Withstanding the obstructive sleep apnea syndrome at the expense of

Journal of Integrative Neuroscience, Vol. 14, No. 2 (2015) 169–193 c Imperial College Press ° DOI: 10.1142/S0219635215500144

Withstanding the obstructive sleep apnea syndrome at the expense of arousal instability, altered cerebral autoregulation and neurocognitive decline Mohammad Torabi-Nami*,†,‡,**, Samrad Mehrabi†,§, Afshin Borhani-Haghighi¶,* and Sabri Derman|| *Department of Neuroscience, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran †Sleep Disorders Laboratory, Namazi Hospital Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran ‡

Brain and Cognition Study Group (BCSG), Shiraz Neuroscience Research Center Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran §

Division of Pulmonology, Department of Internal Medicine, School of Medicine Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran

¶

Clinical Neurology Research Center, Shiraz University of Medical Sciences Shiraz 71348-14336, Iran ||Sleep

Disorders Unit, American Hospital, Koc Foundation Istanbul 34365, Turkey **[email protected] [Received 28 December 2014; Accepted 20 March 2015; Published 28 April 2015] The present review attempts to put together the available evidence and potential research paradigms at the interface of obstructive sleep apnea syndrome (OSAS), sleep micro- and macrostructure, cerebral vasoreactivity and cognitive neuroscience. Besides the signi¯cant health-related consequences of OSAS including hypertension, increased risk of cardio- and cerebrovascular events, notable neurocognitive lapses and excessive daytime somnolence are considered as potential burdens. The intermittent nocturnal hypoxia and hypercapnia which occur in OSAS are known to a®ect cerebral circulation and result in brain hypoperfusion. Arousal instability is then resulted from altered cyclic alternating patterns (CAPs) re°ected in sleep EEG. In chronic state, some pathological loss of gray matter may be resulted from obstructive sleep apnea. This is proposed to be related to an upregulated proin°ammatory state which may potentially result in apoptotic cell loss in the brain. On this basis, a pragmatic framework of the possible neural mechanisms which underpin obstructive sleep apnea-related neurcognitive decline has been discussed in this review. In addition, the impact of OSAS on cerebral autoregulation and sleep microstructure has been articulated. Keywords: Obstructive sleep apnea; sleep microstructure; cyclic alternating patterns; cerebral autoregulation; neurocognitive performance.

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1. Introduction The current state of knowledge about the signi¯cance of obstructive sleep apnea syndrome (OSAS) e®ects on arousal instability, cerebrovascular autoregulation and neurocognitive functions is the focus of the present review paper. OSAS, characterized by frequent episodes of breathing cessation during sleep secondary to obstruction of the upper airway, is a signi¯cant and relatively common sleep disorder (Baldi et al., 2014). A meta-analysis reported the prevalence of sleep apnea between 3% and 28% suggesting a wide range of di®erence in its prevalence in general population across studies (Young et al., 2009). The condition is diagnosed according to the mean number of apneas and hypopneas per hour during sleep, referred to as the apnea–hypopnea index (AHI) (Madbouly et al., 2014). Periodic nocturnal oxygen desaturations, heightened blood pressure and sleep fragmentation are amongst the most common nighttime consequences of OSAS (Muraja-Murro et al., 2014). Moreover, the condition is linked to increased cardiovascular risks including hypertension, coronary heart disease and stroke (Hsieh et al., 2012). On the other hand, OSAS may result in a®ective, cognitive and autonomic nervous system changes (Cortelli et al., 1994; Beebe et al., 2003; Sateia, 2003; El-Sherbini et al., 2011) suggesting central nervous systems alterations in cerebral areas mediating such behaviors. Neurocognitive de¯cits tend to occur with a high frequency in OSAS (Ferini-Strambi et al., 2003; El-Ad & Lavie, 2005; AddisonBrown et al., 2014; Gelir et al., 2014). The two broad areas of abnormalities studied in OSAS include cognitive function and psychomotor performance. The impact of OSAS on visual and verbal memory function is found to be variable (Beebe et al., 2003), while OSAS tend to a®ect reasoning, comprehension and learning, which are collectively termed as executive functions (Naismith et al., 2004; Wong et al., 2006). The persistent increase in sympathetic out°ow as well as cognitive and mood changes, despite standard treatments including continuous positive airway pressure (CPAP) therapy (Ferini-Strambi et al., 2003), indicate that impaired neural mechanism account for at least some of the characteristics observed in OSAS. It has been shown that cognitive, respiratory and autonomic challenges are responsible for the altered neural function in this condition (Henderson et al., 2003; Macey et al., 2003, 2006; Zimmerman et al., 2006). According to the available evidence, severe sleep apnea may not only increase the risk of dementia in the elderly (Kim et al., 2011), but also a®ect cognitive domains, including learning, memory and attention in other populations (Naismith et al., 2004; Addison-Brown et al., 2014). OSAS su®erers may frequently demonstrate irritability, impaired attention and vigilance and emotional instability (Owens, 2009) and such cognitive impairments would potentially cause problematic behavioral manifestations. The neurocognitive decline is not con¯ned to severe and chronic cases. In fact, neurobehavioral manifestations can also arise in subjects with habitual snoring. This indicates that even the patients with less intense sleep-disordered breathing are potentially prone to neurocognitive decline (Chervin et al., 2002).

WITHSTANDING THE OSAS AT THE EXPENSE OF AROUSAL INSTABILITY. . .

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The neurocognitive burden of OSAS is not only seen as a personal issue but also a social concern. The OSAS patients who involve in critical jobs may end up with work-related injuries or occupational disasters (Arita et al., 2015). The consequence of OSAS becomes more critical in professionals such as commercial bus or lorry drivers who demonstrate excessive somnolence (Sadeghniiat-Haghighi et al., 2014; Arita et al., 2015). The signi¯cantly impaired vigilance can increase the risk of road tra±c accidents when this syndrome is left untreated (Batool-Anwar et al., 2014). Vigilance, or sustained attention, can be evaluated by tests such as the Steer Clear performance test (SCPT) and the psychomotor vigilance test (PVT) (Alakuijala et al., 2014; Batool-Anwar et al., 2014). While the functional changes of the brain in OSA are known to result, at least partly, from injury to neural structures, the nature of such injury is yet to be fully described (Archbold et al., 2009). Based on recent imaging studies, some brain regions such as anterior cingulate, hippocampus and frontal cortical areas (which are involved in regulation of memory, planned functions and a®ect) and other areas including anterior cingulate, cerebellar and brainstem areas (responsible for the regulation of autonomic out°ow) are subject to structural changes in chronic OSAS (Macey et al., 2002; Morrell et al., 2003; Huynh et al., 2014). More imaging studies have demonstrated evidence of diminished neuronal density or altered metabolism in OSAS subjects, however not many cortical and subcortical regions were focused in such studies (regions of interests were limited to hippocampus, parietal-occipital cortex and white matter), and the outcome was constrained by poor spatial resolution of applied imaging techniques (Bartlett et al., 2004; Tonon et al., 2007). Some autonomic, cognitive or emotional consequences of OSAS may result from damaged projection ¯bers which lie between the a®ected brain structures. This can result from cellular damage due to ischemic, hypoxic or in°ammatory processes of sleep disordered breathing (Pae et al., 2005). The animal studies which attempted to model OSAS features by imposing intermittent hypoxia have shown neuronal injury to white matter ¯ber tracts as well as the brain regions similar to those a®ected in the human syndrome (Zhu et al., 2007; Baronio et al., 2013). In OSAS, brain regions such as hippocampus and parietal white matter show alterations in metabolite levels indicative of axonal loss or injury (Tonon et al., 2007). In case of such axonal alterations, communication between brain structures can be potentially a®ected. From the neurophysiology perspective, OSAS is shown to signi¯cantly interfere with duration, depth and continuity of sleep. It also negatively a®ects the sleep restorative properties owing to decreased capacity of the brain to create periods of sustained stable sleep (Parrino et al., 2012). This not only re°ects in sleep EEG but reverberates on autonomic and behavioral functions. OSAS is then shown to a®ect cyclic alternating patterns (CAPs) as a marker of sleep instability (Parrino et al., 2012). As such, repetitive nocturnal apneas as well as post-event cortical activation represented by the abundance of CAPs give rise to the arousal instability during

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sleep (Mariani et al., 2011). OSAS increases the CAPs since most of the apnea or hypopnea events during REM and NREM phases of nocturnal sleep accompany such EEG patterns (Terzano et al., 1996). Untreated OSAS is linked to arousal instability during sleep and continues to negatively a®ect the brain especially in chronic state (Parrino et al., 2012). Additionally, sleep apneas may also leave potential impact on cerebrovascular autoregulation. The cerebral blood °ow velocity (CBFV) of patients with OSAS is shown to be a®ected during wakefulness (Nasr et al., 2009). There is a clear correlation between impaired cerebral autoregulation and the severity index of nocturnal apneas and hypopneas suggesting that severe OSAS a®ects the CBFV in a more signi¯cant way. (Urbano et al., 2008; Nasr et al., 2009). The present review discusses the available evidence on the above-mentioned challenges faced in OSAS and attempts to highlight some future research perspectives which lead to a better understanding about the pathogenesis of OSAS and its neurocognitive consequences. 2. Obstructive Sleep Apnea, Screening, Diagnosis and Treatment Inadequacies Despite the High Prevalence and Burden The prevalence of symptoms, risk of OSAS and associated factors are noticeable (Amra et al., 2011a; Khazaie et al., 2011; Akintunde, 2013; Leong et al., 2013; Mahboub et al., 2013; Mirrakhimov et al., 2013; Liu et al., 2014). In a clinical survey, almost 30% of subjects in samples from general population appeared to be at high risk for OSAS and 50% reported signi¯cant snoring (Khazaie et al., 2011). Some other reports have however indicated that the prevalence of OSAS symptoms is lower in eastern population compared to western countries (Amra et al., 2011b). In general, patients with type 2 diabetes mellitus are at higher risk for OSAS with almost 75% prevalence rate especially in older patients with higher BMI, waist circumference, neck circumference, systolic and diastolic blood pressure. In general, logistic regression analyses have revealed that age, male sex and neck circumference are independent risk predictors for OSA (Supriyatno et al., 2010). Timely screening of patients at OSA risk, con¯rmation of diagnosis in sleep laboratory using polysomnography and providing the standard treatment with CPAP are proposed to improve patients' global cognitive functioning including executive dysfunction, delayed long-term verbal and visual memory, attention, learning and vigilance (Cooke et al., 2009; Berlowitz & Shafazand, 2013; Torabi-Nami et al., 2015). CPAP, as the treatment of choice for OSA, is shown to improve sleep breathing leading to a proper blood oxygen saturation, fewer fragmentations during sleep and a subsequently improved daytime functioning (Lamphere et al., 1989; Sanchez et al., 2009). Some patients however, may continue to experience neurocognitive lapses despite a seemingly adequate CPAP therapy which resulted in AHI normalization (Sanchez et al., 2009; Sforza et al., 2012).


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The current literature on the therapeutic e®ects of CPAP on fatigue, cognitive functioning and mood is mixed and inconsistent, with methodological limitations of association studies complicating interpretation. While some reports demonstrate a signi¯cant reduction in objective and subjective sleepiness and depressive symptoms in CPAP-treated patients, a recent meta-analysis on cognitive functioning after CPAP demonstrates only a slight improvement in evaluated cognitive domains (Bucks et al., 2013; Ferini-Strambi et al., 2013; Kylstra et al., 2013). Notwithstanding this limited evidence for behavioral e®ects of CPAP treatment, there are some emerging evidence corroborating its positive structural e®ects in the brain (Canessa et al., 2011; Ju et al., 2012; O'Donoghue et al., 2012; Ferini-Strambi et al., 2013). An imaging study showed that CPAP treatment was associated with increased cortical thickness in the hippocampus and frontal regions (Ferini-Strambi et al., 2013). The cardiovascular consequences of OSAS are notable of uncontrolled hypertension, atherosclerosis and coronary heart disease which are the most crucial. Once OSAS is diagnosed, the use of CPAP alone, and not oxygen supplementation alone, during sleep may ameliorate systemic hypertension and cardiovascular risk. In addition, weight loss is known to result in decreased cardiovascular morbidity and risk when CPAP is prescribed in these patients (Basner, 2014; Gottlieb et al., 2014). Since the prevalence of OSAS is on the rise (Webber et al., 2011; Guralnick, 2013), practice protocols should be de¯ned to widely screen, timely diagnose and treat this condition in outpatient settings. Moreover, studies on neurocognitive de¯cits in OSAS are obviously required as the condition impacts a growing number of subjects. 3. OSAS and its Potential Neurocognitive Consequences Neurocognitive functions are cognitive functions attributed to speci¯c brain areas, cortical networks and neural pathways which are regulated at neurological matrix and cellular-molecular levels (Green, 1998). Chronic neuroin°ammatory insults are known to deleteriously a®ect the integrity and function of neural pathways and cortical networks (Wee Yong, 2010). Meanwhile, neurocognitive de¯ciencies are frequently seen in OSAS (Ferini-Strambi et al., 2013). Given this and based on the available evidence (Imagawa et al., 2004; Gozal et al., 2010; De Luca Canto et al., 2015), neuroin°ammatory processes are suggested to play a role in neurocognitive decline during the course of chronic OSAS. The broad range of neurocognitive de¯ciencies in OSAS potentially results from the intermittent hypoxia and sleep fragmentations (Ferini-Strambi et al., 2013). Vigilant attention, verbal and visual memory, visuospatial abilities and executive functions are the main cognitive domains a®ected in OSAS (Ferini-Strambi et al., 2013). To better understand the level of cognitive dysfunctions, the extent of improvement following CPAP therapy and the optimal cognitive rehabilitation interventions for residual symptoms, one should consider patients' characteristics, disease severity index, proper selection of neurocognitive testing batteries and follow up measures (Bucks et al., 2013). Some cognitive testing batteries used to evaluate

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vigilance (sustained attention), executive- (working memory, reasoning, planning and problem solving) and motor functioning in OSAS include PVT, SCPT, Wisconsin card sorting test, digit span and ¯nger-tapping tests (Sforza et al., 2004; Batool-Anwar et al., 2014). Results have demonstrated that vigilance and executive functions are the mostly a®ected cognitive domains in these patients (Table 1). Many patients who su®er from OSAS may experience a signi¯cant decline in their neurocognitive performance and the condition is often associated with excessive daytime sleepiness (EDS) (Ronksley et al., 2011; Nami, 2012). EDS and fatigue are the mostly reported daytime symptoms among OSAS subjects. Studies have suggested critical changes in cognitive functioning and mood among OSAS patients with vigilant attention, executive functions, memory and motor coordination being the mostly a®ected cognitive domains (Aloia et al., 2004). Some possible mechanisms including the altered cerebral vasoreactivity, as well as structural and functional changes particularly in frontal and limbic cortices are proposed as underlying etiology for neurocognitive impairments following OSAS (Zimmerman & Aloia, 2006; Furtner et al., 2009; Canessa et al., 2011). The neurocognitive compromise seen in OSAS patients appears to be a consistent ¯nding across studies with a unique pattern of cognitive de¯cits (Ferini-Strambi et al., 2003; El-Ad & Lavie, 2005). Notably, the cognitive impairments of OSAS are complicated by various comorbidities, including aging, genetic factors, level of hypoxemia, EDS, neurological and cerebrovascular diseases (Macey et al., 2008; Kim et al., 2011; Lal et al., 2012). A clinical syndrome characterized by impaired attention, working memory, vigilance and executive functions have been described in OSAS (Naismith et al., 2004; Wong et al., 2006), while language and global cognitive functioning tend to be relatively spared (Aloia et al., 2004). Recent studies have used functional and structural neuroimaging to delineate the brain areas a®ected in patients with OSAS with neurocognitive dysfunction. A common ¯nding in several of these studies is decreased hippocampal volume. Other a®ected brain areas include the frontal and parietal lobes of the brain, which show focal reductions in gray matter (Macey et al., 2008). Based on the imaging studies (Gale & Hopkins, 2004; Zimmerman et al., 2006; Macey et al., 2008; Lal et al., 2012), some areas involved in key cognitive functions including vigilant attention, memory and executive functions (prefrontal cortices, hippocampi and fronto-parietal areas, respectively) are shown to be a®ected in the course of chronic OSAS. Executive functions which are regulated by the prefrontal cortex in concert with the anterior cingulate and posterior parietal systems appear to be vulnerable to OSAS-induced chronic hypoxemia (Saunamaki & Jehkonen, 2007; Borges et al., 2013). Such changes however can be at least partially reversed following the proper use of CPAP (Huynh et al., 2014). This highlights the signi¯cance of early diagnosis and treatment of OSAS. The destabilized neurocognitive functions in OSAS may be related to alterations in both cortical and subcortical neural processing as shown in neuroimaging and

Cognitive Domain De¯nition

Test

Test Components

Degree A®ected by OSAS

Ability to maintain alertness for a prolonged period of time

Vigilance (sustained attention) SCPT

PVT

PVT: Subject presses a button when þ þ þþ a light appears randomly every few seconds for 5–10 min SCPT: Subject presses a button to avoid hitting obstacles that appear randomly in a two-lane street

(Tatemichi et al., 1990; Antonelli Incalzi et al., 2004; Minoguchi et al., 2007) (Moore & O'Kee®e, 1999; Desmond et al., 2000; Shirani et al., 2011) (Findley et al., 1995; Beebe et al., 2003; Naismith et al., 2004; Sforza et al., 2004)

(Wong et al., 2006; Redline et al., 2010)

References

Note: þ ¼ mild impairment, þþ ¼ moderate impairment, þ þ þ ¼ severe impairment, þ þ þþ ¼ very severe impairment, IQ: intelligence quotient, OSAS: Obstructive Sleep Apnea Syndrome, PVT: Psychomotor Vigilance Test, SCPT: Steer Clear Performance Test.

Ability for abstract thought, reasoning, and comprehension

Intelligence

No e®ect Wechsler adult Measures four index scores: verbal comprehension index, working intelligence memory index, perceptual reasonscale-revised ing index, processing speed index IQ tests þþþ Executive functioning Working memory, planning, problem Wisconsin card Measures the ability of set-shifting with a reported sensitivity to sorting test solving, inductive reasoning frontal lobe dysfunction (moving from a speci¯c observaNumber of digits a subject can absorb Digit span tion to a broad generalization), and recall in correct serial order deductive reasoning (moving from after hearing or seeing them generalizations to speci¯c outcomes) Motor functioning A learned sequence of movements Finger tapping Subject presses a switch repeatedly as þþ required to perform a task fast as possible with the index ¯nger.

Cognitive Domains

Table 1. Main cognitive domains studied in OSAS and the related testing batteries. Studies have revealed that sustained attention and executive functions are the typically a®ected cognitive domains in OSAS.

WITHSTANDING THE OSAS AT THE EXPENSE OF AROUSAL INSTABILITY. . . 175

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electrophysiological studies (Greneche et al., 2011; Zhang et al., 2011; Jones et al., 2014). With regard to the pathogenesis, the chronic OSA-induced hypoxia in the brain potentially trigger proin°ammatory cytokines release and promote neuroin°ammatory processes in the central nervous system (Gozal & Kheirandish, 2006; Aviles-Reyes et al., 2010). This in°ammation can result in microvascular alterations (Kim et al., 2006), changes in microglial morphology and function (Zhang et al., 2000), as well as functional dysregulations in brainstem structures including the nucleus tractus solitarius (NTS) and hypoglossal nucleus (Kaur et al., 2011). The in°ammation-induced dysfunction in such nuclei would cause dysfunction in genioglossus muscle and lead to upper airway collapse with subsequent hypoxia and respiratory microarousals (Boyd et al., 2004; Svanborg, 2005). These microarousals clearly impact sleep's micro- and macrostructures and give rise to arousal instability during sleep (Zucconi et al., 1995; Terzano et al., 1996; Sforza et al., 1999; Halasz et al., 2004). Such a physiological challenge further enhances in°ammation, and the resultant oxidative damage leads to gray matter volume decrease (Ferini-Strambi et al., 2013). As such, the hypoxia-induced neural stress and the consequent neuroin°ammatory processes may underpin the cognitive dysfunctions in OSAS. The NTS not only possesses an important role in sympathetic and parasympathetic functions, but also integrates several a®erents from amygdala and hypothalamus with the somatosensory, gustatory, respiratory and cardiovascular a®erents originated from central baroreceptor and chemoreceptor zones (Ricardo & Koh, 1978; Jean, 1991; Potts, 2002; Hu et al., 2013). Based on such a hypothesis, NTS dysfunction may play a central role in OSASrelated neuropathogenesis and the consequent neurocognitive decline. This framework uniquely connects proin°ammatory cytokines, reactive oxygen species and the resultant oxidative stress to impaired function of the NTS and hypoglossal nucleus. Sleep disordered breathing with its related hypoxia and hypoxemia is expected to contribute to neuroin°ammation and impairment in key physiological functions in the brain with potentially declined cognitive performance in a®licted subjects (Fig. 1). Why neurocognitive functions are impaired in OSAS and how neural in°ammation contributes as an underlying mechanism has not been clearly experimentalized. The suggested paradigm is a hypothesis to test in this regard. Elderly subjects with OSA are at increased risk for progressive cognitive decline with transformed mild cognitive impairment into Alzheimer's disease (Buratti et al., 2014). Results from a recent study indicated that continued and long-term CPAP treatment in elderly OSA patients may halt or slow down cognitive deterioration and cause sustainable improvements in sleep and mood (Cooke et al., 2009; Buratti et al., 2014). Moreover, neuroimaging studies performed during cognitive testing have provided insight into CPAP's e®ect on the function of neuroanatomical circuits in the brain (Ferini-Strambi et al., 2013). Prospective randomized controlled trials are anyway required to further substantiate this e®ect in larger populations. In contrary to some reports suggesting potential positive e®ects of CPAP on cognitive


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Fig. 1. The proposed pathogenesis of OSA-related neurocognitive decline. The augmented neuroin°ammatory processes negatively a®ect the neuronal, glial and vascular endothelial cells (Kim et al., 2006; Zhang et al., 2000). The intermittent hypoxia and related oxidative challenge results in the NTS and hypoglossal nucleus in°ammation and dysfunction (Kaur et al., 2011). This would cause diminished genioglossal tonicity and results in pharyngeal collapse (Boyd et al., 2004; Svanborg, 2005). Snoring, apneas and resultant hypoxia will then arise. Therefore, sleep apnea-induced neuroin°ammation is considered as a key contributor to neuronal degeneration and provoked cognitive dysfunctions (Daulatzai, 2012; Grigg-Damberger & Ralls, 2012). Note: NTS: Nucleus Tractus Solitarius, OSA: Obstructive Sleep Apnea.

performance, systematic approach to the literature reveals no consistent e®ect of CPAP use on cognitive performance (Berlowitz & Shafazand, 2013). The disparity in study results may be in part related to their variability in design and sampling methods. The use of stimulant medications such as moda¯nil and ramelteon is generally reported to yield positive e®ects on cognitive performance. However, it is believed that using stimulants would not necessarily ameliorate the natural course and underlying cause of the condition (Kielb et al., 2012). According to a recent investigation, cognition and disease-severity associations are age-dependent. Cognition and quality of life are dramatically di®erent between the subjects at high and low risk for OSAS during middle age and such di®erence becomes narrower after the age of 70 years (Addison-Brown et al., 2014). A recent study used electrophysiological measures to evaluate the impact of OSAS on cognitive domains such as attention, learning and memory in which neuropsychological tests including n-back and trail-making tests were simultaneously administered during evoked-related potential (ERP) recording. The study also used the mirror-drawing test to assess executive and ¯ne motor functions. Results demonstrated adverse e®ects of OSAS on attention and executive functions while memory was less a®ected (Gelir et al., 2014). The consequences of cognitive lapses due to OSAS is detrimental and may result in devastating accidents in tasks which require vigilance and sustained attention (Basoglu & Tasbakan, 2014). The potential mechanisms proposed to explain cognitive dysfunction in OSAS and possible neural circuits involved in di®erent regions of the brain mainly prefrontal cortex and limbic structures should be better explored during the course of OSAS and the use of standard treatment (Kielb et al., 2012). Employing typical cognitive neuroscience techniques such as high-density quantitative electroencephalography (HD-QEEG) (Farabi et al., 2014), ERPs (Peng et al., 2004) and real-time functional

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imaging such as functional magnetic resonance imaging (fMRI) (Prilipko et al., 2014) may provide useful data on some neuropathological aspects of OSAS. When cognitive insu±ciencies remain despite a seemingly adequate CPAP therapy, above insights would assist investigators and clinicians to design and deliver individualized and tailored neurocognitive rehabilitation interventions. Rehabilitation programs for residual cognitive impairments may include cognitive-behavioral therapy, neurofeedback, transcranial direct current stimulation (tDCS) of the cerebral cortex or repetitive transcranial magnetic stimulation (rTMS) (Kilpinen et al., 2014). 4. OSAS and Sleep Microstructure Sleep EEG provides not only macrostructural information for sleep stages including non-rapid-eye movement (NREM) sleep (N1, N2, N3), rapid-eye movement (REM) sleep and wake stages, but also microstructural features referred to as CAPs (Simor et al., 2013). CAPs are periodic EEG activities which translate to sustained arousal instability oscillating between a greater and lesser arousal levels labeled as phase A and phase B, respectively (Mariani et al., 2012). Although CAPs are generated as physiological cerebral rhythms in response to the external stimuli, they are essentially endogenous (Parrino et al., 2012). The intrinsic CAPs root in spontaneously generated slow (< 1 Hz) periodic EEG at decasecond oscillation patterns which are functionally correlated to long-lasting arousal instability (Mariani et al., 2011). These cycling alternative oscillations are also shown to be related to motor control and regulation of autonomic mechanisms during the repetitive nocturnal apneas (Thomas et al., 2004). Since CAPs provide insight into the complexities of arousal organization in sleep, one can expect that CAP features and their source localization di®er in OSA patients as compared to controls (Terzano et al., 1996; Thomas et al., 2004). The arousal instability during sleep can become frequently evident following repetitive nocturnal apneas as well as post-event cortical activation represented by the abundance of CAPs (Mariani et al., 2011). Both A and B phases of CAPs are signi¯cantly a®ected in OSAS as compared to control subjects (Thomas et al., 2004). A vast majority of respiratory pauses both in REM and NREM phases of nocturnal sleep are shown to be coupled with CAPs (Terzano et al., 1996). CAP-related respiratory pauses are seen in close temporal connection with a phase B whereas the subsequent e®ective breathing always recovers during phase A (Mariani et al., 2012). As such, phase B of CAP is shown to o®er a critical background for upper airway collapse during which biochemical and neural mechanisms of respiratory drive control are activated (Terzano et al., 1996). In fact, this is not only the issue with OSAS, and the periodicity of EEG arousals can also be recognized during other short physiological rhythms of 20–40s such as periodic leg movements during sleep (PLMS) (Parrino et al., 1996). Furthermore, CAP abundance can be forced in sleep, irrespective of any concurrent disordered breathing. The physiologic CAPs may alter under perturbed conditions including


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internal (insomnia, depression, epilepsy, periodic limb movements, circadian constraints) or external (noise, ambient temperature) sources of disturbance (Terzano et al., 1988). There remain some unanswered questions with respect to CAPs in OSAS including: 1- How can arousal instability be measured by means of CAP parameters in OSAS? 2- Is the altered CAP abundance associated with cognitive consequences of OSAS? and 3- Could source localization of CAPs in sleep disorders including OSAS explain the extent of neurocognitive consequences in speci¯c domains? 5. Using the Neural Networks with Sleep Data in OSAS Subjects Before pursuing qualitative and quantitative analyses on the sleep EEG signals in patients with OSAS, a profound understanding of normal sleep is necessary. Based on some previous reports, neural network methods are considered as bene¯cial approaches towards visualization, clustering and classi¯cation of sleep EEG data in normal sleep and sleep-related pathologies including OSAS (Schaltenbrand et al., 1993; Sinha, 2003, 2008; Aksahin et al., 2012). According to earlier ¯ndings (Zucconi et al., 1995; Aksahin et al., 2012; Jones et al., 2014; Fietze et al., 2015; Zhou et al., 2015), OSAS su®erers have sleep EEG of same characteristics as normal subjects, while the number of rapid transitions from sleep to wakefulness in OSAS patients is signi¯cantly higher. This can be proportional to the distorted pattern of CAP signals in OSAS (Thomas et al., 2004; Parrino et al., 2005). Quantitative analysis on sleep EEG in OSAS subjects using preprocessing, autoregressive analysis, K-means algorithms and multilayer perceptron (MLP) networks will be expected to provide useful data based on which one would be able to follow the abrupt transitions in the sleep EEG of OSAS patients (Teferra et al., 2014; Ventouras et al., 2014; Zhou et al., 2015). The current qualitative analysis performed on the sleep EEG of OSAS patients includes fast Fourier transform (FFT) of the signals using the in-built Matrix Laboratory (Mathworks, Inc.) software in polysomnography (PSG) setups. Patients with OSAS who tend to have AHI of more than 15–20 demonstrate frequent respiratory-microarousals concurrently occurred with respiratory events and associated with signi¯cant O2 desaturations. To perform brain mapping (using quantitative EEG) during sleep, clinically suspected patients for OSAS would undergo standard overnight PSG while sleep EEG is the focus of analysis for this purpose. During the PSG test, following data are simultaneously recorded to a software and later scored and analyzed by a sleep specialist: EEG (F3A2, F4-A1, C3-A2, C4-A1, O1-A2 and O1-A2), electro-oculography (right and left), electromyography (submental), electromyography (right and left anterior tibialis), breathing e®ort (chest and abdomen), air intake (mouth/nose air °ow), snoring sounds, oxygen saturation, plethysmogram, electrocardiography, heart rate and sleeping position (Ruehland et al., 2011). Upon data analysis, FFT is usually employed to isolate possible fast frequency intrusions into di®erent sleep stages. When these fast frequency intrusions

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Fig. 2. (Color online) Brain mapping which represents respiratory-related microarousals. This short segment of sleep EEG is extracted from full-night PSG test in a patient with OSAS, showing a typical microarousal in stage 2 of NREM sleep (N2). The color-coded brain mapping images in the right panel are the QEEG maps using FFT to isolate beta-frequency intrusions during NREM sleep. Hot colors represent fast frequencies intruded into NREM sleep resulting in micro-arousals concurrently occurred with an apnea event. In NREM sleep, the EEG is generally dominated by alpha activity which is often interpreted as light sleep by the neural network. The left panel shows a 19-second EEG segment and the corresponding output during a microarousal event in this patient. The start and end of the event, as marked by an expert polysomnography scorer, are shown by vertical dashed lines. The wakefulness minus deep-sleep output [P(W)–P(S)] is approaching 1 (wakefulness) in many instances during the microarousal event (the red box). Note: FFT: Fast Fourier Transform, NREM: Non-rapid-eye movement sleep, PSG: polysomnography, QEEG: quantitative electroencephalography. Source: Sleep Disorders Laboratory, Namazi Hospital, Shiraz University of Medical Sciences.

(which represent microarousals) are associated with respiratory pauses and subsequent desaturations in O2, the events are referred to as respiratory-related microarousals. A typical respiratory-related microarousal in a patient with OSAS, with its corresponding QEEG color-coded brain maps, is illustrated in Fig. 2. 6. Altered Cerebral Vasoreactivity and DCA in OSAS Cerebral autoregulation during wakefulness is shown to be a®ected in patients with OSAS (Nasr et al., 2009). This clearly demonstrated the correlation between impaired cerebral autoregulation and the severity index of nocturnal apneas and hypopneas has suggested that patients with severe OSAS are subject to pronounced CBFV alterations (Urbano et al., 2008; Nasr et al., 2009). Cerebral autoregulation can be evaluated via the assessment of transiently altered cerebral blood °ow (CBF) which follow spontaneous changes in arterial blood pressure (ABP) in few seconds (Nasr et al., 2009). Owing to high temporal resolution, transcranial Doppler (TCD) together with continuous blood pressure monitoring is considered as a noninvasive investigation of


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Fig. 3. An interface of sleep microstructure (CAPs), impaired DCA and cognitive functions in OSAS. Solid and dashed lines indicate strong and weak body of evidence for the proposed interrelations, respectively. Colored lines indicate standard therapy with possibly expected outcomes. Black lines link the potentially inter-related aspects of pathophysiology in OSAS. Moderate to severe OSAS with frequent O2 desaturations during sleep possibly alters the cortical neurons' electrophysiology resulting in periodic EEG activity which underlie sustained arousal instability. The arousal instability oscillates between a greater and lesser arousal levels characterized as phases A and B of CAPs, respectively. Whether altered CAPs or impaired DCA in wakefulness, or both, contribute to impaired neurocognitive compromise in OSAS patients in unclear. Association studies would assist de¯ning correlation between neurocognitive pro¯le and patients' performance score in various domains of their cognitive function in relation to CAPs as well as TCD indices such as CBFV and ABP. Well-designed prospective studies are required to determine whether standard treatment i.e., CPAP can improve such impaired indices. Note: OSAS: Obstructive Sleep Apnea Syndrome, EEG: electroencephalography, CAPs: Cyclic Alternating Patterns, TCD: Transcranial Doppler, CBFV: Cerebral Blood Flow Velocity, ABP: Arterial Blood Pressure, CPAP: Continuous Positive Airway Pressure, Mx: Mean °ow velocity index, COX: Cerebral Oximetry Index.

cerebral autoregulatory changes (Lal et al., 2012). Determining the mean velocity index (Mx) with continuous analysis of spontaneous alterations in ABP and CBFV would yield a clear image in this respect (Nasr et al., 2009). The cerebral oximetry index (COx Þ is yet another key variable. Cerebral autoregulation is impaired as Mx and COx approach 1. Whereas, functional autoregulation is observed when Mx and COx approach zero indicating no correlation between the CBF and the mean arterial pressure. The mean Mx value of above 0.5 shown in earlier studies, indicates an impaired cerebral autoregulation in OSAS patients as compared to controls (Urbano et al., 2008). Studies attempting to ¯nd correlation between the extent of sleep apneas and impaired dynamic cerebral autoregulation (DCA) need to carefully consider confounding factors (including carotid stenosis or occlusion as well as history of cerebrovascular disease) which may °aw autoregulation assessment (Angarita-Jaimes et al., 2014). To avoid interference with patients' sleep, DCA measurements should

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apparently be done during daytime wakefulness. Although this assessment is remote from CO2 retention episodes, which took place during sleep apneas, a persistent impact will be possibly noted during wakefulness (Urbano et al., 2008; Nasr et al., 2009; Tsivgoulis & Alexandrov, 2009). While earlier studies have observed an OSA-related DCA impairment during wakefulness, the body of evidence on cerebral autoregulation impairment in OSAS patients is scant. Some reports have also introduced parallel variations in ABP and CBFV during or instantly after the obstructive sleep apnea events (Klingelhofer et al., 1992; Urbano et al., 2008). One possible reason for these changes may be the concurrent hypercapnia which profoundly a®ect DCA (Nasr et al., 2009; Tsivgoulis et al., 2009). There are emerging research ¯ndings to indicate impaired cerebral vasoreactivity to CO2 in OSAS patients (Furtner et al., 2009; Virtanen et al., 2012; Schytz et al., 2013). Awake OSAS patients with normal end-tidal PCO2 have demonstrated intrinsic DCA impairments. Furthermore, literature suggests that both cerebrovascular chemoregulation and mechanoregulation are notably a®ected in patients with OSAS (Virtanen et al., 2012; Schytz et al., 2013). OSAS patients are at increased risk for stroke (Koehler et al., 2014; Li et al., 2014). The elevated risk of cerebrovascular events in OSAS is attributed to the impaired DCA, subsequent vulnerability to ABP drops and cerebral ischemia, as well as surges in ABP and excessive °ow in cerebral vessels which results in capillary endothelial injuries (Li et al., 2014). Cerebral autoregulation is drastically impaired following stroke (Li et al., 2014). On the other hand, the impaired DCA may also result in a less favorable neurological outcome in stroke patients who are found to have sleep apneic episodes (Davis et al., 2013; Li et al., 2014). 7. Basic and Clinical Neuroscience of Altered Cerebral Autoregulation, Arousal Instability and Neurocognitive Decline in OSAS Cerebral autoregulation is maintaining CBF in a constant range in a wide range of the blood pressure or intracranial pressure over a period of time. Cerebral autoregulation is accomplished by metabolic, neurogenic or myogenic mechanism. In metabolic mechanism, the increased PaCO2 and decreased PaO2 is shown to result in cerebral vasodilation. Neural networks such as alpha- and beta-adrenergic, muscarinic and histaminergic systems are contributing to the control of the cerebrovascular resistance (Basner, 2014; Yadollahikhales et al., 2014). Further investigations on the pathogenesis of OSAS from neuroscience prospective are needed to explain what neural circuits, metabolic, molecular and cellular pathways are potentially involved. One key issue is to explain what mechanisms are involved in neurocognitive compromise of OSAS su®erers during wakefulness. Along these lines, the role of neuroin°ammatory mediators such as proin°ammatry cytokines (including IL1, IL6, IL10 and tumor necrosis factor


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alpha or TNF-alpha), reactive oxygen species and the resultant oxidative stress leading to neuroprogression should be taken into account in related studies (Imagawa et al., 2004; Gozal et al., 2010; De Luca Canto et al., 2015). As discussed, neuropsychological functions are a®ected following OSAS. On the other hand, decreased levels of antioxidants have been observed in these patients. To what extent the imbalance between antioxidants and pro-oxidants contribute to the °awed neuropsychological performance in this patient population, is yet to be de¯ned (Sales et al., 2013). In summary, there appears to be a potential link between frequent oxygen desaturations during sleep, arousal instability, altered DCA and cognitive insu±ciencies in OSAS. Identifying the interface of these parameters not only provides a better understanding of basic mechanisms involved in the brain-related consequences of OSAS, but also helps consolidating a proposed model for follow up evaluation in response to the established and investigational treatments (Fig. 3). 8. Concluding Remarks There are emerging evidence suggesting that the proper and timely diagnosis and treatment of OSAS may potentially ameliorate its cardiovascular, cerebrovascular and neurocognitive consequences and improve patients' functionality and health-related quality of life (Ferini-Strambi et al., 2013; Chirinos et al., 2014). Weight loss, sleep hygiene, mandibular advancement devices and compliant use of CPAP are shown to be e±cient preventive and therapeutic measures (TorabiNami, 2011; Alpher & Klein, 2013; Li et al., 2013; Milano et al., 2013). In addition some recent approaches such as upper airway- and hypoglossal-nerve stimulation are found to provide bene¯cial outcome in treating OSAS (Malhotra, 2014; Strollo et al., 2014). Large size cross-sectional studies and well-powered prospective investigations are needed to screen high-risk patients for OSA using the validated questionnaires, and to con¯rm the diagnosis in clinically suspected OSA subjects using full PSG, and also to assess di®erent aspects of treatment e±cacy and safety. Secondly, association analyzes among the severity index of OSA based on AHI, sleep marco- and microstructural features (i.e., hypnogram and CAPs), DCA (using TCD) and neurocognitive functions are needed to demystify controversial aspects of neurological and psychological burden of OSA. Using the neural networks with sleep data in OSAS subjects is expected to provide useful data in this regard. Considering the lack of concordance of the clinical research ¯ndings to date, studies in the same vein should further inform whether four weeks of CPAP therapy results in improvement of neurocognitive functions in patients who show cognitive decline upon baseline evaluation. A comprehensive knowledge on domains of cognitive dysfunction in patients who may demonstrate persistent or at least residual cognitive lapses despite CPAP therapy, would allow designing individual cognitive rehabilitation plans in OSAS.

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