Elie Hammam

Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea

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.

Brainstem changes associated with increased muscle sympathetic drive in obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with significantly increased bursts of muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. The underlying mechanism responsible for this sympathoexcitation is unknown. The aim of this investigation was to determine brainstem sites that contribute to this increased on-going muscle vasoconstrictor drive. We measured regional grey matter volume using voxel-based morphometry of T1-weighted anatomical images in 20 subjects with OSA and 19 healthy age-matched controls. We also performed concurrent recordings of MSNA and Blood Oxygen Level Dependent (BOLD) signal intensity of the brainstem, using high-resolution functional magnetic resonance imaging, in 15 subjects with OSA and 15 controls. OSA subjects had significantly elevated MSNA, which was correlated to altered BOLD signal intensity changes in the dorsolateral pons, rostral ventrolateral medulla, medullary raphe and midbrain. The medullary raphe, rostroventrolateral medulla and dorsolateral pons also had significantly increased grey matter volumes in subjects with obstructive sleep apnoea compared with controls. Furthermore, we also found that obstructive sleep apnoea was associated with increases in grey matter volume in the region of the hypoglossal nucleus. These data suggest that the elevated muscle vasoconstrictor drive in obstructive sleep apnoea may result from functional and anatomical changes within the dorsolateral pons, rostroventrolateral medulla and medullary raphe. These brainstem regions are known to modulate sympathetic output either directly or indirectly via sympathetic preganglionic neurons within the spinal cord. In addition, the known increase in genioglossus muscle activity in OSA may reflect the increase in grey matter volume of the hypoglossal nucleus.

Vestibular modulation of muscle sympathetic nerve activity during sinusoidal linear acceleration in supine humans

The utricle and saccular components of the vestibular apparatus preferentially detect linear displacements of the head in the horizontal and vertical planes, respectively. We previously showed that sinusoidal linear acceleration in the horizontal plane of seated humans causes a pronounced modulation of muscle sympathetic nerve activity (MSNA), supporting a significant role for the utricular component of the otolithic organs in the control of blood pressure. Here we tested the hypothesis that the saccule can also play a role in blood pressure regulation by modulating lower limb MSNA. Oligounitary MSNA was recorded via tungsten microelectrodes inserted into the common peroneal nerve in 12 subjects, laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal linear accelerations-decelerations (peak acceleration ±4 mG) were applied in the rostrocaudal axis (which predominantly stimulates the saccule) and in the mediolateral axis (which also engages the utricle) at 0.08 Hz. The modulation of MSNA in the rostrocaudal axis (29.4 ± 3.4%) was similar to that in the mediolateral axis (32.0 ± 3.9%), and comparable to that obtained by stimulation of the utricle alone in seated subjects with the head vertical. We conclude that both the saccular and utricular components of the otolithic organs play a role in the control of arterial pressure during postural challenges.

Vestibular Modulation of Sympathetic Nerve Activity to Muscle and Skin in Humans

We review the existence of vestibulosympathetic reflexes in humans. While several methods to activate the human vestibular apparatus have been used, galvanic vestibular stimulation (GVS) is a means of selectively modulating vestibular afferent activity via electrodes over the mastoid processes, causing robust vestibular illusions of side-to-side movement. Sinusoidal GVS (sGVS) causes partial entrainment of sympathetic outflow to muscle and skin. Modulation of muscle sympathetic nerve activity (MSNA) from vestibular inputs competes with baroreceptor inputs, with stronger temporal coupling to the vestibular stimulus being observed at frequencies remote from the cardiac frequency; “super entrainment” was observed in some individuals. Low-frequency (<0.2 Hz) sGVS revealed two peaks of modulation per cycle, with bilateral recordings of MSNA or skin sympathetic nerve activity, providing evidence of lateralization of sympathetic outflow during vestibular stimulation. However, it should be noted that GVS influences the firing of afferents from the entire vestibular apparatus, including the semicircular canals. To identify the specific source of vestibular input responsible for the generation of vestibulosympathetic reflexes, we used low-frequency (<0.2 Hz) sinusoidal linear acceleration of seated or supine subjects to, respectively, target the utricular or saccular components of the otoliths. While others had discounted the semicircular canals, we showed that the contributions of the utricle and saccule to the vestibular modulation of MSNA are very similar. Moreover, that modulation of MSNA occurs at accelerations well below levels at which subjects are able to perceive any motion indicates that, like vestibulospinal control of posture, the vestibular system contributes to the control of blood pressure through potent reflexes in humans.

Skin Sympathetic Nerve Activity is Modulated during Slow Sinusoidal Linear Displacements in Supine Humans

Low-frequency sinusoidal linear acceleration (0.08 Hz, ±4 mG) modulates skin sympathetic nerve activity (SSNA) in seated subjects (head vertical), suggesting that activation of the utricle in the peripheral vestibular labyrinth modulates SSNA. The aim of the current study was to determine whether SSNA is also modulated by input from the saccule. Tungsten microelectrodes were inserted into the common peroneal nerve to record oligounitary SSNA in 8 subjects laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal (0.08 Hz, 100 cycles) linear acceleration-decelerations (peak ±4 mG) were applied rostrocaudally to predominately activate the saccules, or mediolaterally to predominately activate the utricles. Cross-correlation histograms were constructed between the negative-going sympathetic spikes and the positive peaks of the sinusoidal stimuli. Sinusoidal linear acceleration along the rostrocaudal axis or mediolateral axis both resulted in sinusoidal modulation of SSNA (Median, IQR 27.0, 22–33% and 24.8, 17–39%, respectively). This suggests that both otolith organs act on sympathetic outflow to skin and muscle in a similar manner during supine displacements.

Neck movement but not neck position modulates skin sympathetic nerve activity supplying the lower limbs of humans

We previously showed that dynamic, but not static, neck displacement modulates muscle sympathetic nerve activity (MSNA) to lower limbs of humans. However, it is not known whether dynamic neck displacement modulates skin sympathetic nerve activity (SSNA). Tungsten microelectrodes inserted into the common peroneal nerve were used to record SSNA in 5 female and 4 male subjects lying supine on a table that fixed their head in space but allowed trapezoidal ramp (8.1 ± 1.2°/s) and hold (17.5° for 53 s) or sinusoidal (35° peak to peak at 0.33-0.46 Hz) horizontal displacement of the body about the head. SSNA recordings were made before, during, and after trapezoidal and sinusoidal displacements of the body. Spike frequency analysis of trapezoidal displacements and cross-correlation analysis during sinusoidal displacements revealed that SSNA was not changed by trapezoid body-only displacement but was cyclically modulated during sinusoidal angular displacements (median, 95% CI: 27.9%, 19.6-48.0%). The magnitude of this modulation was not statistically ( P > 0.05) different from that of cardiac and respiratory modulation at rest (47.1%, 18.7-56.3% and 48.6%, 28.4-59.3%, respectively) or during sinusoidal displacement (10.3%, 6.2-32.1% and 26.9%, 13.6-43.3%, respectively). Respiratory frequency was entrained above its resting rate (0.26 Hz, 0.2-0.29 Hz) during sinusoidal neck displacement; there was no significant difference ( P > 0.05) between respiratory frequency (0.38 Hz, 0.25-0.49 Hz) and sinusoidal displacement frequency (0.39 Hz, 0.35-0.42 Hz). This study provides evidence that SSNA is modulated during neck movement, raising the possibility that neck mechanoreceptors may contribute to the cutaneous vasoconstriction and sweat release associated with motion sickness. NEW & NOTEWORTHY This study demonstrates that dynamic, but not static, stretching of the neck modulates skin sympathetic nerve activity in the lower limbs.

Microneurography from the posterior tibial nerve: a novel method of recording activity from the foot in freely standing humans

The posterior tibial nerve, located behind the medial malleolus of the ankle, supplies the intrinsic muscles of the foot and most of the skin of the sole. We describe a novel approach for recording from this nerve via a percutaneously inserted tungsten microelectrode and provide examples of recordings from presumed muscle spindle endings recorded in freely standing human subjects. The fact that the angular excursions of the ankle joint are small as the foot is loaded during the transition from the seated position to standing means that one can obtain stable recordings of neural traffic in unloaded, loaded, and freely standing conditions. We conclude that this novel approach will allow studies that will increase our understanding of the roles of muscle and cutaneous afferents in the foot in the control of upright posture. NEW & NOTEWORTHY We have performed the first microneurographic studies from the posterior tibial nerve at the ankle. Stability of the recording site allows one to record from muscle spindles in the intrinsic muscles of the foot as well as from cutaneous mechanoreceptors in the sole of the foot during the transition from seated to standing. This novel approach opens up new opportunities for studying the roles of muscle and cutaneous afferents in the foot in the control of upright stance.

Reversal of functional changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea following CPAP

developing a single-subject parcellation model by 1) obtaining high SNR and BOLD sensitivity with MRI at ultra-high-field (7 T), and, 2) development of a novel and sensitive parcellation algorithm that incorporates spatial priors and nonlinear manifold learning. Ten minutes of eyes-closed resting state data were gathered from 2 subjects in a Siemens MAGNETOM 7 T scanner using a multiband EPI pulse sequence (TE = 16 ms, TR = 750 ms, 1.5 mm isotropic). The time series of each voxel in the medulla and pons was correlated to the time series of each voxel in the cortex. Our new manifold learning algorithm was then used to cluster together voxels with similar patterns of functional connectivity. Two preliminary observations are available: 1) The entire cortex is functionally connected to some, but not all, regions of the brainstem. 2) Distinct clusters in the ventral and caudal ventrolateral medulla, and posterior-superior medulla, displayed connectivity to known cortical autonomic regions in themedial prefrontal cortex, insula and anterior cingulate. The parcellations were similar but not identical between subjects.