Exercise, mental effort and emotional states are accompanied by reproducible changes in peripheral cardiovascular function affecting regional and systemic perfusion. The sympathetic and parasympathetic axes of the autonomic nervous system act to produce these integrated cardiovascular response patterns necessary for the metabolic support of behaviour, and are controlled directly by central autonomic nuclei within the brainstem and cerebellum. These autonomic regions receive afferent inputs from cortical and subcortical systems implicated in emotional and volitional behaviours. Peripheral autonomic responses may be an integral component of learning within cortical and subcortical systems (apparent in classical fear conditioning), and feedback of such responses may also influence emotional behaviour and decision making (Damasio et al. 1991). There is, as yet, only limited understanding of how ‘higher’ brain areas control and represent altered peripheral autonomic states in humans.
Studies in experimental animals have helped to identify components of the ‘central autonomic network’ and have enhanced our understanding of the functional relationships between cortical and subcortical centres in cardiovascular control (reviewed in Cechetto & Saper, 1990; Bennarroch, 1997). Changes in heart rate and blood pressure have been reported to result from electrical or chemical stimulation of a set of discrete brain areas, including regions implicated in (1) attention, motivation, decision making and episodic memory – anterior cingulate, ventromedial prefrontal cortex and hippocampus (Kaada, 1951; Buchanan et al. 1985; Neafsey, 1990); (2) representation of aversive emotions – amygdaloid complex (Kaada, 1951; Gelsema et al. 1989); (3) initiation and control of limb movements – motor cortex, nigrostriatal tract, neostriatum and cerebellum (Kaada, 1951; Delgado, 1960; Bradley et al. 1987, 1991; Angyan, 1994; Lin & Yang, 1994); (4) representation of internal sensory, somatic and endocrine states – insula, dorsomedial and lateral hypothalamus, and nucleus tractus solitarii (Oppenheimer & Cechetto, 1990; DiMicco et al. 1992; Allen & Cechetto, 1992; Spyer, 1999) and (5) brainstem sympathetic and parasympathetic nuclei (e.g. Willette et al. 1984). In addition, electrophysiological recordings indicate that these putative efferent autonomic centres also receive afferent information concerning peripheral autonomic states (e.g. Cechetto & Saper, 1987; reviewed in Cechetto & Saper, 1990).
There have been a limited number of similar studies in humans; stimulation of the insula (Oppenheimer et al. 1992), medial prefrontal cortex and anterior cingulate (Pool & Ransohoff, 1949), and medial temporal lobe (Fish et al. 1993) elicit changes in blood pressure and heart rate (occasionally accompanied by subjective mood changes). Lesions of discrete brain areas may also modulate autonomic responsivity. Thus, orbitofrontal damage reduces anticipatory arousal to emotive stimuli (Damasio et al. 1990), while lesions of the amygdala block autonomic responses that accompany conditioning (Bechara et al. 1995). Lesions to these areas are also associated with marked changes in social and emotional behaviour, suggesting that feedback of altered autonomic arousal (represented in cortical regions such as the orbital/ventromedial prefrontal cortex) may directly influence social behaviour and decision making (Damasio et al. 1991). There is a long history to the notion that autonomic feedback influences emotions; the James-Lange theory of emotion (James, 1894) proposed that subjective emotional experience was the by-product of perceiving visceral responses that are the essence of emotion.
Functional imaging studies have been used to investigate the central control of the cardiovascular system. In a single-photon emission tomography study, Williamson et al. (1997) reported activation of the left insula during dynamic exercise (cycling) but not passive exercise (cycling movements induced by moving pedals independently), suggesting involvement in autonomic cardiovascular regulation. Using positron emission tomography (PET), Nowak et al. (1999) showed that activation of sensory motor cortex accompanied effortful handgrip exercise, an activity pattern that was unaffected by removing afferent feedback from the arm by anaesthesia. Mental effort, a common component of many cognitive studies in functional imaging, has been associated with increased activity in anterior cingulate (Paus et al. 1998), and hyperactivity of anterior cingulate during mental stress has been reported in patients with coronary artery disease, relative to controls (Soufer et al. 1998). Using functional magnetic resonance imaging (fMRI), Harper et al. (1998) reported increased activity of orbitofrontal cortex, amygdalo-hippocampal complex, hypothalamus and cerebellum during hypertension elicited by cold pressor stimuli and performance of the Valsalva manoeuvre (breathing against a closed glottis), manipulations that undoubtedly engender altered autonomic states.
Thus, animal experiments have implicated diverse brain regions in the central control of blood pressure and heart rate. In humans, similar regions are implicated in the performance of complex cognitive, emotional or physical behaviours. Functional imaging techniques allow the in vivo measurement of changes in regional brain activity during the performance of behavioural tasks, though few studies have examined the representation and control of autonomic responses in the cardiovascular system. In the present study, we investigated the functional neuroanatomy of central cardiovascular control, using PET in volunteer subjects, to identify brain regions that respond to changes in heart rate and blood pressure common to exercise- and mental effort-induced states of autonomic arousal.
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We have demonstrated significant changes in rCBF in discrete cortical and subcortical brain regions associated with states of altered peripheral cardiovascular arousal. The findings provide functional evidence for the involvement of areas previously implicated in cognitive and emotional behaviours in the central generation or representation of peripheral cardiovascular arousal. The data are consistent with a functional organization of the central nervous system designed to produce integrated cardiovascular response patterns for the metabolic support of volitional and emotional behaviours.
Although we were able to define brain areas associated with peripheral cardiovascular arousal, the methodology we have used does not allow us to differentiate between the generation, maintenance or representation (through feedback) of different states of autonomic arousal. Additionally, due to the prolonged nature of the activation/scanning conditions, the study may fail to identify brain regions that are transiently activated during short-term changes and fluctuations in physiological responses. For example, in fear conditioning, transient activity of the amygdala is seen in early, but not late, phases of conditioning (Buchel et al. 1998). Nonetheless, there is independent evidence suggesting that both efferent and afferent autonomic responses are represented in areas such as the anterior cingulate and insula (Cechetto & Saper, 1990) – implying that it may be difficult to dissociate efferent activity from afferent representation. Despite limitations in temporal resolution of our PET technique the use of conjunction analyses, across two dissimilar tasks, provides a powerful means of identifying brain areas involved in autonomic responses. We identified commonalities in regional brain activation associated with cardiovascular states induced by exercise and mental stress, and our results consequently identify components of a central autonomic control system that are likely to be involved in both generating and representing peripheral cardiovascular arousal across a range of behavioural states.
An important finding of our study was that changes in systemic blood pressure are reflected in activity changes of right anterior cingulate. The anterior cingulate is a large cortical structure located around the rostral corpus callosum that is frequently activated during functional imaging studies involving difficult cognitive tasks (Paus et al. 1998). The human anterior cingulate is anatomically divisible into distinct sub-areas, and is implicated in both cognitive and affective processes: attentional control, motor and cognitive executive functions; willed action and response selection; declarative short-term memory; subjective emotional states, anxiety and painful experience; involuntary and autonomic changes during emotional states, and affective and social behaviour (reviewed in Devinsky et al. 1995). Our data suggest that peripheral changes in blood pressure are reflected in activity within a distinct region of right anterior cingulate, Brodmann area 32 extending caudally into area 24. This region may be important for integrating peripheral cardiovascular changes with cognitive effort, motor preparedness and emotional states. More posterior cingulate regions (Brodmann areas 23, 24 and 31) showed reduced activity with increasing heart rate and blood pressure, perhaps consistent with a proposed behavioural dissociation of anterior and posterior cingulate functions (Bussey et al. 1997).
The cerebellum is an important component in a central autonomic network (Spyer, 1999) but is underemphasized in many neurological models of autonomic control (e.g. Benarroch, 1997). A range of autonomic functions appear to involve pathways through the cerebellum, including representation of cardiovascular responses (Lisander & Martner, 1975; Bradley et al. 1987, 1991; Harper et al. 1998), postural control of blood pressure and heart rate (Nisimaru et al. 1998), conditioned cardiovascular responses (Gherlarducci et al. 1996), and modulation of autonomic components of emotional behaviour (Martner, 1975). Moreover, cerebellar pathology is a feature of multiple system atrophy in which there is central autonomic dysregulation (Smith & Mathias, 1996). In healthy individuals, the cerebellum, like the anterior cingulate, is frequently activated in functional imaging studies of sensorimotor, cognitive or emotional processes. Recently, the cerebellum has been implicated in mood and cognition – executive deficits and affective changes follow cerebellar damage – indicating the importance of pathways linking the cerebellum with prefrontal and anterior cingulate regions implicated in emotional and cognitive processes (Schmahmann & Sherman, 1998). We observed midline cerebellar activity during the performance of difficult, arousing exercise and mental stress, together with some lateral cerebellar cortical activity at a lower level of significance. Previous studies have directly implicated cerebellar vermis areas in cardiovascular control and cardiovascular responses during aversive conditioning (a model for emotional learning (Bradley et al. 1987, 1991; Ghelarducci et al. 1996). The activity we observed in lateral cerebellar cortex may indicate that changes in somatic physiology may also influence cerebellar regions subserving other functions, e.g. motor co-ordination. Together, our findings suggest peripheral states of cardiovascular arousal are represented in cerebellum, which may serve to integrate cardiovascular responses with on-going cognitive or motor behaviour. Thus, the cerebellum may act as a functional relay between cortex and brainstem through which brainstem autonomic nuclei are modulated by cortical activity related to cognitive, motor and emotional behaviours.
Our findings also confirmed the role of brainstem structures in the representation of autonomic responses. Increased activity in discrete areas within the pons was apparent in the analysis of effortful vs . effortless task performance, e.g. activity in the region of pontine reticular nuclei was associated with the performance of effortful (compared to effortless) tasks. Moreover, increases in heart rate covaried notably with midline and lateral pontine activity. However our analyses were not able to identify an association between changes in cardiovascular states and activity in the medulla, despite evidence for the important role played by structures within the medulla (e.g. nucleus of the solitary tract) in homeostatic mechanisms, such as autonomic control of the cardiovascular system (e.g. Benarroch, 1997; Spyer, 1999). Among the possible reasons that may contribute to our failure to find medulla activation in association with cardiovascular arousal is that increased cardiac- (and respiratory-) related, pulsatile motion of the brainstem leads to greater residual variance in measurable activity and consequent reduced sensitivity. Consistent with this, very few functional imaging studies have been able to detail activity within the medulla compared to activity within the pons, which is both larger and less affected by pulsatile motion. Techniques to overcome this problem are developing in some imaging modalities (e.g. cardiac gating in fMRI), but were not available for use in our study.
The role of the insula in the control and representation of autonomic states has been well established from stimulation and electrophysiological studies in animals (reviewed in Cechetto & Saper, 1990; Benarroch, 1997). The insula is anatomically and functionally connected with ‘autonomic’ centres such as the amygdala, orbital and ventromedial prefrontal cortex, and the hypothalamus. In humans, intra-operative electrical stimulation of the insula elicits changes in cardiovascular function which appear to be lateralized; tachycardia and hypertension result from stimulation of the right insula, and bradycardia and hypotension from stimulation of the left (Oppenheimer et al. 1992). However, despite the apparent association between the right insula and sympathetic arousal, functional imaging studies have not reported a consistent lateralization of insula activity elicited by emotive and aversive stimuli (e.g. Phillips et al. 1997; Buchel et al. 1998). In our study, increases in MAP and HR were associated with right insula activity, whereas low stress conditions and decreasing MAP and HR were associated with left insula activity. Thus, our findings are consistent with lateralization of cardiovascular control within the insula, as proposed by Oppenheimer et al. (1992). However, we note that there was also some right insula activation with decreasing heart rate.
One difficulty in interpreting our results is whether increases in activity associated with the performance of effortless vs. effortful tasks, or with relatively lower HR and MAP, reflect the representation of parasympathetic activity, or a deactivation of brain regions (involved in other representations) during sympathetic arousal. We take the view that areas predicted apriori to be involved in autonomic representations are likely to reflect autonomic activation. Thus, medial temporal lobe structures (amygdala, uncus, hippocampus and parahippocampal gyrus), orbitofrontal and ventromedial prefrontal cortices and some insula areas appear to preferentially represent states of low sympathetic arousal and high parasympathetic tone, manifest as decreased MAP and HR. This finding is of interest since these brain areas are reported to be activated during emotional stress, anxiety and the processing of emotive stimuli (e.g. McGuire et al. 1994; Morris et al. 1996; Buchel et al. 1998) which are typically associated with increased HR and blood pressure. However, activity within these brain areas is often context dependent, and it may be that an interaction between affective processing and systemic arousal potentiates the activity of these regions, perhaps to enable the interruption of on-going behaviours. Nevertheless, bradycardia accompanies anticipatory arousal to threatening stimuli (Roozendaal et al. 1990) and strongly emotive stimuli elicit patterns of parasympathetic activity, e.g. fear-induced bradycardia, vasovagal syncope and ‘freezing’. Our results suggest that these states of parasympathetic activity may be represented in medial temporal lobe regions.
The findings reported may have important clinical implications; central autonomic failure is a core feature of multiple-system atrophy (MSA, Shy-Drager syndrome), but may also occur in other degenerative disorders, e.g. cortical Lewy-body disease and Alzheimer-type dementia. Our study identifies a set of brain areas whose integrity is important for peripheral cardiovascular control, and which may be compromised by neurodegenerative conditions such as MSA (Mathias & Bannister, 1999). Moreover, many of these brain (e.g. limbic and paralimbic) areas are also involved in cognitive and behavioural functions that are dysfunctional in neurodegenerative conditions.
Our study also has relevance for the interpretation of brain-imaging findings across a range of experimental designs. Our data indicate that some brain areas are involved in representing states of cardiovascular arousal independently of how the arousal is engendered. Activity in regions such as right anterior cingulate (often attributed to cognitive, anticipatory or emotional processing) might occur whenever a difficult or arousing task – associated with increases in blood pressure – is contrasted with a low-level task that does not induce cardiovascular changes. Consistent with this, Paus et al. (1998) demonstrated a relationship between reported anterior cingulate PET (rCBF) activity and task difficulty. Other measures of arousal, e.g. skin conductance, have also been correlated with cingulate (and right insula) activity during the processing of emotive stimuli (Fredrikson et al. 1998), and increased anterior cingulate activity is associated with the induction of subjective mood states, which combines attentional effort with emotional processing (e.g. Lane et al. 1997). However, although right anterior cingulate activity did covary with MAP in both tasks, it is unlikely that this region acts simply as a generic cardiovascular monitor or response generator. The emphasis placed on attentional and emotional representations within the anterior cingulate (e.g. Devinsky et al. 1995), suggests that it is specialized for the integration of autonomic responses with cognitive and affective processes. However, in the anterior cingulate, and in regions such as the insula and amygdala, activity associated with processing emotive material remains difficult to disentangle from concurrent changes in peripheral cardiovascular status. Measurement of cardiovascular arousal during performance of cognitive and emotional tasks, or the use of peripherally acting drugs to diminish autonomic responses to test stimuli, may be a useful means of overcoming ambiguity in the interpretation of task-related activity in putative autonomic regions.
In summary, we have described activity, independently of whether arousal was induced by exercise or cognition, in right anterior cingulate, right insula, cerebellum and brainstem during peripheral cardiovascular arousal (and hence peripheral sympathetic autonomic activity). Activity in the amygdala, hippocampus, orbitofrontal/ventromedial prefrontal cortex, left insula and regions of cingulate, cerebellum and brainstem reflect decreased cardiovascular arousal, corresponding perhaps to parasympathetic autonomic activity. Thus, we describe a network of brain centres in which peripheral cardiovascular changes are generated and represented. It is also through these brain areas that cognitive, somatomotor and affective brain systems are integrated with the autonomic nervous system to provide the metabolic support for thought, action and emotion.