Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnoea (OSA) during daytime wakefulness, leading to hypertension, but the underlying mechanisms are poorly understood. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI) of the brain we aimed to identify the central processes responsible for the sympathoexcitation. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted percutaneously into the common peroneal nerve in 17 OSA patients and 15 healthy controls lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. Fluctuations in BOLD signal intensity covaried with the intensity of the concurrently recorded bursts of MSNA. In both groups there was a positive correlation between MSNA and signal intensity in the left and right insulae, dorsolateral prefrontal cortex (dlPFC), dorsal precuneus, sensorimotor cortex and posterior temporal cortex, and the right mid-cingulate cortex and hypothalamus. In OSA the left and right dlPFC, medial PFC (mPFC), dorsal precuneus, anterior cingulate cortex, retrosplenial cortex and caudate nucleus showed augmented signal changes compared with controls, while the right hippocampus/parahippocampus signal intensity decreased in controls but did not change in the OSA subjects. In addition, there were significant increases in grey matter volume in the left mid-insula, the right insula, left and right primary motor cortices, left premotor cortex, left hippocampus and within the brainstem and cerebellum, and significant decreases in the mPFC, occipital lobe, right posterior cingulate cortex, left cerebellar cortex and the left and right amygdala in OSA, but there was no overlap between these structural changes and the functional changes in OSA. These data suggest that the elevated muscle vasoconstrictor drive in OSA may result from functional changes within these brain regions, which are known to be directly or indirectly involved in the modulation of sympathetic outflow via the brainstem. That there was no overlap in the structural and functional changes suggests that asphyxic damage due to repeated episodes of nocturnal obstructive apnoea is not the main cause of the sympathoexcitation.

New Findings r What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is increased in obstructive sleep apnoea (OSA), leading to hypertension. Is this due to an increase in respiratory-sympathetic coupling, as has been demonstrated in the spontaneously hypertensive rat? r What is the main finding and its importance?Using direct microelectrode recordings of MSNA in hypertensive OSA patients and normotensive control subjects, we show that the magnitude of respiratory modulation is not increased in OSA, arguing against an amplified respiratory-sympathetic coupling as the underlying cause of the neurogenic hypertension, although the temporal coupling of MSNA to respiration was stronger in OSA.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 ± 2 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.

Non-technical summary High blood pressure is known to be caused by an increase in activity of the sympathetic nerves that constrict blood vessels in skeletal muscle and the gut. Experiments in the spontaneous hypertensive rat (SHR) suggest that the hypertension is brought about by an increase in coupling between respiration and sympathetic outflow. We tested whether this mechanism occurs in two models of elevated muscle sympathetic nerve activity (MSNA) in human subjects: essential hypertension (HT) and chronic obstructive pulmonary disease (COPD). Unlike the SHR model, respiratory modulation of MSNA was not increased in either HT or COPD. These results help us understand how the cardiovascular and respiratory systems interact in health and disease.Abstract 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. Abbreviations COPD, chronic obstructive pulmonary disease; HT, essential hypertension; MSNA, muscle sympathetic nerve activity; OHC, older healthy controls; OSAS, obstructive sleep apnoea syndrome; SHR, spontaneous hypertensive rat; YHC, young healthy controls.

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Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnea (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 MSNA likely due to its effects on restoring brainstem structure and function.