Background: Isometric handgrip (IHG) exercise increases heart rate (HR) and mean arterial pressure (MAP); MAP can be sustained after exercise via post-exercise ischemia (PEI). HR and MAP responses are mediated by feed-forward cortical signals (central command, CC) and neural feedback from active muscles (exercise pressor reflex, EPR). Purpose: Differentiate between cortical regions involved with CC versus the EPR via changes in alpha (8-12Hz) and beta (13-30Hz) power using magnetoencephalography (MEG). Methods: Participants (n=11, 22 ± 2 years) completed a repeated IHG and PEI protocol at 5% (control) and 40% maximum force. Results: HR and MAP increased (p<0.04) early during IHG (CC only), while MAP increased further (p=0.03) as IHG continued (CC & EPR). The MAP response persisted during PEI (EPR, p=0.07). During IHG, alpha and beta power decreased within the contralateral sensorimotor cortex. Power increased within MEG sensors associated with the ipsilateral (IHG-alpha) and contralateral (IHG-beta and PEI-beta) insular cortex.

Master of Science / Department of Kinesiology / Steven W. Copp / Mechanical signals within contracting skeletal muscles contribute to the generation of the exercise pressor reflex; an important autonomic and cardiovascular control mechanism. In decerebrate rats, GsMTx4, a mechanically–activated channel inhibitor that is partially selective for piezo channels, was found recently to reduce the pressor response during static hindlimb muscle stretch; a maneuver used to investigate the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). However, the effect was found only during the very initial phase of the stretch when muscle length was changing which may have reflected the inhibition of rapidly-deactivating piezo 2 channels and the fact that different mechanically-activated channels with slower deactivation kinetics evoked the pressor response during the static phase of the maneuver. We tested the hypothesis that in decerebrate, unanesthetized rats, GsMTx4 would reduce the pressor response throughout the duration of a 30 second, 1 Hz dynamic hindlimb muscle stretch protocol. We found that the injection of 10 µg of GsMTx4 into the arterial supply of a hindlimb reduced the peak pressor response (control: 15±4, GsMTx4: 5±2 mmHg, p<0.05, n=8) and the pressor response at multiple time points throughout the duration of the stretch. GsMTx4, however, had no effect on the pressor response to the hindlimb arterial injection of lactic acid. Moreover, the injection of GsMTx4 into the jugular vein (a systemic control, n=5) or the injection of saline into the hindlimb arterial supply (a vehicle control, n=4) had no effect on the pressor response during dynamic stretch. We conclude that GsMTx4 reduced the pressor response throughout the duration of a 1 Hz dynamic stretch protocol which may have reflected the inhibition of piezo 2 channels throughout the dynamic stretch maneuver.

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.