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

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

doi:10.1016/j.neuroimage.2014.09.031

Cited by 46 publications

(46 citation statements)

References 49 publications

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“…[11][12][13][14][15][16] This finding has been attributed to an elevation in the set point for efferent sympathetic outflow resulting from progressive carotid body hypersensitivity and altered structure and function of catecholaminergic neurons in brain stem and cortical regions involved in autonomic cardiovascular regulation. 10,[17][18][19][29][30][31][32] Johnson et al 33 have recently reviewed experimental literature demonstrating induction, by transient challenges, of long-lasting changes in synaptic function within a widely distributed network of brain regions engaged in the longterm regulation of blood pressure and the amplification of initial hemodynamic responses by subsequent rechallenge. These data indicate that short-term external stimuli can induce afferent neural and circulating hormonal changes that in turn facilitate molecular neuroplasticity in subcortical and preganglionic components of the sympathetic nervous system, resulting in an elevated prevailing set point for efferent sympathetic nerve firing and consequent norepinephrine release.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15][16] Este hallazgo se ha atribuido a una elevación del punto de regulación del flujo simpá-tico eferente, que resulta de la hipersensibilidad progresiva del cuerpo carotídeo, y de la alteración de la estructura y función de las neuronas catecolaminérgicas del tronco cerebral y las regiones corticales involucradas en la regulación cardiovascular autónoma. 10,[17][18][19][29][30][31][32] Recientemente, Johnson et al revisaron la bibliografía experimental que demostraba inducción, mediante desafíos transitorios, de cambios duraderos de la función sináptica dentro de una red ampliamente distribuida de regiones encefálicas involucradas en la regulación a largo plazo de la presión arterial y la amplificación de las respuestas hemodinámicas iniciales por re-desafío ulterior. Estos datos indican que los estímulos externos a corto plazo pueden inducir cambios neurales aferentes y hormonales circulantes que, a su vez, facilitan la neuroplasticidad molecular de componentes subcorticales y preganglionares del sistema nervioso simpático, lo que determina un punto de regulación elevado prevalente para la descarga nerviosa simpática eferente y la consiguiente liberación de noradrenalina.…”

Section: Discussionunclassified

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Arousal From Sleep and Sympathetic Excitation During Wakefulness

et al. 2016

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Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea–hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea–hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index ( r =0.53; P <0.001), minimum oxygen saturation ( r =−0.43; P =0.002), apnea–hypopnea index ( r =0.41; P =0.004), age ( r =0.36; P =0.013), and body mass index ( r =0.33; P =0.022) but not with oxygen desaturation index ( r =0.28; P =0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted R 2 (0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea–hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionunclassified

Arousal From Sleep and Sympathetic Excitation During Wakefulness

et al. 2016

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“…CBF is decreased in the right midbrain of OSA subjects (Yadav et al, 2013), which may reflect lower perfusion demand, perhaps from an altered functional state (for example, lower tonic activity), or impaired cerebral perfusion. Structural changes consistent with inflammatory or glial changes, namely diffusion decreases and volume increases, appear in the hypothalamus in OSA (Lundblad et al, 2014; Tummala et al, 2016), which projects heavily to the midbrain (Sakuma and Tada, 1984; Thompson and Swanson, 1998). The combined data suggest that the midbrain is compromised in OSA, potentially interfering with regulatory roles for cardiovascular and breathing control, as well as other physiological functions in the disorder.…”

Section: Introductionmentioning

confidence: 99%

“…Functional MRI studies show increased activation of the ventral and dorsal midbrain during inspiratory loading exercises (Macey et al, 2006, 2003) and decreased activity during cold pressor and expiratory loading challenges in OSA (Harper et al, 2003; Macey et al, 2003). Elevated muscle sympathetic nerve activity (MSNA) correlates with altered Blood Oxygen-Level-Dependent (BOLD) signals in the midbrain in OSA, suggesting a midbrain role in eliciting the high sympathetic tone in the sleep disorder (Fatouleh et al, 2014; Lundblad et al, 2014). CBF is decreased in the right midbrain of OSA subjects (Yadav et al, 2013), which may reflect lower perfusion demand, perhaps from an altered functional state (for example, lower tonic activity), or impaired cerebral perfusion.…”

Section: Introductionmentioning

confidence: 99%

Obstructive sleep apnea is associated with altered midbrain chemical concentrations

et al. 2017

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Obstructive sleep apnea (OSA) is accompanied by altered structure and function in cortical, limbic, brainstem, and cerebellar regions. The midbrain is relatively unexamined, but contains many integrative nuclei which mediate physiological functions that are disrupted in OSA. We therefore assessed the chemistry of the midbrain in OSA in this exploratory study. We used a recently developed accelerated 2D magnetic resonance spectroscopy (2D-MRS) technique, compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (4D-EP-JRESI), to measure metabolites in the midbrain of 14 OSA (mean age ± SD:54.6 ± 10.6 years; AHI:35.0 ± 19.4; SAO2 min:83 ± 7%) and 26 healthy control (50.7 ± 8.5 years) subjects. High-resolution T1-weighted scans allowed voxel localization. MRS data were processed with custom MATLAB-based software, and metabolite ratios calculated with respect to the creatine peak using a prior knowledge fitting (ProFit) algorithm. The midbrain in OSA showed decreased N-acetylaspartate (NAA; OSA:1.24 ± 0.43, Control:1.47 ± 0.41; p = 0.03; independent samples t-test), a marker of neuronal viability. Increased levels in OSA over control subjects appeared in glutamate (Glu; OSA:1.23 ± 0.57, Control:0.98 ± 0.33; p = 0.03), ascorbate (Asc; OSA:0.56 ± 0.28, Control:0.42 ± 0.20; (50.7 ± 8.5 years; p = 0.03), and myo-inositol (mI; OSA:0.96 ± 0.48, Control:0.72 ± 0.35; p = 0.03). No differences between groups appeared in γ-aminobutyric acid (GABA) or taurine. The midbrain in OSA patients shows decreased NAA, indicating neuronal injury or dysfunction. Higher Glu levels may reflect excitotoxic processes and astrocyte activation, and higher mI is also consistent with glial activation. Higher Asc levels may result from oxidative stress induced by intermittent hypoxia in OSA. Additionally, Asc and Glu are involved with glutamatergic processes, which are likely upregulated in the midbrain nuclei of OSA patients. The altered metabolite levels help explain dysfunction and structural deficits in the midbrain of OSA patients.

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“…We found that in OSA subjects, each sympathetic burst was associated with altered MSNA-coupled fMRI signal intensity in the region of the medullary raphe nucleus, rostral ventrolateral medulla and dorsolateral pons [14] (Fig. 2).…”

Section: Msna-related Functional Changes and Structural Changes In Brmentioning

confidence: 89%

Obstructive Sleep Apnoea and Hypertension: the Role of the Central Nervous System

Henderson

Macefield

2016

Curr Hypertens Rep

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Recent human brain imaging investigations and, in particular, combined microneurography recording of resting sympathetic activity with high-resolution functional magnetic resonance imaging have provided some important insights into changes in brain function and anatomy associated with resting sympathetic activity. Functional and anatomical changes occur in OSA, including in regions of the brainstem circuitry known to be responsible for setting resting sympathetic activity. Furthermore, these changes are reversed following continuous positive airway treatment in concert with reductions in resting sympathetic drive. These resent findings suggest that the central changes may contribute significantly to the hypertension associated with OSA.

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

Cited by 46 publications

References 49 publications

Arousal From Sleep and Sympathetic Excitation During Wakefulness

Arousal From Sleep and Sympathetic Excitation During Wakefulness

Obstructive sleep apnea is associated with altered midbrain chemical concentrations

Obstructive Sleep Apnoea and Hypertension: the Role of the Central Nervous System

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