Abstract
End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans (9♀, 35±4 years) we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29±6 (rest) to 49±6 (BH) and 47±6 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices (3.74, 3.64), dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei (3.02, 3.34). Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure.
Highlights
Obstructive and central apneas elicit entrained cyclical surges in efferent sympathetic vasoconstrictor discharge [1,2,3]
Individual and mean muscle sympathetic nerve activity (MSNA) burst incidence responses to the Mueller manoeuvres (MM) and BH are displayed in Figures 2A and B, respectively
Perspective and Conclusion This study establishes the functional organization of the cortical brain network associated in awake healthy individuals with the sympathoexcitatory responses elicited by Mueller manoeuvres and breath holds
Summary
Obstructive and central apneas elicit entrained cyclical surges in efferent sympathetic vasoconstrictor discharge [1,2,3]. Individuals with these two forms of sleep apnea exhibit increased central sympathetic outflow to skeletal muscle even during wakefulness [4,5]. The key regulatory nuclei involved with the generation of sympathetic outflow are located within the brainstem, experimental evidence indicates that higher cortical regions participate in its regulation [10,11,12,13,14]. In humans the central neural sources of sympathetic excitation in conditions such as sleep apnea have yet to be elucidated. Before we can determine whether aberrant central neural regulation occurs in pathological conditions characterized by exaggerated sympathetic outflow we must first determine the brain sites involved with its generation and regulation in healthy individuals.
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