Effects of 12 Months Continuous Positive Airway Pressure on Sympathetic Activity Related Brainstem Function and Structure in Obstructive Sleep Apnea

Luke A Henderson, Rania H Fatouleh, Linda C Lundblad, David K McKenzie, Vaughan G Macefield, Luke A Henderson, Rania H Fatouleh, Linda C Lundblad, David K McKenzie, Vaughan G Macefield

Abstract

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.

Keywords: dorsolateral pons; hypertension; medullary raphe; rostral ventrolateral medulla; sleep disordered breathing.

Figures

Figure 1
Figure 1
Upper panel shows a typical microneurographic recording in an individual subject during concurrent functional magnetic resonance imaging (fMRI). Brainstem images were collected during a 4 s at which time muscle sympathetic nerve activity (MSNA) activity was not distinguishable. However, due to the fMRI haemodynamic delay (~5 s) and the delay for MSNA traffic to travel from the brain to the recording electrode (~1 s), brain activity during the MSNA collection period was reflected in signal intensity changes during the subsequent 4 s period. The vertical gray shading represents a 1 s period of MSNA recording and the associated 1 s period of fMRI image collection. During each 1 s epoch of the collection period (4 s), if a MSNA burst occurred, a “1” was entered into an fMRI search model (lower left panel). This was repeated for each of the 200 fMRI volumes to create a 200 point fMRI model. The MSNA burst in the above recording is entered into the fMRI search model (vertical gray bar). The MSNA burst that occurred during the 2nd second of the collection period arose during collection of fMRI images through the rostral medulla and pons. This brainstem region is represented by the gray horizontal shading on a sagittal section of an individual's fMRI images set (lower right panel). RMS: root mean square. This figure is modified from our previous publication (Fatouleh et al., 2015).
Figure 2
Figure 2
Multiunit recording of muscle sympathetic nerve activity (MSNA) from a 50-year-old male patient with obstructive sleep apnea (OSA) acquired during functional magnetic resonance imaging sessions prior to, following 6 months and following 12 months of continuous positive airway pressure (CPAP) treatment. Each recording shows four consecutive sets of the 4s-ON and 4s-OFF scanning sequences; the black areas represent the scanning artifacts. MSNA burst amplitudes were measured during the OFF periods. The mean-voltage neurogram is shown in the nerve RMS (root mean square) trace; this was used to quantify the number of sympathetic bursts. Note the high number of MSNA bursts (identified by *) pre-CPAP which is reduced following 6 and 12 months of CPAP treatment.
Figure 3
Figure 3
Plots of muscle sympathetic nerve activity (MSNA) during the laboratory session and the brainstem functional magnetic resonance imaging (fMRI) session in controls and in individuals with obstructive sleep apnea (OSA) prior to and following 6 and 12 months of continuous positive airway pressure (CPAP) treatment. Individual values of bursts/min for the laboratory session and total MSNA bursts during the fMRI session are represented by the open circles. Note that CPAP results in a reduction in resting MSNA toward control levels.
Figure 4
Figure 4
Brainstem regions in which fMRI signal intensity changes correlated to muscle sympathetic nerve activity (MSNA) were significantly altered by continuous positive airway pressure (CPAP) treatment over 12 months in subjects with obstructive sleep apnea (OSA). Hot color scale indicates brainstem regions in which signal intensity (SI) changes were significantly altered by CPAP treatment. Significant clusters are overlaid onto a T1-weighted anatomical template image. Slice location in Montreal Neurological Institute space are indicated at the upper right of each image. The lower panel shows plots of mean (±SEM) percentage changes in signal intensity during each MSNA burst compared to periods of no MSNA bursts for each significant cluster in controls and OSA subjects prior to and following 6 and 12 months of CPAP treatment. Significant difference were determined using two-sample and paired t-tests (*p < 0.05). dlPons, dorsolateral pons; RVLM, rostral ventrolateral medulla. Note that for most brainstem regions, CPAP treatment restores brainstem function to control levels.
Figure 5
Figure 5
Brainstem regions in which gray matter (GM) concentrations were significantly altered by continuous positive airway pressure (CPAP) treatment over 12 months in subjects with obstructive sleep apnea (OSA). Hot color scale indicates brainstem regions in which gray matter concentration changes were significantly altered by CPAP treatment. Significant clusters are overlaid onto a T1-weighted anatomical template image. Slice location in Montreal Neurological Institute space are indicated at the upper right of each image. The lower panel shows plots of mean (±SEM) gray matter concentrations for each significant cluster in controls and OSA subjects prior to and following 6 and 12 months of CPAP treatment. Significant difference were determined using two-sample and paired t-tests (*p < 0.05). dlPons, dorsolateral pons; RVLM, rostral ventrolateral medulla. Note that for most brainstem regions, CPAP treatment restores brainstem anatomy to control levels.

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