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Experimental Physiology 91.1 pp 51-58
DOI: 10.1113/expphysiol.2005.032037
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New insights into central cardiovascular control during exercise in humans: a central command update

J. W Williamson1, P. J Fadel2 and J. H Mitchell3

1 Department of Kinesiology, Health Promotion & Recreation University of North Texas, Denton, TX, USA 2 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA 3 Department of Internal Medicine, The Harry S. Moss Heart Center, University of Texas South-western Medical Center, Dallas, TX, USA


   Abstract
Top
 Abstract
Introduction
 References
 
The autonomic adjustments to exercise are mediated by central signals from the higher brain (central command) and by a peripheral reflex arising from working skeletal muscle (exercise pressor reflex), with further modulation provided by the arterial baroreflex. Although it is clear that central command, the exercise pressor reflex and the arterial baroreflex are all requisite for eliciting appropriate cardiovascular adjustments to exercise, this review will be limited primarily to discussion of central command. Central modulation of the cardiovascular system via descending signals from higher brain centres has been well recognized for over a century, yet the specific regions of the human brain involved in this exercise-related response have remained speculative. Brain mapping studies during exercise as well as non-exercise conditions have provided information towards establishing the cerebral cortical structures in the human brain specifically involved in cardiovascular control. The purpose of this review is to provide an update of current concepts on central command in humans, with a particular emphasis on the regions of the brain identified to alter autonomic outflow and result in cardiovascular adjustments.

(Received 19 August 2005; accepted after revision 5 October 2005; first published online 20 October 2005)
Corresponding author J. W. Williamson: Univeristy of North Texas, College of Education, PO Box 311337, Denton, TX 76203-1337, USA. Email: jwilliamson{at}coe.unt.edu


   Introduction
Top
 Abstract
 Introduction
References
 
Neural control of the circulation during exercise is a complex phenomenon involving many sites within the central nervous system from sacral portions of the spinal cord to higher regions of the cerebral cortex. The concept of descending signals from higher brain centres capable of influencing cardiovascular responses during exercise (Johansson, 1895; Zuntz & Geppert, 1886), originally termed ‘cortical irradiation’ (Krogh & Lindhard, 1913) and later termed ‘central command’ (Goodwin et al. 1972), has been well studied and is widely accepted throughout the scientific community. Most would concur that the magnitude of central command during exercise can be largely dictated by an individual's perception of effort during actual or even attempted physical exertion, independent of the actual workload or force production (Mitchell, 1990). While increases in an individual's rating of perceived exertion or effort sense during exercise are coupled with elevated cardiovascular responses, the specific region(s) within the higher brain responsible for generating the neural signals resulting in autonomic adjustments has remained elusive. It is postulated that these signals can affect neural activity within the thalamus, hypothalamus and mesencephalon prior to reaching medullary regions of cardiovascular integration. Animal investigations have employed stimulation of both diencephalic and mescenphalic regions to represent the descending central command signals and have provided valuable information as to the role of central command in cardiovascular regulation (Waldrop et al. 1996). What remains of interest are the specific cerebral cortical regions of the human brain activated by central command during exercise. By mapping the human brain during exercise, it is possible to gain further insight as to the specific regions involved in central command or, more specifically, the neural networks that are altered by changes in perception of effort and result in cardiovascular adjustments.

Defining and re-defining central command

Before one can begin to discuss the functional importance of central command and the location of the brain regions participating in a central command response, one must first consider how the term central command is being used. The concept of central command during exercise has been classically defined as ‘a feedforward mechanism involving parallel activation of motor and cardiovascular centres’. The primary focus of central command-related investigations has been the modulation of motor effort and the resulting alterations in cardiovascular responses. We would contend that the cerebral cortical regions involved in a ‘central cardiovascular command’ do not always require the parallel activation of ‘central motor command’ systems to exert their influence. This contention is based on findings that indicate that the magnitude of a central command-mediated cardiovascular response during exercise can be independent of force production (e.g. imagined exercise) and dictated more by an individual's perception of effort (see Fig. 1; Nowak et al. 1999, 2005; Williamson et al. 1999, 2001, 2002). Thus, central command implies an ‘effort-induced modulation of autonomic function’. Nevertheless, the classically used terminology in reference to a parallel activation of both cardiovascular and motor regions during exercise remains accurate, since the activation of motor and cardiovascular centres in the higher brain is requisite for physical activity. However, an important finding from recent research is that a network of structures exist that are involved in a centrally mediated cardiovascular activation, which do not require a parallel motor activation to exert their influence (Nowak et al. 1999, 2005; Williamson et al. 1999, 2001; 2002,). Therefore, central command during exercise may actually involve the simultaneous activation of two separate networks, one for central motor control and one for central cardiovascular control. While these two networks may interact as components of central command during exercise, they can function independently of one another. In this regard, we will focus our discussion specifically on those brain regions believed to be involved in central cardiovascular regulation.



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  		Figure 1.  Heart rate, mean blood pressure and perceived exertion responses during actual and imagined handgrip exercise
Subjects with high hypnotizability exhibited significant increases in heart rate, mean blood pressure and perceived exertion during imagined handgrip (right-hand side) compared to subjects with low hypnotizability. Importantly, muscle electromyographic recordings demonstrated that no measurable increases in force were produced during imagined handgrip. The data are presented as means ± S.D. and significant differences between groups are shown as *P < 0.05. (Reproduced with permission from Williamson et al. 2002.)

 
A second issue involving the classic definition of central command is the term ‘feedforward’ mechanism. Feedforward typically implies a control system operating without continuous negative feedback. This feedforward characterization may be largely based on the immediate cardiovascular response to the onset (or even anticipation) of exercise, such that there would not be sufficient time for feedback from the periphery (i.e. working skeletal muscle afferent signals) to reach the cardiovascular centres in the brainstem (Johansson, 1895; Zuntz & Geppert, 1886). However, there is evidence that the effects of central command on cardiovascular responses are closely related to the intensity or perceived effort of the exercise (Asmussen et al. 1965; Gandevia et al. 1993; Leonard et al. 1985), even at the onset of exercise (Smith et al. 1997). Studies employing partial and complete neuromuscular blockade have reported greater cardiovascular responses resulting from a greater level of central command as indexed by an individual's perceived effort (Asmussen et al. 1965; Leonard et al. 1985; Gallagher et al. 2001; Gandevia et al. 1993). From these findings, a strong case could be made that an individual's perception or sense of effort can serve as a means of ‘feedback’ to establish the magnitude of the central command response. Although feedback from the working muscles during exercise may certainly modulate the central command response, the aforementioned studies show that muscle afferent feedback is not a requisite component of the central command response. A key point for consideration in human studies is that an increase in motor unit recruitment or force production, resulting in an increased afferent feedback, is typically coupled with increased ratings of perceived exertion or effort. More importantly, changes in perception of effort, even without alterations in muscle afferent input during constant exercise, can modify cardiovascular responses (Williamson et al. 2001, 2002). Thus, it is the sense of effort that appears to be driving the central command response. Therefore, we propose that ‘central command’ can function as a feedback system, responding to an individual's sense of effort, to elicit proportional changes in cardiovascular responses, which does not necessarily require a parallel motor activation to exert its influence.

Importance of central command in cardiovascular control during exercise

The cardiovascular and haemodynamic adjustments to exercise are primarily mediated by alterations in parasympathetic and sympathetic neural activity (Mitchell, 1990). These exercise-induced changes in autonomic neural outflow, which are designed to meet the metabolic demands of the exercising muscle, are mediated via multiple neural mechanisms working in concert. It is well accepted that central command (Waldrop et al. 1996), the exercise pressor reflex (McCloskey & Mitchell, 1972; Mitchell et al. 1983; Kaufman & Forster, 1996) and the arterial baroreflex (Raven et al. 1997; Fadel et al. 2004) are all involved in mediating the characteristic cardiovascular and haemodynamic adjustments to exercise (Fig. 2). The importance of central command in initiating the autonomic adjustments to exercise is further emphasized by the key role central command plays in the resetting of the arterial baroreflex during exercise (Gallagher et al. 2001; Querry et al. 2001; Ogoh et al. 2002; Raven et al. 2002). By using an innovative tendon vibration protocol (Goodwin et al. 1972) to alter central command input, Ogoh et al. (2002) recently demonstrated that the resetting of the carotid baroreflex stimulus–response curve during exercise could be reduced to lower pressures or increased to higher pressures by selectively decreasing or augmenting central command activation, respectively. These findings confirm and extend previous studies in both animals (McIlveen et al. 2001) and humans (Gallagher et al. 2001; Querry et al. 2001) demonstrating that central command is actively involved in baroreflex resetting during exercise.



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  		Figure 2.  A schematic illustration of the mechanisms of neural cardiovascular control during exercise
Neural signals originating from the brain (central command), the aorta and carotid arteries (arterial baroreceptor reflex) and skeletal muscle (exercise pressor reflex) are known to modulate sympathetic and parasympathetic nerve activity during exercise. The alterations in autonomic outflow mediate changes in heart rate and contractility, as well as the diameter of resistance and capacitance vessels within various tissue beds (e.g. splanchnic region). As a result, changes in heart rate (HR), stroke volume (SV) and systemic vascular resistance (SVR) mediate alterations in mean arterial pressure (MAP) appropriate for the intensity and modality of the exercise.

 
Aside from its critical role in the actual resetting of the baroreflex stimulus–response curve, central command input appears also to be responsible for the relocation of the operating point (prestimulus blood pressure) away from the centring point (point at which there is an equal depressor and pressor response to a given change in blood pressure) and closer to the threshold of the cardiac baroreflex stimulus–response curve (see Fig. 3; Potts et al. 1993; Gallagher et al. 2001; Ogoh et al. 2002). This effect of central command on the operating point appears to be mediated via vagal withdrawal associated with increases in exercise intensity (Ogoh et al. 2005). It has been shown to occur in order to allow the arterial baroreflex to adapt to and potentially modify the increases in blood pressure induced by activation of the exercise pressor reflex (Sheriff et al. 1990; Potts & Mitchell, 1998). Thus, the relocation of the operating point by central command may be very important in preventing excessive increases in blood pressure during exercise, since it places the baroreflex in a more optimal position to counter hypertensive stimuli.



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  		Figure 3.  A schematic illustration of a baroreflex stimulus–response curve and the resetting that occurs during exercise, with a particular emphasis on the movement of the operating point away from the centring point and closer to the threshold of the curve
The centring point is the point at which there is an equal depressor and pressor response to a given change in blood pressure, the operating point is the prestimulus blood pressure, threshold is the point where no further increases in heart rate are elicited by further reductions in blood pressure, and saturation is the point where no further decreases in heart rate are elicited by further increases in blood pressure. This relocation of the operating point away from the centring point and closer to the threshold of the stimulus–response curve with increasing exercise intensity positions the baroreflex in a more optimal position to counter hypertensive stimuli.

 
Functional anatomy

Based on our ‘proposed’ definition of central command, a network of higher brain structures (or a single structure) capable of interpreting an individual's sense of effort and making appropriate autonomic adjustments should be considered within any anatomical framework. Primary regions of the cerebral cortex with the capacity for modulation of autonomic function have been carefully reviewed, and it was concluded that both the insular cortex and the infralimbic cortex, more specifically the medial prefrontal cortex, were well suited for this role (Cechetto & Saper, 1990; Verberne & Owens, 1998). Efferent pathways from the insular cortex to well-recognized sites of cardiovascular control, including the lateral hypothalamus, rostral ventrolateral medulla and nucleus of the solitary tract, have also been well documented (see Fig. 4; Yasui et al. 1991). Changes in heart rate and blood pressure have been reported in response to activation of the insular cortex in both rats (Ruggiero et al. 1987) and humans (Oppenheimer et al. 1992). Saper (1982) noted a convergence of autonomic and limbic connections within the rat insula (Fig. 4). There also exist reciprocal connections between the insular cortex and the infralimbic cortex (medial prefontal region), suggesting a potential for interaction between these regions. The medial prefrontal cortex has multiple limbic sensory inputs and appears to have a significant role in ‘stress-related modulation’ of sympathetic outflow (Verberne & Owens, 1998). Taken together, the insular cortex and medial prefrontal cortex may function in concert or independently to interpret sensory input and elicit appropriate autonomic adjustments. It would seem plausible to predict that these same brain regions that alter cardiovascular responses during non-exercise conditions could also be activated during exercise conditions. Therefore, given the importance of the insular and medial prefrontal regions in overall cortical modulation of autonomic function, human studies have focused on assessing their possible roles in central neural regulation of autonomic function during exercise.



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  		Figure 4.  A schematic diagram of a horizontal cross-section through the rat brain, illustrating both the afferent inputs (left) and efferent outputs (right) to and from the insular cortex
(Adapted from Cechetto & Saper, 1990.)

 
Neuroimaging studies

Studies investigating the functional anatomy of central command-induced changes in regional cerebral blood flow (rCBF) have identified a network of structures activated in the human brain. These regions include the insular cortex (King et al. 1999; Nowak et al. 1999, 2005; Williamson et al. 1999, 2001, 2002; Critchley et al. 2000) and anterior cingulate cortex or the medial prefrontal region (King et al. 1999; Critchley et al. 2000; Thornton et al. 2001; Williamson et al. 2001, 2002) as well as thalamic regions (King et al. 1999; Thornton et al. 2001; Williamson et al. 2001, 2002). These structures appear to be activated in response to an increased perception of effort during exercise when heart rate and blood pressure are elevated.

Focusing first on the insular cortex, it is possible that the observed rCBF changes within the insular cortex during exercise were related to the blood pressure increases (Zhang & Oppenheimer, 1997) or the activation of skeletal muscle afferents (Ichiyama et al. 2004). Although the activation of muscle afferents can lead to rCBF changes within specific regions of the insular cortex, insular activation has been reported during attempted movement in spinal cord-injured subjects when afferent feedback was absent (Nowak et al. 2005). In addition, imagined exercise has also been shown to cause insular activation, but only when the imagined effort elicited cardiovascular responses (Williamson et al. 2002). Therefore, it is likely that there are different regions within the insular cortex that are responsive to skeletal muscle afferent input and to central command during exercise. In this regard, numerous afferent and efferent connections to and from the insular cortex have been identified in the rat brain (Fig. 4). Of note are the primary projections from the insular cortex to the hypothalamus, which may identify an important linkage between the human studies focusing on activation of the insular cortex and the animal studies using electrical stimulation of hypothalamic or mesencephalic locomotor regions to evoke ‘central command’-induced cardiovascular responses.

In an attempt to localize regions of the insular cortex responding to central command that are independent of skeletal muscle afferent input or blood pressure elevations, a recent study compared rCBF changes during volitional static handgrip alone (central command/muscle metaboreflex) and postexercise circulatory occlusion alone (no central command/muscle metaboreflex; Williamson et al. 2003). Blood pressures between the two protocols were closely matched. The primary finding was that there were distinct regions of the insular cortex and anterior cingulate cortex activated during static handgrip exercise by central command that were independent of muscle metaboreflex activation or blood pressure elevations (see Fig. 5). More specifically, the right inferior posterior and left inferior anterior insular regions were activated to a greater extent during exercise, but not during postexercise circulatory occlusion with elevated blood pressure. Findings of the left inferior anterior activation are consistent with previous work demonstrating a significant correlation between left inferior anterior activation and heart rate during exercise (Williamson et al. 1999). Careful examination of data provided by King et al. (1999) during a brief bout of handgrip exercise identifies that the right posterior insular region was activated during the handgrip, but not immediately postexercise. Critchley et al. (2000) also reported activation of the right posterior insular region during handgrip, as well as in response to mental stress. Insular activation during mental stress supports the concept of similar cortical regions modulating cardiovascular responses for both exercise and non-exercise conditions. It should be noted that activation of the right inferior posterior insular region was also reported to covary with blood pressure changes (Williamson et al. 1999; Critchley et al. 2000).



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  		Figure 5.  Differences in brain activation from rest for static handgrip (SHG) (left) and postexercise circulatory occlusion (PECO; middle) matched for the same mean blood pressure elevation
Coregistered single-photon-emission computed tomography (SPECT) and magnetic resonance imaging (MRI) data representing a transaxial slice from one subject. The coronal and sagittal MRI panels (right) show lines of orientation for the tranasxial slice. The top and bottom of the transaxial panels correspond to an anterior and posterior orientation, respectively. Changes in regional cerebral blood flow (rCBF) distribution from SPECT data were mapped on the MRI by using an arbitrary colour scale with a positive range from 5 to 25% (from green through yellow to red) and a negative range from –5 to –25% (from purple through dark blue to light blue). The white lines denote the specific regions of interest assessed in this brain slice and encompass the right and left insular cortexes for inferior anterior (ICia) and inferior posterior (ICip) regions, right and left inferior thalamic regions (THi), and anterior cingulate cortex (AC). The image shows that during SHG there were significant increases in activation for both anterior cingulate and insular regions that were not present during PECO. However, there is significant activation in the thalamus and right inferior anterior insula during PECO, similar to that observed during handgrip. (Reproduced with permission from Williamson et al. 2003.)

 
With regard to a specific role of the anterior cingulate cortex as related to central command, it is largely involved in the discrimination of peripheral somatosensory input. Thus, it could serve to interpret an individual's level of central command (or effort sense). This region, defined as the anterior cingulate cortex by both Critchley et al. (2000) and Williamson et al. (2003), is included within the region termed the medial prefrontal cortex by King et al. (1999). These investigators reported that activation of this medial prefrontal region during handgrip exercise was associated with cardiovascular activation. Reviews by Cechetto & Saper (1990) and Verberne & Owens (1998) have defined a significant role for the medial prefontal cortex in cardiovascular regulation, and this area appears to have a role in central command during exercise (Williamson et al. 2001, 2002, 2003). This suggests that the anterior cingulate cortex may work in conjunction with portions of the insular cortex as a ‘central command network’, functioning to interpret an individual's sense of effort and then eliciting appropriate autonomic adjustments to affect cardiovascular responses.

Regions of the thalamus appear to be involved in the pathway from higher brain regions to midbrain areas. As noted previously, animal investigations often elicit central command signals via stimulation of mesencephalon and posterior hypothalamic regions (Waldrop et al. 1996). Findings of thalamic activation coupled with that of higher brain centres provides some indirect evidence towards establishing a central command pathway to brainstem structures. From human studies, activation of the right and left inferior thalamic regions has been reported during both handgrip exercise and postexercise circulatory occlusion (Williamson et al. 2003). The inferior (or ventral) region of the thalamus activated was analogous to the ventroposterior region previously demonstrated to have reciprocal connections with the insular cortex (Saper, 1982; Cechetto & Saper, 1990), which may be further related to baroreceptor activation (Cechetto & Saper, 1990). Blood pressure changes have been show to elicit activation in the thalamus (Cechetto & Saper, 1990; Zhang & Oppenheimer, 2000). Zhang & Oppenheimer (1997) determined that a significant portion of baroreceptor-related neurones from the ventrobasal thalamus were reciprocally connected with the posterior insula in the rat. Further, it has been reported that regions of the human ventrocaudal nucleus of the thalamus are involved in the integration of afferent baroreceptor information (Oppenheimer et al. 1998). When directly stimulated, these thalamic regions can elicit increases in heart rate and blood pressure in humans (Thornton et al. 2002). Thus, regions of the human thalamus appear to have a key role in the overall regulation of blood pressure via baroreflex mechanisms and probably play a role in central command-induced changes in baroreflex function.

Summary

The neural circuitry of central command appears to encompass regions of the insular cortex and anterior cingulate cortex that interact with thalamic and brainstem structures of cardiovascular integration, although there may be other cerebral cortical regions involved. While we have redefined central command to imply an ‘effort-induced modulation of autonomic function’, the classically used terminology in reference to a parallel activation of both cardiovascular and motor regions during exercise remains accurate. However, it would appear that central command can function as a feedback system, based on an individual's sense of effort or exertion, and does not require a parallel motor activation to exert its influence. Further, it is likely that the same regions of the higher brain involved in cardiovascular modulation during exercise are involved in cardiovascular modulation during non-exercise conditions.

The study of central command and its functional anatomy poses unique challenges in trying to uncouple the role of higher brain cardiovascular centres from those of the motor centres and the influences of working skeletal muscle afferents and blood pressure changes during exercise. The redundancy between central command and skeletal muscle afferent feedback mechanisms during exercise may be explained, at least in part, in that an individual's perception of effort can be largely influenced by somatomotor sensations arising from working skeletal muscle during exercise. These signals may serve as some type of feedback to help gauge the level of required effort or central command. Further, an individual's perception of effort, independent of afferent feedback, such as the perception of effort occurring during attempted exercise with paralysis, contributes importantly to the central cardiovascular command response.

The insular cortex and anterior cingulate cortex appear to be capable of responding to multiple inputs. However, comparisons regarding activation patterns between studies are complicated by potential species differences as well as anatomical and neurophysiological variations within species. Human investigation is hampered somewhat in that it is not possible to determine the specific type of neural activity (i.e. excitatory or inhibitory) based upon changes in patterns of brain activity. However, defining the regions involved in centrally mediated cardiovascular modulation is of critical importance in furthering our understanding of this concept and may have clinical implications related to various types of autonomic dysfunction (e.g. emotional syncope, white coat hypertension). Future investigations must be performed in humans to more clearly define the specific sites within these regions responsible for changes in autonomic function and how they interact to effectively modulate cardiovascular responses during exercise as well as during non-exercise conditions.


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   Acknowledgements
 
J. W. Williamson was supported by an American Heart Association Grant-in-Aid from the Texas Affiliate, Inc. no. 0050726Y (J.W.W.) and NIH R01 HL59145-04 (J.W.W.).




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