Identifying neurocircuitry controlling cardiovascular function in humans: implications for exercise control

This thesis is concerned with the neurocircuitry that underpins the cardiovascular response to exercise, which has thus far remained incompletely understood. Small animal studies have provided clues, but with the advent of functional neurosurgery, it has now been made possible to translate these findings to humans. Chapter One reviews the background to the studies in this thesis. Our current understanding of the cardiovascular response to exercise is considered, followed by a discussion on the anatomy and function of various brain nuclei. In particular, the rationale for targeting the periaqueductal grey (PAG) and the subthalamic nucleus (STN) is reviewed. Chapter Two reviews the use of deep brain stimulation (DBS), in which deep brain stimulating electrodes are implanted into various brain nuclei in humans, in order to treat chronic pain and movement disorders. This technique not only permits direct electrical stimulation of the human brain, but also gives the opportunity to record the neural activity from different brain regions during a variety of cardiovascular experiments. This chapter also gives a detailed methodological description of the experimental techniques performed in the studies in this thesis. Chapter Three identifies the cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery. It shows for the first time in humans that the exercise pressor reflex is associated with significantly increased neural activity in the dorsal PAG. The other sites investigated, which had previously been identified as cardiovascular active in both animals and humans, seem not to have a role in the integration of this reflex. Chapter Four investigates whether changes in exercise intensity affect the neurocircuitry involved in the exercise pressor reflex. It demonstrates that the neural activity in the PAG is graded to increases in exercise intensity and corresponding increases in arterial blood pressure. This chapter also provides evidence to suggest that neural activity in the STN corresponds to the cardiovascular changes evoked by the remote ischaemic preconditioning stimulus in humans. Chapter Five identifies the cardiovascular neurocircuitry involved during changes in central command during isometric exercise at constant muscle tension using muscle vibration. It shows that, in humans, central command is associated with significantly decreased neural activity in the STN. Furthermore, the STN is graded to the perception of the exercise task, i.e. the degree of central command. The other sites investigated appear not to have as significant a role in the integration of central command during the light exercise task that was undertaken. Chapter Six studies the changes in muscle sympathetic nerve activity (MSNA) during stimulation of various brain nuclei in humans. Regrettably, the results presented in this chapter are not convincing enough to support the hypothesis that stimulation of particular subcortical structures corresponds to changes in MSNA. However, the cardiovascular changes that were recorded during stimulation of the different subcortical structures are congruous with previous studies in both animals and humans. Chapter Seven presents a brief summary of the findings in this thesis.</p

Mapping the central neurocircuitry that integrates the cardiovascular response to exercise in humans.

There are abundant animal data attempting to identify the neural circuitry involved in cardiovascular control. Translating this research into humans has been made possible using functional neurosurgery during which deep brain stimulating electrodes are implanted into various brain nuclei for the treatment of chronic pain and movement disorders. This not only allows stimulation of the human brain, but also presents the opportunity to record neural activity from various brain regions. This symposium review highlights key experiments from the past decade that have endeavoured to identify the neurocircuitry responsible for integrating the cardiovascular response to exercise in humans. Two areas of particular interest are highlighted: the periaqueductal grey and the subthalamic nucleus. Our studies have shown that the periaqueductal grey (particularly the dorsal column) is a key part of the neurocircuitry involved in mediating autonomic changes adapted to ongoing behaviours. Emerging evidence also suggests that the subthalamic nucleus is not only involved in the control of movement, but also in the mediation of cardiovascular responses. Although these sites are unlikely to be the 'command' areas themselves, we have demonstrated that the two nuclei have the properties of being key integrating sites between the feedback signals from exercising muscle and the feedforward signals from higher cortical centres

Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans

Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting

Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans

Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting

Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans

Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting. © 2014 American Heart Association, Inc

Identifying cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery.

Groups III and IV afferents carry sensory information regarding the muscle exercise pressor reflex, although the central integrating circuits of the reflex in humans are still poorly defined. Emerging evidence reports that the periaqueductal gray (PAG) could be a major site for integrating the "central command" component that initiates the cardiovascular response to exercise, since this area is activated during exercise and direct stimulation of the dorsal PAG causes an increase in arterial blood pressure (ABP) in humans. Here we recorded local field potentials (LFPs) from various "deep" brain nuclei during exercise tasks designed to elicit the muscle pressor reflex. The patients studied had undergone neurosurgery for the treatment of movement or pain disorders, thus had electrodes implanted stereotactically either in the PAG, subthalamic nucleus, globus pallidus interna, thalamus, hypothalamus, or anterior cingulate cortex. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Our PAG patients showed significant increases in LFP power at frequencies from 4 to 8 Hz (P < 0.01), 8 to 12 Hz (P < 0.001), and 12 to 25 Hz (P < 0.001). These periods were associated with maintained elevated ABP during muscle occlusion following exercise. Further increases in exercise intensity resulted in corresponding increases in PAG activity and ABP. No significant changes were seen in the activity of other nuclei during occlusion. These electrophysiological data provide direct evidence for a role of the PAG in the integrating neurocircuitry of the exercise pressor reflex in humans