Functional imaging of the brainstem and cortical sites of blood pressure control in subjects with obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a common sleep disorder associated with repeated bouts of nocturnal hypoxaemia during collapse of the upper airways during sleep. The hypoxaemia leads to a physiologically appropriate increase in total peripheral resistance, brought about by an increase in sympathetically-mediated vasoconstriction in the muscle vascular bed. The increase in muscle sympathetic nerve activity (MSNA) persists in the awake state, leading to neurogenic hypertension and an elevated cardiovascular morbidity and mortality. However, the mechanisms underlying the elevated MSNA in OSA are poorly understood. This thesis composes a series of studies I conducted in healthy subjects and OSA patients, before and after treatment with continuous positive airway pressure (CPAP), to improve our understanding of the disturbances in autonomic control that manifests in OSA. In Studies I-IV, I recorded MSNA in healthy controls and in OSA subjects before and after treatment with CPAP. I confirmed that MSNA was significantly elevated in newly diagnosed OSA patients compared to control subjects and that there was a significant fall in MSNA after 6 months of CPAP, with no further change after 12 months. In Study I, I tested the hypothesis that respiratory-sympathetic coupling, postulated to be the underlying cause of neurogenic hypertension, is increased in OSA. In 21 OSA patients and 21 control subjects, cross-correlation analysis revealed no significant difference in the magnitude of respiratory modulation of MSNA between the OSA patients and controls, but the temporal coupling of MSNA to respiration was tighter in OSA, with more activity occurring in post-inspiration and less in inspiration and expiration. This was largely reversed following long-term treatment with CPAP. In Study II-IV, I concurrently recorded MSNA and fMRI to identify regions within the brain that are functionally coupled to the generation of the elevated. I also measured regional grey matter volume using voxel-based morphometry. In Study II, in 17 OSA patients, the elevated MSNA drive was associated with significant changes in Blood Oxygen Level Dependent signal intensity within dorsolateral and medial prefrontal cortices (dlPFC, mPFC), dorsal precuneus, anterior cingulate (ACC) and retrosplenial cortices, caudate nucleus, as well as the right hippocampus/parahippocampus, compared to 17 healthy controls. Surprisingly, none of the regions displayed significant anatomical changes. In addition, in Study III, elevated MSNA in OSA was correlated to altered changes in signal intensity in the dorsolateral pons, rostral ventrolateral medulla (RVLM), medullary raphe and midbrain in comparison to the healthy controls. Except for the midbrain, those regions had significantly increased grey matter volumes in OSA compared with controls. Furthermore, OSA was also associated with grey matter volume increases in the region of the hypoglossal nucleus. Finally, in Study IV, I aimed to assess the changes to brain activity following 6 months of CPAP treatment in 13 OSA patients before and after 6 months of treatment with CPAP and in 15 healthy control subjects. The reduction in resting MSNA after 6 months of CPAP described earlier was coupled with significant changes in signal intensity in precuneus bilaterally, as well as in the insula, retrosplenial cortex bilaterally, right mPFC, right ACC, and right parahippocampus. In addition, CPAP treatment had no significant effect on grey matter volume in any of those brain regions. These data suggest that the elevated muscle vasoconstrictor drive that occurs in individuals with OSA may be driven by activity changes in these suprabulbar sites through influences on brainstem regulatory nuclei

Cardiorespiratory coupling of sympathetic outflow in humans : a comparison of respiratory and cardiac modulation of sympathetic nerve activity to skin and muscle

It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross-correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold-induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions, and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n=20) and MSNA (n=18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomials to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5±3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6±3.2%). Both were comparable to the respiratory modulation of MSNA (47.7±4.2%), while cardiac modulation of MSNA was significantly higher (89.8±1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors

Respiratory modulation of muscle sympathetic nerve activity is not increased in essential hypertension or chronic obstructive pulmonary disease

We examined cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA) in 13 patients with essential hypertension (HT) and 15 with chronic obstructive pulmonary disease (COPD), and compared these with a group of young healthy controls (YHC) and older healthy controls (OHC). There were no significant differences in age of the OHC and HT subjects. MSNA was recorded via a tungsten microelectrode inserted percutaneously into the common peroneal nerve. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Cardiac and respiratory modulation of MSNA was quantified by fitting polynomials to the cross-correlation histograms constructed between the sympathetic spikes and ECG or respiration. Cardiac modulation was high across all groups, but was significantly lower in COPD (75.9 ± 4.4%) than in the HT (92.4 ± 3.0%), OHC (93.7 ± 1.3%) or YHC (89.1 ± 1.6%) groups. Across all groups, respiratory modulation was significantly lower than cardiac modulation. Respiratory modulation in HT (45.2 ± 5.7%) and COPD (37.5 ± 6.3%) was not higher than in the OHC (47.2 ± 5.4%) or YHC (49.5 ± 6.0%) groups. We have shown that respiratory modulation of MSNA is present in all groups, is consistently lower than the magnitude of cardiac modulation, and is not increased in HT or COPD, arguing against an amplified respiratory-sympathetic coupling in hypertension. Moreover, given that patients with COPD are chronically asphyxic, these data indicate that an increased chemical drive does not increase respiratory modulation of MSNA

Respiratory modulation of muscle sympathetic nerve activity in obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is associated with elevated muscle sympathetic nerve activity (MSNA) during normoxic daytime wakefulness, leading to hypertension. We tested the hypothesis that respiratory-sympathetic coupling, postulated to be the underlying cause of neurogenic hypertension, is increased in OSA. Muscle sympathetic nerve activity, blood pressure, ECG and respiration were recorded in 21 normotensive control subjects and 21 newly diagnosed patients with OSA before and after 6 and 12 months of treatment with continuous positive airway pressure. Muscle sympathetic nerve activity was recorded via tungsten microelectrodes inserted percutaneously into the peroneal nerve. Cardiac and respiratory modulation of MSNA was quantified from the cross-correlation histograms constructed between the sympathetic spikes and either ECG or respiration. Muscle sympathetic nerve activity was significantly elevated in newly diagnosed OSA patients compared with control subjects (53 +- 2 versus 28 +- bursts min-1). There was a significant fall in MSNA after 6 months of continuous positive airway pressure (37 +- 2 bursts min-1), with no further change after 12 months (37 +- 2 bursts min-1). There were no significant differences in the magnitude of respiratory modulation of MSNA between the OSA patients and control subjects (40 +- 3.1 versus 39 +- 3.4%). However, when considering the normalized temporal profile there were changes in the respiratory patterning of MSNA in OSA, with more activity occurring in postinspiration and less in inspiration and expiration. This was largely reversed following long-term continuous positive airway pressure

Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects : a longitudinal investigation

Obstructive sleep apnea (OSA) is associated with significantly elevated muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. Although little is known about the mechanisms responsible for the sympathoexcitation, we have recently shown that the elevated MSNA in OSA is associated with altered neural processing in various brain stem sites, including the dorsolateral pons, rostral ventrolateral medulla, medullary raphe, and midbrain. Given the risk associated with elevated MSNA, we aimed to determine if treatment of OSA with continuous positive airway pressure (CPAP) would reduce the elevated MSNA and reverse the brain stem functional changes associated with the elevated MSNA. We performed concurrent recordings of MSNA and blood oxygen level-dependent (BOLD) signal intensity of the brain stem, using high-resolution functional magnetic resonance imaging, in 15 controls and 13 subjects with OSA, before and after 6 mo CPAP treatment. As expected, 6 mo of CPAP treatment significantly reduced MSNA in subjects with OSA, from 54 ± 4 to 23 ± 3 bursts/min and from 77 ± 7 to 36 ± 3 bursts/100 heart beats. Importantly, we found that MSNA-coupled changes in BOLD signal intensity within the dorsolateral pons, medullary raphe, and rostral ventrolateral medulla returned to control levels. That is, CPAP treatment completely reversed brain stem functional changes associated with elevated MSNA in untreated OSA subjects. These data highlight the effectiveness of CPAP treatment in reducing one of the most significant health issues associated with OSA, that is, elevated MSNA and its associated elevated morbidity

Effects of 12 months continuous positive airway pressure on sympathetic activity related brainstem function and structure in obstructive sleep apnea

Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnoea (OSA) during normoxic daytime wakefulness. Increased MSNA is a precursor to hypertension and elevated cardiovascular morbidity and mortality. However, the mechanisms underlying the high MSNA in OSA are not well understood. In this study we used concurrent microneurography and magnetic resonance imaging to explore MSNA related brainstem activity changes and anatomical changes in 15 control and 15 OSA subjects before and after 6 and 12 months of continuous positive airway pressure (CPAP) treatment. We found that following 6 and 12 months of CPAP treatment, resting MSNA levels were significantly reduced in individuals with OSA. Furthermore, this MSNA reduction was associated with restoration of MSNA-related brainstem activity and structural changes in the medullary raphe, rostral ventrolateral medulla, dorsolateral pons and ventral midbrain. This restoration occurred after 6 months of CPAP treatment and was maintained following 12 months CPAP. These findings show that continual CPAP treatment is an effective long term treatment for elevated MNSA likely due to its effects on restoring brainstem structure and function

The metaboreflex does not contribute to the increase in muscle sympathetic nerve activity to contracting muscle during static exercise in humans

Both central command and metaboreflex inputs from contracting muscles increase muscle sympathetic nerve activity (MSNA) to non‐contracting muscle during sustained isometric exercise. We recently showed that MSNA to contracting muscle also increases in an intensity‐dependent manner, although whether this can be sustained by the metaboreflex is unknown. MSNA was recorded from the left common peroneal nerve and individual spikes of MSNA extracted from the nerve signal. Eleven subjects performed a series of 4 min dorsiflexions of the left ankle at 10% of maximum voluntary contraction under three conditions: without ischaemia, with 6 min of post‐exercise ischaemia, and with ischaemia during and after exercise; these were repeated in the right leg. Compared with pre‐contraction values, MSNA to the contracting muscles increased and plateaued in the first minute of contraction (50 ± 18 vs. 34 ± 10 spikes min−1, P = 0.01), returned to pre‐contraction levels within 1 min of the contraction ending and was not influenced by ischaemia during or after contraction. Conversely, MSNA to the non‐contracting muscles was not different from pre‐contraction levels in the first minute of contraction (34 ± 9 vs. 32 ± 5 spikes min−1, P = 0.48), whereas it increased each minute and was significantly greater by the second minute (44 ± 8 spikes min−1, P = 0.01). Ischaemia augmented the MSNA response to contraction (63 ± 25 spikes min−1 after 4 min, P < 0.05) and post‐exercise ischaemia (63 ± 27 spikes min−1 after 6 min, P < 0.01) for the non‐contracting muscles only. These findings support our conclusion that the metaboreflex is not expressed in the contracting muscle during sustained static exercise