Central sympathetic nervous system reinforcement in obstructive sleep apnoea

Accepted Manuscript Central sympathetic nervous system reinforcement in obstructive sleep apnoea Magdalena Wszedybyl-Winklewska, Jacek Wolf, Arkadiusz Szarmach, Pawel J. Winklewski, Edyta Szurowska, Krzysztof Narkiewicz PII:

S1087-0792(17)30172-7

DOI:

10.1016/j.smrv.2017.08.006

Reference:

YSMRV 1059

To appear in:

Sleep Medicine Reviews

Received Date: 14 March 2016 Revised Date:

29 August 2017

Accepted Date: 31 August 2017

Please cite this article as: Wszedybyl-Winklewska M, Wolf J, Szarmach A, Winklewski PJ, Szurowska E, Narkiewicz K, Central sympathetic nervous system reinforcement in obstructive sleep apnoea, Sleep Medicine Reviews (2017), doi: 10.1016/j.smrv.2017.08.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Central sympathetic nervous system reinforcement in obstructive

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sleep apnoea

1#

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Running title: Central SNS outflow and obstructive sleep apnoea

Magdalena Wszedybyl-Winklewska , Jacek Wolf

2,3#

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1,5*

, Arkadiusz Szarmach , Pawel J. Winklewski

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, Edyta

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Szurowska , Krzysztof Narkiewicz

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The authors equally contributed to the manuscript

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Institute of Human Physiology, Medical University of Gdansk, Gdansk, Poland Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland 3 Department of Cardiovascular Diseases, International Clinical Research Center, St. Anne’s University Hospital in Brno (FNUSA), Brno, Czech Republic 4 nd 2 Department of Radiology, Medical University of Gdansk, Gdansk, Poland 5 Institute of Health Sciences, Pomeranian University of Slupsk, Slupsk, Poland

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*Corresponding author: Pawel Winklewski, M.D., Ph.D. Institute of Human Physiology, Medical University of Gdansk Tuwima Str. 15, 80-210 Gdansk, Poland E-mail: [email protected]; Tel./Fax: +48 58 3491515

Summary

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The available studies on cerebrovascular reactivity and cerebral oxygenation in obstructive sleep apnoea (OSA) patients brought conflicting results, yet the overall evidence suggests that resting state cerebral perfusion is diminished in these patients. Interestingly, in a group of healthy

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professional breath-hold divers who are exercising very long apnoeas - episodes corresponding to the ones observed in patients with OSA - demonstrated that cerebral oxygenation may remain stable at the expense of extreme sympathetic nervous system (SNS) activation.

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In the present review we address several mechanisms that could potentially explain these discrepancies. We focus in depth on mechanisms of central SNS reinforcement in OSA including

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dysfunctional baroreflex response, and inflammatory processes within the brain centres controlling the cardiovascular system. Additionally, novel insights into physiology of cerebral blood flow regulation are proposed, including the role of short-term blood pressure changes, heart rate fluctuations and baroreflex alterations. Finally, a potential role of increased blood flow

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pulsatility in cerebrospinal fluid circulation changes and its influence on SNS drive is highlighted. The presented review provides insights into how sympathetic nervous system reinforcement in OSA promotes maladaptive mechanisms that could alter cerebral perfusion

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regulation, and result in functional and structural cerebral changes.

Key words: obstructive sleep apnoea, cerebral perfusion, functional neuroanatomy, central nervous system, autonomic regulation

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Abbreviations ASL - arterial spin labelling BBB - blood brain barrier

BOLD-MRI - blood oxygen level dependent magnetic resonance imaging CVLM - caudal ventrolateral medulla CBF - cerebral blood flow CNS - central nervous system

fMRI - functional magnetic resonance imaging

IIH - idiopathic intracranial hypertension IL - interleukin MSNA - muscle sympathetic nerve activity NIRS - Near infrared spectroscopy

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ICP - intracranial pressure

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CO2 - carbon dioxide

NIR-T/BSS - near-infrared transillumination back scattering sounding

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NTS - nucleus of the solitary tract OSA - obstructive sleep apnoea

PVN - paraventricular nucleus of the hypothalamus RVLM - rostral ventrolateral medulla

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SaO2 - oxyhaemoglobin saturation

SNS - sympathetic nervous system

SPECT - single-photon emission computed tomography

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TNF-α – tumor necrosis factor α WM – white matter

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BP - blood pressure

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Introduction

Obstructive sleep apnoea (OSA) is the most prevalent form of disordered breathing pattern during sleep in adults. Clinical consequences of untreated OSA include not only daily activity

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impairment but also may confer cardiovascular risk 1 2 3. Screening for sleep apnoea has become a standard in several non-communicable diseases such as hypertension, cardiac arrhythmias or coronary artery disease 4 5 6 7 8. Although the pathogenesis of target organ damage in sleep

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apnoea is rather complex including a line of independent factors simultaneously evoked by

morbidity and mortality 9 10.

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repetitive apnoeas, evidently, the hypoxic stimulus substantially deteriorates cardiovascular (CV)

Repetitive apnoeas, characteristic for OSA, gradually evoke intermittent hypoxia, followed by rapid re-oxygenation upon restoration of breathing. These changes are accompanied by marked alterations in vessel reactivity secondary to sympathetic nervous system (SNS) over-excitation.

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Altogether, these phenomena have the potential to induce ischaemic-, and/or reperfusion-related neural tissue injury 11 12. Untreated OSA patients commonly have depression, anxiety disorders 13 14 15

and significant memory deficits 16 17, which suggests central nervous system malfunction,

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especially in autonomic, affective and cognitive regulatory areas 11 High SNS activity is a predominant feature of OSA

19 20 21

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, however, the direct role of

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sympathetic tone on the regulation of cerebral perfusion is a matter of controversy 22 23 24 25 26 12. The link between SNS and cerebral perfusion encompasses several indirect mechanisms including repetitive hypoxia, systemic and central nervous system inflammation, abrupt blood pressure (BP) swings and baroreceptors alternating firing all of which have been reported in untreated OSA 21 27 28 29.

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Technical developments over the last few years made it possible to considerably progress in our understanding of central nervous system (CNS) structural and functional changes in patients with obstructive sleep apnoea (OSA). However, a variety of new methods employed in this field of

studies in OSA patients

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research produced conflicting results. Additionally, the discrepant results of the morphologic , coincide with even less consistent data on the regulation of cerebral

perfusion in these patients. The latter data usually come from invasive and complex study

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techniques with clearly limited repeatability and reproducibility. Due to the overall complexity of the problem, in the following paragraphs a brief characterisation of the concept and methodology the main findings and study

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of the discussed techniques will be provided along with

contributions to our understanding of the role of OSA in the regulation of cerebral perfusion as well as the pathogenesis of brain malfunction. In this review, we present the most recent data providing novel insights into cerebral oxygenation, perfusion and cerebrovascular reactivity. We

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also discuss the central mechanisms governing SNS discharge in OSA. Additionally, we focus on the novel concepts in the physiological regulation of cerebral blood flow (CBF), pathophysiology of cerebral perfusion in OSA and their clinical consequences. We propose a link between

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hypoxia, SNS activation and cerebral perfusion. Finally, future perspectives are outlined with

OSA.

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particular emphasis put on the understanding of altered cerebral blood flow (CBF) regulation in

The presented review provides insights into how sympathetic nervous system

reinforcement in OSA promotes maladaptive mechanisms that could alter cerebral perfusion regulation, and result in functional and structural cerebral changes.

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Cerebral hemodynamics in OSA Brain circulation in OSA is characterized by marked instability. During apnoeic episodes CBF

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velocity (CBFV) measured with transcranial Doppler ultrasound may increase by 200%. After restoration of breathing CBFV often drops below the baseline level to finally recover after approximately 60 seconds 31

32 33

. The reported changes in CBF, with subsequent cerebral blood

volume increases, bear a potential to perturb cerebral oxygenation and cerebrovascular reactivity.

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Although the problem has been addressed previously, the magnitude of such impairments are controversial with conflicting findings for most of the aspects related to brain perfusion

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regulation.

Cerebral oxygenation

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Oxygen is critical for neuron metabolism and function (e.g. memory formation). Both, oxygen delivery impairment and oxygen excess immediately result in increased neuron vulnerability

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.

In the last two decades, cerebral oxygenation was commonly assessed by a near infrared

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spectroscopy (NIRS) technique. NIRS allows semi-quantitative or quantitative monitoring of (1) oxygenated haemoglobin (O2Hb), (2) deoxygenated haemoglobin (HHb), (3) total haemoglobin

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(tHb), and (4) O2Hb saturation. Given the fact that the arterial blood volume fraction represents approximately 30% in the human brain

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, the NIRS technique provides the information on

oxygenation changes occurring mainly within the venous compartment

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. This fact may be of

importance in the setting of OSA since the NIRS signal is highly dependent on cerebral blood volume, a variable influenced by the duration of apnoea (carbon dioxide (CO2) concentration increases).

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NIRS studies have consistently shown decreased cerebral oxygenation during apnoea or hypopnea episodes in OSA subjects

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, and cerebral oxygenation was reported to be linked to

the magnitude of decrease of oxyhaemoglobin saturation (SaO2)

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. The longer the apnoea

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(usually observed during rapid eye movement sleep) the greater the cerebral deoxygenation documented. However, recent studies based on the infrared light signal processing methodology completed in animal OSA-models produced conflicting results. Almendros et al. 39 suggested that

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apnoea was overall associated with increases in brain oxygenation and also oxidative stress. The level of oxidative stress, however, appears to be negatively influenced by advancing age as

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documented in the rat model 40. Interestingly, increased oxygenation and oxidative stress was not seen in animal models of intermittent hypoxia, with low baseline brain oxygenation

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. In

addition to differences in applied methods, baseline oxygenation and the age of study subjects, several other factors could possibly explain the reported discrepancies. Apparently, different

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levels of hypercapnia seem to be an important confounding variable. Increasing concentrations of CO2 induce higher oxygen delivery from erythrocytes pial arteriolar bed resistance

42 43 44 45

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and dilate pial arteries thus decreasing

. In healthy subjects, maximal breath-hold time (high CO2

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accumulation) leads to pial artery dilation and subsequent augmentation of CBF 46, an effect that is much less prominent in shorter periods of apnoea or the intermittent hypoxia model 47. Another

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factor which should not be entirely disregarded is the process of adaptation to intermittent hypoxia which is a possible scenario in untreated sleep apnoea or in trained athletes. Long-term conditioning with intermittent hypoxia has been previously described with relation to the heart in animal and human studies 48

49,50 51

. However, the possible role of conditioning with intermittent

hypoxaemia/hypoxia in relation to the CNS remains unclear 52. Nevertheless, recent studies have shown that highly selected groups of elite breath-hold divers are characterised by normal brain oxygenation during even extremely long apnoea periods

53

. Taken together, in light of very

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limited evidence and discrepant results, the influence of apnoeic episodes on cerebral oxygenation in OSA subjects needs further clarification. However, as for now, the weight of evidence overbalance suggests that cerebral oxygenation is more closely related to apnoeas

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duration and subsequent changes in CO2 concentration rather than intermittent hypoxia itself.

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Cerebrovascular reactivity

Cerebrovascular reactivity may be defined as a vasomotor mechanism modulating CBF through

changes in CO2 concentration 54.

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constriction and dilation of pre-capillary arterioles in response to a given stimulus, most often

Transcranial Doppler, first described in by Aaslid et al. 55, is a non-invasive ultrasound technique that involves the use of a low-frequency (≤2 MHz) transducer probe to insonate the basal cerebral

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arteries through relatively thin bone windows. Transcranial Doppler is widely used for cerebrovascular reactivity studies as it allows the monitoring of dynamic changes in CBFV and vessel pulsatility over extended time periods with a high temporal resolution. The main drawback

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of Doppler-based studies in OSA subjects is that CBF estimation is based on the assumption that changes in CBFV match fluctuations in CBF, i.e. vessel diameter remains constant. In fact,

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cerebral artery diameter may adjust after exposure to different stimuli secondary to repetitive apnoea such as hypercapnia, excess catecholamines or extreme hypoxia 56 57 58 59. Klingelhofer et al.

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proposed that transient increases in CBFV during apnoeic episodes in OSA

subjects are primarily related to changes in CO2 concentration. In particular, reactivity to CO2 may be increased during REM sleep (maximal recorded CBFV), whereas the reactivity to CO2 remains normal during the wakeful state

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. Partially in line with these findings are the

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conclusions by Placidi et al. 60. Authors have suggested that cerebrovascular reactivity to breathholding in OSA subjects follows the normal physiologic pattern but it is a weaker response; it is also diminished after awakening and recovers to normal within several hours of activity

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et al.

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However, recent studies testing the same phenomena produced more conflicting results. Urbano suggested that CO2-dependent reactivity in OSA subjects is normal during the wakeful

state whereas Morgan et al.

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showed that reactivity to CO2 is blunted both during sleep and in

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the wakeful state. Taken together, CO2-related CNS haemodynamic reactivity is rather lower in OSA subjects compared to healthy subjects. Most interestingly, this phenomenon can be

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normalised after short-term continuous positive airway pressure (CPAP) therapy implying the direct causality of untreated OSA in altered brain vasculature reactivity 63. Functional magnetic resonance imaging (fMRI) utilizes the “BOLD contrast” phenomenon resulting from the differing influences on local image signal intensity of deoxy- vs.

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oxyhemoglobin. Activity associated with peripheral stimulation, task performance or cognitive activity generate a transient increase in regional CBF to match the augmented demands of the active neurons. This augmented CBF is, however, higher than demand for neural tissue oxygen.

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As a result, there is a net increase of oxyhemoglobin in the capillary bed, compared to the period prior to the neuronal activity. An elevated oxy-hemoglobin concentration leads to a relative

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decrease in deoxyhemoglobin. Since deoxyhemoglobin, being paramagnetic, is associated with signal loss on T2-weighted images, its transient decrease in concentration is visible as a transient increase in local signal. Consequently, in the capillary bed of tissue closely coupled to the active neurons, signal intensity is increased 64. Local increase in vessel diameters and subsequent CBF elevation is evident in response to breathing a CO2 enriched gas mixture. Thus, as hypercapnia influences local deoxy- vs.

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oxyhemoglobin concentration changes subsequently a dependent image signal intensity BOLDMRI may be also used as a powerful method to assess cerebrovascular reactivity. Actually, recently published BOLD-MRI-based studies in healthy volunteers who were exposed to gas

complex dynamics in time and space

65 66

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mixtures of increasing CO2 concentration unveiled that cerebrovascular reactivity is a process of . In line with that, cerebrovascular reactivity changes

observed in a breath-holding BOLD-MRI imaging task study in OSA subjects were neither

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homogeneous throughout the brain nor followed vascular territories, but rather corresponded to underlying neuronal networks, suggesting a relationship between cerebrovascular reactivity and 67

. Apparently, the design of cerebrovascular reactivity studies in

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surrounding neuronal activity

different cohorts (especially in OSA patients) should take into account regional differences, process dynamics, and impact on functional aspects.

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Cerebral perfusion

The brain accounts for 2% of body weight but utilizes about 20% of total cardiac output and oxygen consumption to maintain normal function. Due to high energy consumption cerebral

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perfusion is one of the most important parameters defining neurons physiological activity 68.

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Comparison of various studies reporting cerebral perfusion changes in OSA is complicated by a myriad of imaging techniques used for this purpose. Positron emission tomography (PET) imaging is often considered to be the gold standard 69 for measuring perfusion metrics, however single-photon emission computed tomography (SPECT) and computed tomography perfusion are cheaper and provide comparable results 70

71

. Arterial spin labelling (ASL) is another emerging

MRI method for obtaining CBF. ASL is a subtractive technique and generates an image from the difference between the two volumes acquired: one with a magnetic tag applied (achieved by

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inversion pulses) and the other one without it

72 73

. ASL is the least invasive method because

there is no ionizing radiation involved and no need for an intravenous contrast agent injection. Thus, ASL competes with PET techniques as well as computed tomography and magnetic

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resonance contrast bolus passage imaging in providing CBF measurements. Nevertheless, ASL still requires certain developments in the standardization to become a method of choice in CBF assessment 74. Importantly, combining either ASL or PET with the T1-weighted MRI voxel-

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based morphometry signal-volume optimum normalization may be obtained 75 76.

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Resting CBF in subjects suffering from OSA seems to persistently decrease both during sleep and wakefulness 77 78. Meyer et al. was the first to report rates of CBF (mL/100g/min.) in OSA subjects using computed tomography-based techniques (utilizing stable xenon and xenon-133). The authors showed a reduction of CBF in OSA patients in the frontal and occipital cortex, pons and cerebellum 77. The decrease in CBF occurred despite relatively greater end-tidal CO2 in

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subjects with OSA versus controls both during wakefulness and sleep (2 mm Hg and 4 mm Hg, respectively) 77. A SPECT study found that severe OSA is associated with reduced CBF in the

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parahippocampal gyrus bilaterally, right lingual gyrus, pericentral gyrus, and cuneus 79. ASL perfusion imaging and a voxel-based morphometry study revealed that resting regional

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perfusion was decreased during wakefulness in participants with moderate-to-severe OSA 76. Interestingly, in a study by Baril et al. 80 , which did not confirm regional CBF changes in mild to moderate OSA, the authors reported that participants with severe OSA were characterized by markedly reduced regional CBF compared to controls in several CNS areas (e.g., the magnitude of regional CBF reduction was associated with increased hypopnoea, snoring intensity and magnitude of desaturations, as well as the level of excessive sleepiness). On the other hand, apnoea-, arousal-, and body mass indices positively correlated with increased regional CBF in the

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basal ganglia, insula, and limbic system 80. It is therefore justified to hypothesize that impaired vascular regulation and reduction in regional CBF may actually result in functional deficits such as cognitive decline. Lower CBF may also facilitate altered neuronal integrity, and/or promote

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neurodegenerative processes 76 80.

PET allows the measurement of tissue metabolic activity based on regional glucose uptake.

While such examination does not provide a direct information on CBF, glucose metabolism and

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CBF are closely correlated and often show similar results 81. In a study by Yaouhi et al. 75 which

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utilized a combined PET with voxel-based morphometry techniques, a decrease in brain metabolism was limited to the right hemisphere, it was more restricted than the GM density changes, involved the precuneus, the middle and posterior cingulate gyrus, and the parietooccipital cortex, as well as the prefrontal cortex in OSA patients. Thus, the hypometabolic changes included part of the default mode network (precuneus, cingulate areas and inferior

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parietal cortex), the brain system that participates in internal modes of cognition 82. Hypometabolic changes in the prefrontal cortex in subjects with OSA and persistent sleepiness of

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unclear origin were also reported by Antczak et al. 83.

Cerebral hemodynamics in OSA – Practical Points •

Influence of apnoeic episodes on cerebral oxygenation in OSA subjects remains unclear

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CO2-related brain haemodynamic reactivity is rather lower in OSA subjects

compared to healthy subjects •

Impaired vascular regulation and reduction in regional cerebral blood flow may result in functional deficits

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Central sympathetic nervous system activity in OSA

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The rostral ventrolateral medulla (RVLM) is usually considered the main pressor site of the brain, functioning and controlling SNS outflow and reflex mechanisms. Descending projections to the RVLM arise among others from the neurons in the peri-aqueductal grey and hypothalamic

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paraventricular nucleus (PVN). The RVLM integrates neural reflex mechanisms from afferent arterial baroreceptors, chemoreceptors and various afferent sensors through direct connection

85

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with the upper part of the medulla through the nucleus of the solitary tract (NTS) and the PVN 84 .

Peripheral muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA), may be recorded via a tungsten microelectrode inserted percutaneously into the common

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peroneal nerve, a method known as microneurography. Simultaneously performing a BOLD-MRI of the brain and a microneurography it is possible to functionally identify cortical and subcortical areas involved in the generation of spontaneous fluctuations in sympathetic outflow to muscle or

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skin 86.

Interplay between the central and peripheral sympathetic nervous system in healthy subjects MSNA in healthy subjects is characterised by synchronous bursts 87. Each burst is locked in time to the cardiac cycle through the baroreflex. The MSNA burst aligns with diastole when the BP is relatively low, and hence baroreceptor input is low. The nucleus of the solitary tract (NTS) is the primary receiving area of inputs from the arterial baroreceptors. The NTS sends excitatory

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projections to the caudal ventrolateral medulla (CVLM), which exerts tonic inhibitory control of the RVLM, the primary output nucleus responsible for sympathetic vasoconstrictor control of arterial pressure 88

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. Simultaneous recording of the MSNA signal along with brain a BOLD-

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MRI allows depiction of the baroreflex neural loop in real time. The time-dependant fluctuations in BOLD-MRI signal intensity within the NTS, CVLM and RVLM correlate with the

spontaneous fluctuations in MSNA in humans at rest 90. Furthermore, functional connectivity

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analysis suggests that activity within higher cortical regions, such as the insula, dorsolateral

sympathetic neurons in the RVLM 91.

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prefrontal cortex and hypothalamus, may regulate resting MSNA by projections to the premotor

Interplay between the central and peripheral sympathetic nervous system in OSA subjects

92 20 21 27

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It is now well-established that OSA is associated with a significantly increased resting MSNA 19 and dampened baroreflex 92 27. Despite the fact that experimental animal studies

revealed that brainstem nuclei are critical for the generation and modulation of resting

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sympathetic outflow 93 94, analogous human data have become available only very recently. During wakeful state, OSA subjects display a significantly lower BOLD-MRI signal intensity

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compared with matched-controls in the region of the medullary raphe nuclei, left RVLM, right and left dorsolateral pons as well as right midbrain in the region of the periaqueductal grey matter. Importantly, an elevated resting MSNA commonly recorded in OSA subjects is not paralleled by an increased BOLD-MRI signal intensity within the region of the RVLM. Oxygen level dependent signalling appears to reflect intensity of synaptic activity rather than neural electrical output 95. Therefore, a decrease in signal intensity within the RVLM in OSA patients

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may actually represent a reduction in active inhibition of the RVLM (Figure 1). Taken together, the elevated sympathetic drive in OSA may result from functional changes within discrete regions of the human brainstem, including the dorsolateral pons, RVLM and medullary raphe.

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These brainstem regions are known to modulate sympathetic output via either direct or indirect inputs to the sympathetic preganglionic neurons in the spinal cord 96. As documented, six months of CPAP treatment significantly reduces MSNA in subjects with OSA, an effect that is sustained

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for at least twelve months 21 28 97. Importantly, MSNA-coupled changes in BOLD-MRI signal intensity recorded in wakeful subjects within the dorsolateral pons, medullary raphe, and rostral

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ventrolateral medulla return to control levels. That is, CPAP application reverses brain stem functional changes associated with elevated MSNA in OSA subjects 98 97. Higher centres involved in cardiovascular control may be also affected in the course of untreated sleep apnoea, as suggested by associations between increased MSNA and BOLD-MRI signalling

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recorded in wakeful OSA-subjects within several structures such as left and right dorsolateral and medial prefrontal cortices, dorsal precuneus, anterior cingulate cortex, retrosplenial cortex and caudate nucleus. Another alteration seen in sleep apnoea refers to the right

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hippocampus/parahippocampus where BOLD-MRI signal intensity decreases significantly in

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controls but does not change in OSA 99. Quite surprisingly, authors reported that changes in BOLD-MRI signal intensity associated with increased MSNA did not coincide with regional structural changes in individuals with OSA 99. Following six months of CPAP-treatment the reduction in resting MSNA is coupled with significant drops in signal intensity in the precuneus bilaterally, left and right insula, right medial prefrontal cortex, right anterior cingulate cortex, right parahippocampus and left and right retrosplenial cortices. These data further support the

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concept that functional changes in these suprabulbar sites are driving the augmented sympathetic outflow (via projections to the brainstem) to the muscle vascular bed in untreated OSA 100.

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The possible limitation of the reviewed research testing the interplay between central and peripheral sympathetic nervous systems in healthy and OSA subjects is that all of the presented studies were based on one-site data, therefore their replication is still awaited. Yet, the concept of bringing BOLD-MRI and MSNA together seems compelling and may enormously advance our

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knowledge in this field.

Inflammatory changes within the brain structures controlling sympathetic nervous system outflow Systemic inflammation (including increased levels of TNF-α and IL-6) 101 102, and reninangiotensin-aldosteron system activation 103 104 constitute an important part of OSA pathogenesis.

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Pro-inflammatory cytokines produced in the periphery are capable of penetrating the blood brain barrier (BBB) at points of increased permeability and/or disruption, and thus have the potential to influence the function of the various structures in the CNS. In fact, in animals the stimulation of

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PVN with TNF-α and IL-1β results in augmented adrenocorticotropic hormone release, increased

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sympathetic outflow and an enhanced cardiac sympathetic afferent reflex with subsequent BP elevation 105 106 107. Pro-inflammatory cytokines are also produced by glia and neurons, and the recently identified brain inflammatory response to peripheral inflammation may further contribute to the development of hypertension 108 109 110 111. Interestingly, circulating angiotensin II may influence NTS neuronal networks across the BBB 112, contributing to BBB disruption 113 114 115

, and subsequently gain access to brain areas that are normally protected by the BBB,

including the PVN, RVLM, and NTS 116 (Figure 2). Additionally, pro-inflammatory cytokines

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(IL-1β, IL-6 and TNF-α) may cause dysregulation of adherens and tight junctions leading to BBB permeability 117 118. Angiotensin II and pro-inflammatory cytokines are critical for the development of an inflammatory state within the forebrain and hindbrain nuclei resulting in

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augmented sympathetic outflow to the periphery 108 109 29. Alternatively, oxidative stress

generated during apnoeic episodes may trigger inflammatory changes in PVN and stimulate SNS outflow 119 120 121 39.

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Despite a sound theoretical concept supporting existence of brain inflammation in OSA

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experimental data related to neuroinflammatory changes in OSA is scarce. Cyclooxygenase-2 (COX-2), TNF-α, IL-1b and IL-6 mRNA is elevated in microglia isolated from cortex, medulla and spinal cord tissues dissected from rats exposed to chronic intermittent hypoxia (animal model of OSA) compared to control animals 122. The study, however, did not provide specific

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information related to PVN, RVLM or NTS, the brain structures responsible for SNS activity. The recent study by Chen et al. was the first that attempted to link intracranial white matter (WM) integrity and circulating inflammatory markers in subjects with OSA 123. In this study

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diffusion tensor imaging (DTI) was used, an MRI sequence that is more sensitive for detecting intracranial microstructural change than a T1-weighted MRI. Taking pixel-by-pixel information

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on diffusion anisotropy, the technique allows the visualisation of the pathway of WM tracts through the brain 64. In subjects with severe OSA, WM damage was associated with disease severity (indicated by apnoea–hypopnoea and desaturation indices), decreased O2 saturation and systemic inflammation (indicated by leukocyte early apoptosis) 123. This in turn, may partly explain neurocognitive impairment observed in OSA-patients which has been documented to be correlated to oxidative stress 124.

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Finally, biochemical markers of inflammation were assessed in thalamus and putamen in a small group of subjects with mild to severe OSA 125. A study based on a modified resonance spectroscopy - a noninvasive neuroimaging technique, which allowed for the assessment of

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cerebral metabolite changes, providing information on neuronal cellular viability, cellular energetics, and cellular membrane status was used 126. Subjects with OSA showed

neurochemical changes in the thalamus and putamen suggestive of substantial microglia

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activation, and the presence of mild neurodegenerative processes 125. Similar changes were

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reported in insula by the same group 127.

Taken together, neuroinflammation and oxidative stress in brain centres responsible for SNS outflow provide an interesting conceptual substrate to explain, at least partially, central sympathetic reinforcement in OSA. Although a direct mechanism linking OSA with brain inflammation has not yet been established there is solid theoretical background and limited direct

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evidence supporting the hypothesis that such an association may exist.

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Central sympathetic nervous system activity in OSA – Practice Points Elevated sympathetic drive in OSA corresponds to functional changes within

•

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discrete regions of the human brainstem Higher centres involved in cardiovascular control are implicated in the augmented

sympathetic outflow (via projections to the brainstem) in OSA

•

Inflammatory changes within brain structures responsible for autonomic control

may further enhance central sympathetic outflow in OSA

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Novel concepts questioning the current paradigm on cerebral blood flow control in OSA Recent decades produced several scientific discoveries that challenged our knowledge on CBF

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control in humans. The comprehensive research on CBF tested several aspects including the concept of “cerebral autoregulation”, cardiac compensatory mechanisms and the impact of

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pulsatility ICP changes on brain perfusion regulation.

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Cerebral autoregulation

Throughout several decades the explanation of CBF regulation was to a certain extent arbitrary as several unsolved issues existed. In short, CBF was regarded to be entirely unaffected by systemic BP within the systolic BP range of approximately 60 to 150 mm Hg 128. The Lassen’s concept that the plateau region within the so-called “autoregulatory range” has a slope of zero has had

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considerable influence on the static assessment of cerebral autoregulation in physiologic and clinical studies. However, in 2010 Lucas et al. reported systematic changes in CBF and cerebral oxygenation over a wide range of pharmacologically-induced BP alterations in healthy subjects . CBF changed by approximately 8% per each 10 mm Hg fluctuation in systemic BP for

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129

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subjects with both hypotension and hypertension 130. These findings clearly show that, at least in healthy subjects, the slope between CBF and BP is relatively linear. Assuming that changes in peripheral BP represents an important mechanism to match temporal brain oxygen demand then BP surges following apnoeic episodes could be interpreted from a different perspective. In elite breath-hold divers exercising very long apnoeas, SaO2 saturation may drop by 40% while brain oxygenation remains stable, at a cost of a BP surge by 50-60% and a CBFV increase by over 100% 53. Therefore, a high sympathetic drive and subsequent BP rise

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may be perceived as a trade-off between the immediate need to meet neurons oxygen demand and longer-term stability of the cardiovascular system (increased risk of cardiovascular and cerebrovascular events). Interestingly, SNS activation produce spleen contractions, resulting in

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red blood cells autotransfusion and facilitating oxygen transport 131 132 133 134 the phenomenon recently confirmed also in OSA subjects 135. Taken together, during hypoxia an increase in

sympathetic outflow may represent an adaptive mechanism to stabilize oxygen supply to brain

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(Figure 3).

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Owing to cyclical performance of the heart as a pump, in the aorta and the proximal part of the arterial vascular tree blood flow is characterized by a pulsatile flow. The aorta which consists of a substantial amount of elastic tissue, acts as a temporal buffer for blood during the ejection phase of the heart (Windkessel function), and effectively tends to reduce its afterload. Consequently,

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from the thoracic aorta to the end of the arterioles, pulsatility is progressively attenuated 136. Tzeng et al. 130 indicated that CBF dynamics during acute transient hypotension and hypertension is dominated by cerebrovascular Windkessel properties independent of cerebral autoregulation.

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Furthermore, haemodynamic effects of hypercapnia during transient BP challenges primarily reflect changes in Windkessel properties rather than pure cerebral autoregulatory impairment 130.

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A repeatedly reported increased OSA-related arterial stiffness which has been demonstrated using different pulse wave analysis techniques suggests that the buffering capacities of the aorta is deteriorated in these patients 137 138. The diminished Windkessel function of large arteries may be of particular importance (esp. in the setting of concomitant SNS overdrive) as marked BP surges coupled with apnoeas are transmitted to target organs without sufficient buffering, conceivably negatively influencing morbidity and mortality of OSA-patients.

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Importantly, brain blood volume and its oxygenation changes (measured by global BOLD-MRI signal) evoked by peripheral SNS activation (using handgrip and cold pressor tests) are blunted in OSA patients compared to healthy controls 139. Thus, dysregulation of the SNS system in OSA

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affects cerebral perfusion adaptive responses to external stressors. This finding also suggests that CBF regulation mechanisms in OSA are much more complex than the traditional “cerebral autoregulation” concept.

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Lastly, scientific perspective allows the hypothesis that if a finite slope of the plateau region in

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the so called “autoregulation curve” does not necessarily imply defective autoregulation in healthy subjects, all clinical studies reporting cerebral autoregulation impairment in OSA subjects should be viewed with caution. The topic should then be re-examined and the comparison of the

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slopes in well-matched groups of healthy and OSA patients should be performed.

Baroreflex and cardiac contribution to cerebral blood flow control Georgiadis et al. 140 was the first to demonstrate a long-term brain microcirculation adaptation to

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decreased cardiac output in patients with chronic left ventricle failure. Ogoh et al. 141 showed that

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the cardiac baroreflex plays an important role in the dynamic CBF regulation during acute transient hypotension in healthy subjects. The latest finding was further strengthened by our report suggesting that the baroreflex influences the pial artery response to rapid BP changes 46. The baroreflex and cardiac contribution to the regulation of CBF has profound implications for our understanding of the mechanisms leading to impaired CBF control in OSA subjects. Urbano et al. 61 reported that cerebral autoregulation is impaired in OSA subjects based on the observation that BP and CBF responses to orthostatic tests are delayed in comparison to healthy

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subjects. The described impairment may be partially explained by a damped baroreflex 92 27, and blunted heart rate response 142 in OSA. Interestingly, the cardiac contribution to the relationship between BP and pial artery oscillations in healthy subjects is negatively affected by apnoea,

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hypoxia and increased respiratory resistance 47 46 143 144, and it may be additionally modified by the SNS 145 146. Clearly, the discussed findings warrant further integrated studies to better understand the complexity of these mechanisms in OSA-patients.

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A hypothesis that baroreflex and cardiac output play an important role in regulation of cerebral

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perfusion is now justified; therefore the central SNS reinforcement (as referred to in the above sections) may be of critical significance for the whole system homeostasis and pathogenesis of target organ damage including the brain itself. Various imaging studies consequently show a reduction in the regional perfusion, particularly in subjects with severe OSA. Thus, over-activity of brain regions governing SNS discharge may be perceived as an adaptive mechanism to

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increase CBF, constituting at the same time a vicious circle in OSA-related pathological

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processes.

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Pulse wave encephalopathy

The concept of pulse wave encephalopathy has been initially proposed by the Bateman group 147. Pulsatile flow may be considered a manifestation of the energy stored in the form of the pulse pressure which is dampened by shifting cerebrospinal fluid and venous blood to ensure nonpulsatile continuous perfusion through the capillary bed 147. If dampening of the pulsation energy becomes ineffective, as it may be observed in the impaired venous outflow or increased ICP, it results in an increased pial artery pulsation 147 . Exposure to high pulsatile pressure and

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augmented flow per se is a well-known predictor of cerebral vascular damage, even in the absence of increases in mean BP 148 149 150. High arteriolar pulsatility observed during apnoeas in healthy subjects may potentially provide a mechanistic explanation for the higher risk of

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cerebrovascular events in OSA subjects 144. Increased arterial pulsatility may augment

perivascular shear stress and lead to accumulated damage to perivascular oligodendrocytes, resulting in microstructural changes in white matter and contributing to proliferation of

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leukoaraiosis over time 151. The study by Jolly et al. establishes a potential causal link between

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pulse wave encephalopathy and WM abnormalities in OSA 151.

It is important to underline that changes in cardiac driven arterial flow pulsatility also affect cerebrospinal fluid dynamics. Association between WM lesion formation and increased cerebrospinal fluid pulsatility has been initially reported in subjects with multiple sclerosis 152. Cerebrospinal fluid flow quantification in the aqueduct of Sylvius was performed with a cine

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phase contrast MRI, while WM changes were assessed using T2-weighted MRI imaging. Recently the same group reported that in individuals without neurologic diseases, WM lesions formation appear to be associated with both hypertension and augmented cerebrospinal fluid

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pulsatility, rather than ageing per se 153.

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The near-infrared transillumination-backscattering sounding (NIR-TBSS) implemented by our group may be considered (for explanatory purposes) a modified NIRS methodology (described in detail in the above section). To wit, the distance between emitter and detector of infrared light in NIR-TBSS is very small, thus enabling assessment of the width of subarachnoid space filled with cerebrospinal fluid instead of oxygenated / deoxygenated haemoglobin in the brain 154 155. Association between changes in subarachnoid space width measured with NIR-T/BSS and T1weighted MRI has been proven experimentally 156. Our recent results indicate that apnoea in

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healthy subjects is associated with large swings in the width of the subarachnoid space 46, thus suggesting substantial cerebrospinal fluid shifts. Taking the Jennum and Borgessen study 157, reporting ICP increases during apnoeic episodes in OSA, together with Beggs and Bateman’s

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observations, it is justify to assume that pulse wave encephalopathy might be of clinical relevance in OSA. Unfortunately, this hypothesis needs to be further verified in properly-designed studies

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as there is virtually no data available on this topic in OSA subjects.

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Intracranial pressure and idiopathic intracranial hypertension

In the late eighties, Jennum and Borgessen 157 demonstrated that ICP increases during apnoeic episodes in OSA subjects, and the differences in ICP correlated with systemic BP fluctuations. Several authors postulated that OSA may play a role in the development of idiopathic intracranial

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hypertension (IIH) 158 159 160. It has been proposed that the increases in ICP may result in compression of the cerebral venous sinuses, giving rise to transverse venous sinus stenosis which in turn facilitates persistent elevations of ICP, and thus IIH 160 161. However, the major

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methodological limitation of all the aforementioned studies is the lack of an IIH-free control group. Only one retrospective study performed on 24 newly diagnosed IIH-patients aimed to

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compare sleep apnoea status (prevalence and severity) with IIH-free sample subjects from the general population matched for age, sex, race, body mass index, and sex/hormonal status. Based on this model, those authors concluded that OSA is not an independent risk factor for IIH 162. Given the small number of men included in the Thurtell et al. study 162, further investigation is warranted to see whether or not OSA is a risk factor for IIH in men. This may be of particular importance as the prevalence of OSA is reported to be 2-3 times higher in men than in women 163.

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Larger, prospective and controlled studies are necessary to further evaluate the relationship between OSA and IIH, with special emphasis put on the effects of OSA treatment upon the

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clinical course of IIH. Cushing was the first to demonstrate in animal study that substantial (50-100 mmHg) increases in ICP were associated with matching elevations in arterial pressure, the response being widely known as the so-called Cushing triad (irregular breathing, bradycardia, and severe arterial

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hypertension) 164. Later studies have shown BP surges resulting from much smaller ICP increases

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in humans 165 166. Recent studies support the concept that incremental changes in ICP may result in SNS activation and subsequent BP rise 167. The potential bidirectional link between ICP and SNS fluctuations during apnoeic episodes represents another field for research in OSA that

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requires attention.

Cerebral blood flow regulation in OSA – Practical Points •

SNS activation during apnoeic episodes likely represent adaptive mechanism to

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stabilize cerebral oxygenation

Central SNS reinforcement, with subsequent hypertension, may represent adaptive mechanism to counterbalance decreased cerebral perfusion in OSA subjects Abnormal arterial, venous and cerebrospinal fluid pulsatility may result in brain

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structural impairments in OSA

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Role of OSA in the development of idiopathic intracranial hypertension, and the link

between intracranial pressure fluctuations and SNS activation have yet to be determined

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Perspectives Evidently, OSA affects multiple neural pathways and controlling centres which finally promotes

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high SNS activity as a predominant feature. There is a rationale that SNS augmented tone in OSA largely represents an adaptive response, counteracting intermittent hypoxic episodes and gradual cerebral perfusion declines characteristic for OSA (Figure 3). Although successful treatment of sleep-disordered breathing have a rather modest BP lowering potential 168, the hypotensive effect

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is most likely driven by diminished SNS activity. Reversal of central functional impairments and

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normalization of brain vasculature reactivity with CPAP treatment reinforce the significance of breathing pattern restoration as a clinical target in OSA, supporting the concept that the CPAPrelated benefit goes beyond sheer BP decrease.

In summary, a better understanding of the intriguing link between the central SNS outflow and

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CBF control may open new fields for translation of scientific excellence into clinical applications. Functional BOLD-MRI is one of the most promising tools in such research, although it still suffers from relatively low-time resolution. Multi-signal data acquisition,

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combined with advanced mathematical methods which take into account the complexity of the brain and cardiovascular haemodynamics, represents the most promising network capable of

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describing the interrelations and pathways involved in CBF control which is characteristic for sleep apnoea patients. Additionally, new methods allowing for non-invasive estimation of ICP and high temporal resolution offer additional value in OSA research.

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Research Agenda •

Cardiac and baroreflex contribution to cerebral blood flow control in OSA requires further investigations The link between central sympathetic nervous system activity and cerebral blood

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•

flow control has yet to be clarified •

Sufficiently powered, prospective and controlled studies are needed to evaluate the relationship between OSA and idiopathic intracranial pressure

Multi-signal data acquisition and advanced mathematical methods represents a

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promising approach to understand the complexity of the brain and cardiovascular

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haemodynamics in OSA

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Source of funding Drs. Jacek Wolf, and Krzysztof Narkiewicz are supported by the European Regional

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Development Fund - Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123); by the REGPOT ICRC-ERA Human Bridge grant No. 316345 provided by the EU; and by the NCN-grant „Hypertension and cerebrovascular dysfunction: contribution of neuroanatomical connectivity,

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sympathetic nervous system and cardiovascular risk factors”, UMO-2011/02/A0NZ5/00329.

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Conflict of interest

Drs. Jacek Wolf, and Krzysztof Narkiewicz received fees for lectures on sleep apnoea from

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ResMed.

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Figures Figure 1 Blood pressure increase results in augmented baroreceptor input, and subsequently

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higher activity of both the NTS and CVLM. This is in contrast with lower RVLM activity because of the inhibition provided by the CVLM. A decrease in BOLD-MRI signal intensity within the RVLM in OSA patients may actually represent a reduction in active inhibition of the

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RVLM by the CVLM. As a consequence SNS outflow from RVLM is augmented.

BP – blood pressure; BOLD-MRI - blood oxygen level dependent - magnetic resonance imaging;

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CVLM - caudal ventrolateral medulla; NTS - nucleus of the solitary tract; OSA – obstructive sleep apnoea; RVLM - rostral ventrolateral medulla, SNS – sympathetic nervous system.

Figure 2 Angiotensin II, IL-1β, IL-6 and TNF-α contribute to BBB disruption and subsequently

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gain access to the PVN that is normally protected by the BBB. The hypothalamic PVN is a pivotal centre within the brain neuronal circuitry involved in the maintenance of homeostasis. Stimulation of the PVN with angiotensin II, IL-1β, IL-6 and TNF-α results in augmented

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generation of SNS outflow via projections to the RVLM. BBB - blood brain barrier; IL – interleukin; PVN - paraventricular nucleus of the hypothalamus;

factor

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RVLM - rostral ventrolateral medulla; SNS – sympathetic nervous system; TNF – tumor necrosis

Figure 3 SNS activation as an adaptive mechanism in response to hypoxic episodes. Hypertension and increased blood flow pulsatility may be considered as bystander effects (consequence of trade-off between matching immediate brain oxygen demand and longer-term

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cardiovascular system dysregulation). Hypertension leads to systemic inflammation and RAAS activation, and further reinforcement of central SNS discharge. Increased blood flow pulsatility results in pulse wave encephalopathy and white matter damage. Potential link between

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intracranial pressure and SNS fluctuations has yet to be clarified. Yet, the evidence shows that normal breathing restoration ameliorates SNS overactivity in OSA patients.

OSA – obstructive sleep apnoea; RAAS – renin-angiotensin-aldosterone system; SNS –

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sympathetic nervous system

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** Older individuals with severe OSA are characterized by hypoperfusion in the sensorimotor and parietal areas. Respiratory variables and subjective sleepiness are correlated with extended regions of hypoperfusion in the lateral cortex. OSA severity, sleep fragmentation, and obesity correlates with increased perfusion in subcortical and medial cortical regions. Anomalies with such a distribution could result in cognitive deficits and reflect impaired vascular regulation, altered neuronal integrity, and/or undergoing neurodegenerative processes

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Sica AL, Greenberg HE, Scharf SM, Ruggiero DA. Chronic-intermittent hypoxia induces immediate early gene expression in the midline thalamus and epithalamus. Brain Res. 2000;883(2):224-228. Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature. 2001;412(6843):150-157. Lundblad LC, Fatouleh RH, Hammam E, McKenzie DK, Macefield VG, Henderson LA. Brainstem changes associated with increased muscle sympathetic drive in obstructive sleep apnoea. Neuroimage. 2014;103:258-266. Henderson LA, Fatouleh RH, Lundblad LC, McKenzie DK, Macefield VG. Effects of 12 Months Continuous Positive Airway Pressure on Sympathetic Activity Related Brainstem Function and Structure in Obstructive Sleep Apnea. Front Neurosci. 2016;10:90. Lundblad LC, Fatouleh RH, McKenzie DK, Macefield VG, Henderson LA. Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects: a longitudinal investigation. J Neurophysiol. 2015;114(2):893-901.

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** CPAP treatment completely reverses brain stem functional changes associated with elevated peripheral muscle sympathetic nerve activity in untreated OSA subjects

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Fatouleh RH, Hammam E, Lundblad LC, et al. Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea. Neuroimage Clin. 2014;6:275-283. Fatouleh RH, Lundblad LC, Macey PM, McKenzie DK, Henderson LA, Macefield VG. Reversal of functional changes in the brain associated with obstructive sleep apnoea following 6 months of CPAP. Neuroimage Clin. 2015;7:799-806.

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** Following 6 months of CPAP treatment the reduction in resting peripheral muscle sympathetic nerve activity is coupled with significant falls in signal intensity in the precuneus bilaterally, left and right insula, right medial prefrontal cortex, right anterior cingulate cortex, right parahippocampus and left and right retrosplenial cortices. These data support the concept that functional changes in these suprabulbar sites are driving the augmented sympathetic outflow (via projections to the brainstem) to the muscle vascular bed in untreated OSA.

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* Based on the animal models the concept of brain vascular inflammatory processes in the development of hypertension is discussed.

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** Increased arterial pulsatility may increase perivascular shear stress and lead to accumulated damage to perivascular oligodendrocytes, resulting in microstructural changes in white matter and contributing to proliferation of leukoaraiosis over time. The

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study by Jolly et al. establishes a potential causal link between pulse wave encephalopathy and white matter abnormalities in OSA

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Magnano C, Schirda C, Weinstock-Guttman B, et al. Cine cerebrospinal fluid imaging in multiple sclerosis. J Magn Reson Imaging. 2012;36(4):825-834. Beggs CB, Magnano C, Shepherd SJ, et al. Dirty-Appearing White Matter in the Brain is Associated with Altered Cerebrospinal Fluid Pulsatility and Hypertension in Individuals without Neurologic Disease. J Neuroimaging. 2016;26(1):136-143. Frydrychowski AF, Guminski W, Rojewski M, Kaczmarek J, Juzwa W. Technical foundations for noninvasive assessment of changes in the width of the subarachnoid space with near-infrared transillumination-backscattering sounding (NIR-TBSS). IEEE Trans Biomed Eng. 2002;49(8):887-904. Plucinski J, Frydrychowski AF. New aspects in assessment of changes in width of subarachnoid space with near-infrared transillumination/backscattering sounding, part 1: Monte Carlo numerical modeling. J Biomed Opt. 2007;12(4):044015. Frydrychowski AF, Szarmach A, Czaplewski B, Winklewski PJ. Subarachnoid space: new tricks by an old dog. PLoS One. 2012;7(5):e37529. Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest. 1989;95(2):279-283.

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** Study demonstrated that intracranial pressure increases during apnoeic episodes in OSA subjects, and the differences in intracranial pressure correlated with systemic blood pressure fluctuations

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Sugita Y, Iijima S, Teshima Y, et al. Marked episodic elevation of cerebrospinal fluid pressure during nocturnal sleep in patients with sleep apnea hypersomnia syndrome. Electroencephalogr Clin Neurophysiol. 1985;60(3):214-219. Purvin VA, Kawasaki A, Yee RD. Papilledema and obstructive sleep apnea syndrome. Arch Ophthalmol. 2000;118(12):1626-1630. Wall M, Purvin V. Idiopathic intracranial hypertension in men and the relationship to sleep apnea. Neurology. 2009;72(4):300-301. Fraser CL. Obstructive sleep apnea and optic neuropathy: is there a link? Curr Neurol Neurosci Rep. 2014;14(8):465. Thurtell MJ, Trotti LM, Bixler EO, et al. Obstructive sleep apnea in idiopathic intracranial hypertension: comparison with matched population data. J Neurol. 2013;260(7):1748-1751. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-1014.

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* up-to-date prevalence of sleep apnea in adult population

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Cushing H. Concerning a definite regulatory mechanism of the vasomotor centre which controls blood pressure during cerebral compression. Bull Johns Hopk Hosp. 1901;12:290-292.

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Dickinson CJ, Mc Cubbin J. Pressor effect of increased cerebrospinal fluid pressure and vertebral artery occlusion with and without anesthesia. Circ Res. 1963;12:190-202. Schmidt EA, Czosnyka Z, Momjian S, Czosnyka M, Bech RA, Pickard JD. Intracranial baroreflex yielding an early cushing response in human. Acta Neurochir Suppl. 2005;95:253-256. McBryde FD, Malpas SC, Paton JF. Intracranial mechanisms for preserving brain blood flow in health and disease. Acta Physiol (Oxf). 2017;219(1):274-287. Wolf J, Narkiewicz K. Optimizing the management of uncontrolled/resistant hypertension. The importance of sleep apnoea syndrome. Curr Vasc Pharmacol. 2017.

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Baroreceptors

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( ) CVLM

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SNS outflow

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(+) RVLM

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Blood

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PVN

Angiotensin II

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Blood-brain barrier

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IL-1β IL-6

disintegration

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processes

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TNF-α

SNS outflow

Untreated OSA

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Pulse wave encephalopathy Brain inflammation

Idiopathic intracranial hypertension

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RAAS activation

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Systemic inflammation

SNS activation

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Hypertension

Increased blood flow puslatility

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Cerebral oxygenation instability

Normal breathing restoration in OSA (e.g. nCPAP-use)

Cerebral perfusion instability