those that affect skeletal-motor and respiratory cular function. In particular, these individuals show blunted function. In 1971, the term “central command” was used to emotion, poor decision-making and a failed alteration in describe this neural pattern (Goodwin et al. 1972), a name the skin conductance response that is mediated mainly by that is now used routinely. the sympathetic nervous system (Bechara et al. 1996, 1997; In addition to the observations made by Krogh and Damasio 1994). Lindhard (1913), accumulating observations point to an Defining the specific higher brain regions serving a role in important role for cerebral cortex sites in the regulation central command for exercise-based cardiovascular arousal Content courtesy of Springer Nature, terms of use apply. Rights reserved. European Journal of Applied Physiology vagal dominance over cardiac function (Victor et al. 1987). Inasmuch as “effort” reflects a central command character- istic, these studies suggest that central pathways may affect cardiovagal control differently than sympathetic responses. The search for sites of the brain that mediate the coor- dinated cardiovascular, respiratory and skeletal motor responses to exercise begins with a study of the general cor- tical pathways that are associated with, and/or affect, cardio- vascular function. Primarily using anesthetized rat models, a series of studies over the past four decades have summated to a general knowledge of the cortical autonomic network in that species (Benarroch 1993; Cechetto and Saper 1990), emphasizing the hypothalamus, prefrontal cortex, insula cor- tex, amygdala, and hippocampus. The 1990s brought major breakthroughs in studying cerebral structures involved in cardiovascular control in conscious humans. The first was the development of blood oxygen level-dependent (BOLD) Fig. 5  Original Fig. 1 from (Krogh and Lindhard 1913) illustrating the early rise in heart rate (pulse per minute) and ventilation during neuroimaging using magnetic resonance imaging (Ogawa the transition from rest to moderate intensity cycling exercise. Arrow, et al. 1992). The second was surgical implantation of ste- the tracings flow from right to left in time. Time in 1/10 min; + , reo-electroencephalographic depth electrodes that could “ready”; X, “begin”; ≠ , “stop”. Ventilation scale (right ordinate) is be used to stimulate discreet brain regions (Oppenheimer litres/min. Reproduced with permission from the Journal of Physiol- ogy et al. 1992). These techniques exposed the functional corti- cal anatomy that drives cardiovascular outcomes, and b) the cortical activation patterns that correlate with cardiovascular has proven to be a significant challenge with several barri- outcomes such as heart rate during exercise. ers. First, a conscious animal preparation is required that can Nowak et al. (1999, 2005) investigated cortical outcomes perform volitional work, with corresponding cortical activ- when paraplegic subjects attempted a foot lift and reported ity unimpaired by anesthesia. Second, centrally mediated activation in the cerebellum and insular cortex, with the effects must be separated from rapid reflexive effects. Third, insula being activated under conditions involving isolated methods are required that expose functional outcomes in the feed forward control. Williamson et al. (2001) used hypno- cerebrum with sufficient spatial resolution to study specific sis to change the perception of effort during a constant load candidate brain regions as well as temporal resolution to cycling exercise. Contrasting the baseline exercise with the catch neural patterns as they occur, particularly if examining condition of perceived heavier workload (i.e. effort sense) regulation of the rapid changes in heart rate at the exercise they reported corresponding changes in perceived effort and onset. Finally, peripheral metrics of autonomic function are cortical activation levels in the anterior cingulate cortex, required to fully interpret central neural influences. insular cortex and thalamic regions. Notably, no differences Functional evidence exposes volitional effort as an impor- were found in areas related to motor performance indicating tant component of the central command. Using a conscious that the observed brain activation patterns were not related feline model Matuskawa’s group illustrated greater cardiac to a change in work performed. Williamson et al. (2002) and blood pressure responses to active changes in posture also utilized hypnosis to compare patterns of cortical activa- compared to a passive lifting of the animal into the same tion between actual and imagined handgrip exercise. They position (Ishii et al. 2023). In humans, measures of mus- reported activation of the insular and anterior cingulate cor- cle sympathetic nerve activity (MSNA- discussed in detail tex and these regions appeared to be involved in cardiovas- below in Concept 3) and the electrocardiogram indicate that cular modulation independent of any muscle afferent feed- heart rate responses to brief handgrip contractions are rapid back. While different sites are reported in different models, and express a dose response relationship with workload common patterns emerged from these early studies pointing whereas sympathetic responses are delayed during submaxi- to the insula cortex and cingulate cortex. mal static exercise (Seals and Victor 1991). Otherwise, a Recent developments in surgically implanted electroen- strong muscular contraction (i.e., > 70% of maximal effort) cephalography electrodes to explore sites related to refrac- is needed to generate an immediate sympathetic burst (Gan- tory epileptic seizures have opened new avenues to study the devia and Hobbs 1990; Mitchell and Victor 1996). Phar- cortical sites associated with cardiovascular control in con- macological blockade studies indicated that the rapid heart scious humans. While rare, studies are emerging to explore rate response at the onset of exercise is due to alterations in the impact of regions in the cortical autonomic network and Content courtesy of Springer Nature, terms of use apply. Rights reserved.  European Journal of Applied Physiology their impact on autonomic function. For example, direct from motor or inhibitory versus excitatory neural patterns. electrical stimulation models in both rodents and humans One example of complicating factors that might interfere point to an important role for the insula cortex in cardiac with detection of discreet cortical neural functional patterns function (Butcher and Cechetto 1995a, b; Cechetto et al. using muscle contractions is the sensory input to the brain 1989; Oppenheimer and Cechetto 1990; Oppenheimer et al. from the muscle that will report the extent of muscle ten- 1991). However, caution is encouraged in interpreting the sion through muscle spindle afferents, or metabolic stress insula as a homogenous region of the brain in its function. through muscle chemo/metaboreceptors. We have stud- For example, using electrical stimulation of over 100 sites in ied the potential impact of muscle spinal somatosensory the IC of patients with epilepsy Chouchou (2019) reported afferents in patterns of brain activation in contrast to those that elevated activity (via electrical stimulation) of the ante- achieved during involuntary and voluntary muscle activation rior and median insula regions primarily caused bradycardia (Goswami et al. 2011). These studies indicated that whereas with posterior insula stimulation primarily causing tachy- volitional muscle activation produced reduced activation in cardia. In contrast, functional imaging results during voli- the medial prefrontal cortex and increased anterior insula tional handgrip exercise that elevates HR indicate a role for activation (among other patterns), transcutaneous electrical anterior insula activation in exercise tachycardia (Shoemaker stimulation of somatosensory afferents led to the opposite et al. 2015b). Also, in a case study, direct stimulation of the patterns (decreased anterior insula activation and elevated right inferior posterior insula was associated with brady- medial prefrontal cortex activity). Therefore, in models of cardia at baseline and an impaired heart rate response to conscious volitional work, such sensory inputs could rapidly handgrip exercise (Al-Otaibi et al. 2010) whereas stimula- modulate cortical pathways associated with cardiovascular tion of the superior posterior insula had no effect. Reconcil- adjustments to motor activity, potentially mitigating oppor- ing the conflicting data of similar anterior insula activation tunities to observe regions related to central command inde- patterns but disparate HR responses outlined above remains pendent of sensory inputs. Studies incorporating disruptions difficult. The answer(s) may lie in the complex attributes of of sensory inputs during exercise are not reported to our the insula such as its many subdivisions (Macey et al. 2012), knowledge. its highly viscerotopic organization for sensory inputs from The statement made by Jon Williamson (2015) outlines muscle, gut, and vagus nerve (i.e., cardiac inputs) (Cechetto the current state of our knowledge regarding central deter- 1987; Cechetto and Saper 1990), and its role in processing minants of autonomic cardiovascular control in exercise: viscerosensory inputs with motor/behavioural outcomes. “Several studies have attempted to address these issues and Additionally, the integrated contributions of IC may vary provide more definitive neuroanatomical information. How- when engaged during volitional mechanisms that engage an ever, none have clearly answered the question, “where is entire network versus local stimulation of a single site within central command?”. Difficulties in peering into the brain of the network. a conscious human, complexities of neural networks, and While electrical recordings from the brains of animals redundant pathways under feedback regulation continue to preceded functional neuroimaging models, the non-invasive represent fundamental challenges to studying cortical auto- allowances of the latter approach have enabled tremendous nomic function. Important reviews of the current state of advances in the field. This approach repeatedly points to a knowledge regarding Central Command include (William- group of regions that associate predictably in cardiovascular son 2015; Padley et al. 2007). regulation (Shoemaker et al. 2012; Cechetto and Shoemaker 2009; Ruiz Vargas et al. 2016; Vargas et al. 2016; Beiss- Concept 3: neurovascular transduction ner et al. 2013; Thayer et al. 2012; Henderson et al. 2012; Critchley et al. 2000) (Shoemaker 2022). These regions Sympathetic nerve activity to skeletal muscle include the medial prefrontal cortex, the insula cortex, amygdala, hippocampus, dorsal anterior cingulate cortex, In the 1920s and 1930s, Adrian was studying the general posterior cingulate cortex, dorsolateral frontal cortex and discharge properties of nerves and produced a foundational hippocampus. It is noted that some regions are exposed dur- document in 1932 (Adrian et al. 1932) providing the first ing autonomic challenges such as breath holds or exercise recordings postganglionic sympathetic nerves in mammals. whereas others are apparent under baseline conditions with A critical element of this discovery lies in the provision of a regional activation oscillations that correlate with cardio- method that gains direct access to centrally mediated sympa- vagal function (Thayer et al. 2012) or efferent sympathetic thetic neural information. These recordings highlighted the nerve activity directed to skeletal muscle (Henderson et al. fundamental properties of postganglionic sympathetic nerve 2012). activity that include a neurogram with poor signal-to-noise Nonetheless, when used during volitional activity mod- and a characteristic rhythmic neuronal activity that normally els, functional neuroimaging is not able to separate sensory is entrained to the cardiac cycle, respiratory patterns and to Content courtesy of Springer Nature, terms of use apply. Rights reserved. European Journal of Applied Physiology blood pressure oscillations. Further study of neural rhythms pumping action of contracting muscle to shift blood back to can reveal how the sympathetic nervous system is wired with the heart. Thereafter, MSNA levels increase markedly with other complex networks. For example, searches for the cause the onset of fatigue signalling the influence of both muscle of the respiratory rhythms exposed different types of C1 and reflexes as well as a role for central “effort” as illustrated by non-C1 populations of pre-sympathetic neurons in the ros- the post-exercise circulatory occlusion approach mentioned tral ventrolateral medulla that, through impacts of neurons above. from pre-Botzinger neurons that drive respiratory patterns, One of the rhythms found in efferent muscle sympa- affect rhythmic features of efferent post-ganglionic activity thetic nerve activity reflects synchronization of efferent (Moraes et al. 2013; Menuet et al. 2020). axonal activity in bursts that are entrained to the cardiac cycle through baroreflex neural pathways. The bursts vary Microneurographic measures of postganglionic sympa- in their frequency and size. These patterns are observed thetic nerve activity in conscious humans Direct measures under resting conditions and during stress such as incre- of sympathetic nerve activity directed to skeletal muscle mental exercise where both burst frequency and burst size vasculature (MSNA) were first made in humans by Hag- increase. The bursty pattern appears to be critical to the end barth and Vallbo (1968). A detailed review of the develop- organ response (Ninomiya et al. 1993; Kluess et al. 2006), ment of the microneurographic technique has been provided providing a greater vascular outcome than constant sympa- recently (Vallbo 2018). This work represented a major leap thetic outflow. Furthermore, when measured during baseline forward in autonomic neuroscience by enabling access to, conditions, larger bursts elicit a larger reduction in vascular and routine measures of, the efferent sympathetic neural sig- conductance (Fairfax et al. 2013b) that is sensitive to alpha nal in superficial nerves of conscious humans with signals adrenergic receptor blockade (Fairfax et al. 2013a) indicat- that faithfully represent preganglionic discharge patterns ing the role of norepinephrine released from these neurons. (see (Shoemaker et al. 2018) for review). In addition to con- Therefore, sympathetic nerve rhythms not only reflect wiring scious state measures, this breakthrough opened the door for of the reflex and central networks, but also a unique physi- measures of sympathetic nerve activity while participants ological relevance to the end organ response. experienced or performed varying stress-inducing tasks In addition to physiologically relevant rhythms, the including exercise (Delius et al. 1972; Sundlof and Wallin MSNA bursts exhibit other unique features. For example, 1978; Vallbo et al. 1979; Wallin et al. 2003), enabling tre- Wallin et al. (1994) first reported the timing of sympathetic mendous growth in our knowledge of efferent sympathetic bursts relative to the baroreflex-mediated termination of a nerve activity in basic studies of reflex cardiovascular con- burst. Specifically, under conditions of physical rest, larger trol, as well as clinical studies into the impact of primary bursts seem to travel faster along the brainstem-to-fibular and secondary dysregulation of the sympathetic nervous nerve or radial nerve recording sites, causing them to pro- system on human disability. pose the ideas that either a subpopulation of fast-conducting Previous reviews highlight the changes in MSNA in (i.e., larger diameter) axons exist that are not always active, response to small muscle-mass isometric contractions or the presence of unique and modifiable synaptic delays (Seals and Victor 1991) and dynamic exercise (Katay- affected burst timing. Concurrently with Wallin’s provoca- ama and Saito 2019). In brief, the pattern and magnitude tive report (Wallin et al. 1994), additional groundwork of MSNA responses to exercise depend on factors such as for this hypothesis was provided by Macefield and Wallin mode, intensity and duration of the exercise. In either iso- (1994) who adapted the microneurography technique with metric or dynamic models, the MSNA response appears to higher impedance electrodes to emphasize the activity of be coupled with the progression of muscle fatigue; how- single sympathetic efferent axons that discharged primar- ever, some variations occur. In moderate intensity isometric ily with a probability of 1 Hz (once/burst) but with vari- models, there is little change in MSNA at the exercise onset able latencies. To see if subpopulations of latent neurons (Seals and Victor 1991) lasting about 30 s for a moderate existed, being recruitable either spontaneously or during intensity contraction. It can be surmised that the subsequent reflexive stimulation (Marshall et al. 1961), and following increase in MSNA that occurs with the sustained contraction from the preliminary work performed by Diedrich et al. is linked to muscle metabolic reflex inputs because the sym- (2003), a wavelet-based detection method was developed pathetic activation continues during a post-exercise period to isolate and study all axons in the multi-unit sympathetic of limb ischemia that traps metabolites produced during neurogram as measured with lower impedance electrodes exercise (see Fig. 4). In dynamic contractions, particularly that provided a wider recording field (Salmanpour et al. those involving larger muscle mass, a transient inhibition 2010). The series of studies that emerged exposed variously of MSNA can be observed at the exercise onset (Katayama sized axons (Tompkins et al. 2013) with varying firing prob- and Saito 2019): this inhibition appears to be related to car- abilities whereby medium sized axons provided the high- diopulmonary baroreceptor inhibition of MSNA due to the est probability of firing and are under the greatest control Content courtesy of Springer Nature, terms of use apply. Rights reserved.  European Journal of Applied Physiology by the baroreflex (Klassen et al. 2020; Klassen and Shoe- 2013b). These observations suggest that the variable and maker 2021). Under baseline conditions, the disappearance hierarchical recruitment patterns enable a fine-tuning of of MSNA action potentials following ganglionic blockade total efferent sympathetic outflow as well as vasoactive progresses from largest to smallest (Klassen et al. 2018). control. These variations in sympathetic recruitment and Some larger axonal action potentials not present at baseline firing probabilities may affect variations in neurotrans- become evident only during severe chemoreflex (Steinback mitter release from sympathetic nerves. These patterns et al. 2010) or exercise (Badrov et al. 2016a) stress. These also provide a possible mechanism to support the co- features are interesting in that they expose a hierarchical transmission of different vasoactive neurotransmitters, as recruitment strategy within the sympathetic nervous system, reported by Geoffry Burnstock (1985). This topic has been as well as a neural system that appears to use probability reviewed previously (Shoemaker et al. 2015a). coding, population coding and temporal coding strategies to convey information to the end organ. Catecholamines Focusing primarily on baseline conditions The sympathetic discharge patterns mentioned above, in animal or in situ preparations, a major linkage between particularly those of recruitment of latent subpopulations recordings of sympathetic nerves by Adrian (1932) and during severe stress, create at least two follow-up ques- vasoconstriction was provided by Cannon who first defined tions: (1) what central mechanisms determine these pat- circulating catecholamines in 1933 (Cannon 1933) as neuro- terns, and (2) what is(are) the functional purpose of these transmitters. Concurrently, the concept of vascular cellular recruitment patterns? Since measures of postganglionic responses to catecholamines was introduced by John New- sympathetic nerve activity provide direct access to signals port Langley (1907, 1908) who was studying the idea of a arising from the brainstem where integration of top-down cellular receptor that binds chemicals (or drugs) to affect cortical influence and visceral reflex sensory information cell function. It is understood now that noradrenaline has a occurs, the discussion of Central Command outlined above neural source whereas epinephrine primarily is produced in likely provides some insight into cortical sites that might the adrenal glands in response to noradrenergic activation, have some impact on these features. Several recent observa- although spill-over measures indicate some epinephrine may tions provide support for this idea. Correlations were found have a neural source too (Esler et al. 1991). The measures between cortical thickness in regions of the cortical auto- of organ-specific norepinephrine release in the 1980s (Esler nomic network and sympathetic nerve activity as well as et al. 1988), the influence of sympathetic discharge pattern heart rate variability indices of cardiovagal function (Wood on vascular constriction (Fairfax et al. 2013a), release of et al. 2017). Further, neuroimaging studies highlight correla- purines (Burnstock 1999), adrenergic and peptide-based tions between brain regions within the cortical autonomic sympathetic neurotransmitters (Pernow et al. 1989), and the network and fibular nerve recordings of baseline sympathetic concept of sympathetic co-transmitters from the same axon nerve activity (Fatouleh et al. 2014; Henderson et al. 2012). (Pablo Huidobro-Toro and Verónica Donoso 2004; Burn- Importantly, recruitment of latent sympathetic axonal sub- stock 1995) have begun to fill the gaps in understanding the populations occurs during fatiguing exercise but not during complexity of transduction of sympathetic nerve activity post-exercise circulatory occlusion (Badrov et al. 2016a) into a constrictor response in the vascular end organ. indicate that central mechanisms underly latent axonal As introduced above, a potentially critical aspect regu- recruitment in this context. Also, arousal during sleep elic- lating neurotransmitter release is the neural discharge pat- its K-complexes in electroencephalographic scalp recordings terns. For example, Kluess et al. (2006) reported that P2X that correlate to the size and latency of bursts in muscle sym- receptors and α1-receptors in the femoral artery are sensi- pathetic nerve activity (Xie et al. 1999). These observations tive to frequency and patterns of electrical stimulation of support the hypothesis that the cerebral cortex influences the sympathetic nerves and are decreased in continuous efferent sympathetic discharge patterning. versus “bursty” patterns of stimulation. Furthermore, by Why do variations in sympathetic recruitment and assessing patterns of intracellular calcium transients, Wier action potential firing probabilities exist? Currently, this et al. (2009) demonstrated variations in the mechanisms, question has not been addressed experimentally. We do timing and magnitude of constrictor effects elicited by know that the size of each integrated sympathetic burst P2X, alpha adrenergic and Y1 receptor activation. How- depends on the size and number of action potentials that ever, how patterns of recruitment in efferent sympathetic are synchronized in that cardiac cycle (Salmanpour et al. post-ganglionic axonal subpopulations associated with 2011; Steinback et al. 2010), that during stress (includ- exercise affect release of purines, norepinephrine and/ ing exercise (Badrov et al. 2016a)) larger action poten- or neuropeptide Y, and how these patterns are regulated tials become apparent indicative of recruitment of latent either directly or indirectly by supramedullary brain sites subpopulations, and that larger bursts elicit a larger vaso- or neural pathway modulators between the brain and vas- constrictor outcome (Fairfax et al. 2013a; Fairfax et al. cular end organ, remain unknown. Content courtesy of Springer Nature, terms of use apply. Rights reserved. European Journal of Applied Physiology Concept 4: Tonic sympathetic vasoconstriction blood pressure whereby constraint of that dilatory response, in active skeletal muscle coupled with a high cardiac output, achieves the blood pres- sure necessary to perfuse the active muscle. Exercise blood pressure regulation depends on the sym- A role for sympathetic vasoconstriction also exists under pathetic nervous system’s ability to titrate the relationship baseline conditions. Experiments performed by Claude Ber- between systemic vascular conductance on one hand, and, nard (1813–1878 AD) and Brown-Seguard (1817–1894 AD) on the other, the heart’s ability to support that conductance on the impact of severed nerves on blood flow provided the through the volume of cardiac output. Total blood flow first evidence of active neurogenic control over cardiovas- capacity of contracting skeletal muscle is very high, being cular function under baseline conditions (as cited in Cooper linearly related to the workload. Specifically, Andersen 2008 and Bing et al. 1982). Similar conclusions were made and Saltin (1985) estimated that leg blood flow during max- much later, illustrating the direct vascular impact of sympa- imal effort cycling exercise could reach 250 ml/min/100 thetic adrenergic receptor blockade (O'Leary et al. 1997a), gm of tissue. During whole body exercise this magnitude sympathetic nerve release of norepinephrine (Shoemaker of blood flow would outstrip available cardiac output rais- et al. 1999), and anesthetic blockade of sympathetic nerve ing the question of why hypotension does not occur during fibres (Joyner et al. 1992). This concept of tonic sympa- heavy exercise performed by healthy intact individuals. Of thetic vasoconstriction at rest and during exercise is now note, the high leg blood flow observed by Saltin’s group part of our fundamental knowledge regarding cardiovascular during single-legged dynamic exercise was diminished when control. the exercise was performed by two legs (Magnusson et al. 1984) indicating a constraint on total flow capacity that was affected by the mass of muscle activated. Integrative analysis Summary of these features provided by Niels Secher et al. (Mortensen et al. 2005) illustrated in elite athletes an increase in systemic Landmark studies in the 1903–1932 period along three dis- vascular conductance with exercise until cardiac output was parate lines of inquiry opened investigations that have con- maximal at which time the work rate-induced rise in sys- tributed significantly to the current understanding of how temic vascular conductance was stopped and even reversed, the autonomic nervous system modifies the cardiovascular observations that are supported by more recent reports in system during exercise. These papers include Krogh and humans (Volianitis and Secher 1985; Travers et al. 2022) Lindhard’s (1913) suggestion of a central cerebral cortex and previously in dogs (O'Leary et al. 1997b). Moreover, neural mechanism that coordinates cardiovascular control systemic blockade of sympathetic outflow in dogs resulted with motor function, a concept we now call central com- in syncope as the treadmill work rate increased (Sheriff et al. mand. While our knowledge regarding central contributions 1993). Additionally, activation of the carotid baroreflex to to autonomic function remain incomplete, studies using dif- reduce sympathetic outflow during exercise (Vatner et al. ferent models suggest that neural linkages from cortical and 1970; Collins et al. 2001) revealed substantial vasoconstric- midbrain regions, including the insula cortex, prefrontal tion in active skeletal muscle. Finally, studies of inadequate cortex, hippocampus and mesencephalic locomotor regions sympathetic vasomotor control can provide further insight of the midbrain, converge on baroreceptor sensory inputs into the critical role sympathetic nerve activity in exercise to the nucleus tractus solitarius to affect a resetting of the tolerance. Key studies in this regard were published in the baroreflex set point, allowing both blood pressure and heart early 1960s such as Marshall et al. (1961) who measured rate to increase during exercise. Sensory inputs from mus- a 30–50 mmHg decrease in arterial blood pressure in six cle also impact these autonomic cortical sites to augment individuals diagnosed with idiopathic hypotension during sympathetic drive and reduce vagal outflow, in the case of exercise regardless of whether this exercise was performed the Type III and IV muscle afferents. A summary of these in the supine or upright postures and, thereby, regardless integrated neural effects is presented in Fig. 6. of variations in orthostatic venous pooling. This group The ability to measure directly efferent sympathetic nerve suggested the exercise-induced hypotension, as measured activity in mammals was introduced in 1932 by Adrian and in these patients, was due to the failure of compensatory his group (Adrian et al. 1932). Following the development of constriction of the vascular beds and not of cardiac output. microneurographic techniques that can be used in humans, Therefore, effective sympathetic vasomotor control repre- the nature of the efferent sympathetic nerve activity has been sents a critical element of the integrated responses to exer- explored in detail resulting in an understanding of action cise that regulate blood pressure and blood flow. The major potential emissions that are synchronized by the baroreflex hypothesis here (Rowell 1993; Rowell et al. 1996) is that to produce bursts of activity that increase in size and fre- dilated muscle during maximal exercise represents a key quency during exercise. While heart rate responses occur target organ for the sympathetic nervous system to regulate at the exercise onset, MSNA responses are delayed being Content courtesy of Springer Nature, terms of use apply. Rights reserved.  European Journal of Applied Physiology defined circulating catecholamines in 1933 (Cannon 1933) as neurotransmitters. The presence of co-transmitters ATP, NE and NPY is now recognized and their independent roles and mechanisms of action are being elucidated, although their effects in human models require additional study. When combined, these landmark studies established the foundation upon which we have begun to understand how the autonomic nervous system interacts with the cardiovas- cular system to enable physiological adaptation to the stress of physical exercise. Acknowledgements This work was supported by the Natural Sci- ences and Engineering Research Council of Canada (Grant # RGPIN-2018–06255). Author contribution statement KS conceived the article. RG and KS wrote and edited the document. Declarations Conflict of interest The authors disclose no financial or non-financial interests that are directly or indirectly related to the work submitted for publication. Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, Fig. 6  Schematic representing probably pathways that integrate provide a link to the Creative Commons licence, and indicate if changes central command, baroreflex resetting, muscle activation and auto- were made. The images or other third party material in this article are nomic adjustments to exercise. Top-down signals related to volitional included in the article’s Creative Commons licence, unless indicated effort or action planning (involving Insula, medial prefrontal cortex otherwise in a credit line to the material. If material is not included in (MPFC) and/or mesencephalic locomotor region (MLR)) activate the article’s Creative Commons licence and your intended use is not pathways in the nucleus tractus solitarius (NTS) to affect sympa- permitted by statutory regulation or exceeds the permitted use, you will thetic nerve activity (SNA) and cardio-vagal control. This pathway need to obtain permission directly from the copyright holder. To view a is affected by sensory inputs from baroreceptors and skeletal mus- copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. cle afferents to affect sympathetic nerve activity (SNA) and vagal outflow. NTS, nucleus tractus solitarius; CVLM caudal ventrolateral medulla; RVLM, rostral ventrolateral medulla; NA, nucleus ambigu- ous; DMN, dorsal motor nucleus) References Adrian ED, Bronk DW, Phillips G (1932) Discharges in mammalian modulated by cardiopulmonary baroreceptor loading during sympathetic nerves. 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