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Study Objectives: Patients with obstructive sleep apnea (OSA) show brain injury in sites responsible for autonomic, cognitive, and respiratory functions. Brain changes in OSA may vary with disease severity as assessed by the apnea-hypopnea index (AHI), which does not provide information about the apnea depth and length in contrast to oxygen desaturation. Although significant associations with brain injury and AHI are known in OSA, it is unclear whether AHI or the extent of oxygen desaturations better correlate with brain damage. We evaluated associations between brain changes, AHI, and oxygen desaturation using diffusion tensor imaging-based measures., Methods: We acquired diffusion tensor imaging data from 19 patients with OSA using a 3.0-Tesla MRI scanner and calculated, normalized, and smoothed mean, axial, and radial diffusivity maps that were used for correlations between brain changes, oxygen desaturation, and AHI values., Results: Positive correlations with extent of injury (mean, axial, and radial diffusivity values) and AHI appeared in the frontal areas, cingulate and insula, amygdala, hippocampus, and basal pons, and negative associations emerged in the putamen, internal-capsule, globus-pallidus, and cerebellar cortices. Regional diffusivity values and oxygen desaturation showed positive correlations in the cingulate, frontal, putamen, and cerebellar sites, and negative relationships in several areas, including the occipital cortex., Conclusions: Patients with OSA show negative and positive correlations, indicated by increased and decreased diffusivity values, resulting from chronic and acute changes in those areas. The extent of injury in OSA partially depends on the extent of AHI and oxygen desaturation, with the effects representing continued development from acute to chronic processes., Citation: Sahib A, Roy B, Kang D, Aysola RS, Wen E, Kumar R. Relationships between brain tissue damage, oxygen desaturation, and disease severity in obstructive sleep apnea evaluated by diffusion tensor imaging. J Clin Sleep Med . 2022;18(12):2713-2721., (© 2022 American Academy of Sleep Medicine.)

Background: Obstructive sleep apnea (OSA) is accompanied by both gray and white matter differences in brain areas that regulate autonomic, cognitive, and mood functions, which are deficient in the condition. Such tissue changes have been examined through diffusion tensor and diffusion kurtosis imaging-based procedures. However, poor in-plane spatial resolution of these techniques precludes precise determination of the extent of tissue injury. Tissue texture maps derived from the ratio of T1-weighted and T2-weighted images can provide more adequate in-plane assessment of brain tissue differences., Objectives: To examine brain tissue integrity in recently diagnosed, treatment-naïve OSA subjects, relative to age- and sex-comparable control subjects using T1-weighted and T2-weighted images., Design: A cross-sectional study., Methods: We examined the extent of tissue changes in 106 OSA over 115 control subjects using high-resolution T1- and T2-weighted images collected from a 3.0-Tesla scanner (analysis of covariance; covariates: age, sex, body-mass-index, Pittsburgh sleep quality index, Epworth sleepiness scale, Beck Anxiety Inventory, and Beck Depression Inventory II; false discovery rate corrected; p  < 0.01)., Results: OSA subjects showed significantly lowered tissue integrity in several brain regions, including the frontal, cingulate and insular cortices, cingulum bundle, thalamus, corpus callosum, caudate and putamen, pons, temporal, occipital, and parietal sites, cerebellar peduncles, and medial medullary sites, compared with controls., Conclusion: OSA subjects show widespread lowered tissue integrity in autonomic, mood, and cognitive control sites over healthy controls. The pathological processes contributing to the alterations may include repetitive hypoxic and hypercarbic processes and excitotoxic injury, leading to altered brain tissue integrity in OSA., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Study Objectives: Obstructive sleep apnea (OSA) is accompanied by sleep fragmentation and altered sleep architecture, which can potentially hinder the glymphatic system, increasing risks for Alzheimer's disease (AD), but the status is unclear in OSA. Our aim was to investigate the glymphatic system in OSA subjects and examine the relationships between OSA disease severity, sleep symptoms, and glymphatic system indices in OSA using diffusion tensor imaging (DTI)., Methods: We acquired DTI data from 59 OSA and 62 controls using a 3.0-Tesla MRI and examined OSA disease severity and sleep symptoms with the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Diffusivity maps in the x -axis (D xx ), y -axis (D yy ), and z -axis (D zz ), as well as in x-y axis (D xy ), y-z axis (D yz ), and x-z axis (D xz ) were calculated, diffusion values for the projection and association fibers extracted, and the DTI analyses along the perivascular space (DTI-ALPS index) were performed. The glymphatic system indices were compared between groups and correlated with disease severity and sleep symptoms in OSA subjects., Results: D zz values, derived from projection fiber areas, D yy and D zz values from association fiber areas, as well as ALPS and D yzmean values were significantly reduced in OSA over controls. Significant correlations emerged between disease severity, sleep symptoms, and D xy , D xx , and D zz values in OSA subjects., Conclusion: OSA patients show abnormal glymphatic system function that may contribute to increased risks for AD. The findings suggest that the APLS method can be used to assess the glymphatic system in OSA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roy, Nunez, Aysola, Kang, Vacas and Kumar.)

Study Objectives: Obstructive sleep apnea (OSA) is defined by pauses in breathing during sleep, but daytime breathing dysregulation may also be present. Sleep may unmask breathing instability in OSA that is usually masked by behavioral influences during wakefulness. A breath-hold (BH) challenge has been used to demonstrate breathing instability. One measure of breathing stability is breathing rate variability (BRV). We aimed to assess BRV during rest and in response to BH in OSA., Methods: We studied 62 participants (31 with untreated OSA: respiratory event index [mean ± SD] 20 ± 15 events/h, 12 females, age 51 ± 14 years, body mass index [BMI] 32 ± 8 kg/m 2 ; 31 controls: 17 females, age 47 ± 13 years; BMI 26 ± 4 kg/m 2 ). Breathing movements were collected using a chest belt for 5 minutes of rest and during a BH protocol (60 seconds baseline, 30 seconds BH, 90 seconds recovery, 3 repeats). From the breathing movements, we calculated median breathing rate (BR) and interquartile BRV at rest. We calculated change in BRV during BH recovery from baseline. Group comparisons of OSA vs control were conducted using analysis of covariance with age, sex, and BMI as covariates., Results: We found 10% higher BRV in OSA vs controls ( P < .05) during rest. In response to BH, BRV increased 7% in OSA vs 1% in controls ( P < .001). Resting BR was not significantly different in OSA and controls, and sex and age did not have any significant interaction effects. BMI was associated with BR at rest ( P < .05) and change in BRV with BH ( P < .001), but no significant BMI-by-group interaction effect was observed., Conclusions: The findings suggest breathing instability as reflected by BRV is high in OSA during wakefulness, both at rest and in response to a stimulus. Breathing instability together with high blood pressure variability in OSA may reflect a compromised cardiorespiratory consequence in OSA during wakefulness., Citation: Pal A, Martinez F, Akey MA, et al. Breathing rate variability in obstructive sleep apnea during wakefulness. J Clin Sleep Med . 2022;18(3):825-833., (© 2022 American Academy of Sleep Medicine.)

Background: Inspiratory muscle training (IMT) may improve respiratory and cardiovascular functions in obstructive sleep apnea (OSA) and is a potential alternative or adjunct treatment to continuous positive airway pressure (CPAP). IMT protocols were originally designed for athletes, however, we found some OSA patients could not perform the exercise, so we aimed for a more OSA-friendly protocol. Our feasibility criteria included (1) participants successfully managing the technique at home; (2) participants completing daily practice sessions and recording data logs; and (3) capturing performance plateaus to determine an optimal length of the intervention. Methods: Five sedentary OSA patients participated in this feasibility study (three men, mean age = 61.6 years, SD = 10.2). Using a digital POWERbreathe K4 or K5 device, participants performed 30 daily inhalations against a resistance set at a percentage of maximum, recalculated weekly. Participants were willing to perform one but not two daily practice sessions. Intervention parameters from common IMT protocols were adapted according to ability and subjective feedback. Some were unable to perform the typically used 75% of maximum inspiratory resistance so we lowered the target to 65%. The technique required some practice; therefore, we introduced a practice week with a 50% target. After an initial 8 weeks, the intervention was open-ended and training continued until all participants demonstrated at least one plateau of inspiratory strength (2 weeks without strength gain). Weekly email and phone reminders ensured that participants completed all daily sessions and logged data in their online surveys. Weekly measures of inspiratory resistance, strength, volume, and flow were recorded. Results: Participants successfully completed the practice and subsequent 65% IMT resistance targets daily for 13 weeks. Inspiratory strength gains showed plateaus in all subjects by the end of 10 weeks of training, suggesting 12 weeks plus practice would be sufficient to achieve and capture maximum gains. Participants reported no adverse effects. Conclusion: We developed and tested a 13-week IMT protocol in a small group of sedentary, untreated OSA patients. Relative to other IMT protocols, we successfully implemented reduced performance requirements, a practice week, and an extended timeframe. This feasibility study provides the basis for a protocol for clinical trials on IMT in OSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Krause-Sorio, An, Aguila, Martinez, Aysola and Macey.)

People with obstructive sleep apnea (OSA) often have psychological symptoms including depression and anxiety, which are commonly treated with anti-depression or anti-anxiety interventions. Psychological stress is a related symptom with different intervention targets that may also improve mental state, but this symptom is not well characterized in OSA. We therefore aimed to describe stress in relation to other psychological symptoms. We performed a prospective cross-sectional study of 103 people, 44 untreated OSA (mean ± s.d. age: 51.2 ± 13.9 years, female/male 13/31) and 57 healthy control participants (age: 46.3 ± 13.8 years, female/male 34/23). We measured stress (Perceived Stress Scale; PSS), excessive daytime sleepiness (Epworth Sleepiness Scale; ESS), depressive symptoms (Patient Health Questionnaire; PHQ-9), and anxiety symptoms (General Anxiety Disorder; GAD-7). We compared group means with independent samples t-tests and calculated correlations between variables. Mean symptom levels were higher in OSA than control, including PSS (mean ± s.d.: OSA = 15.3 ± 6.9, control = 11.4 ± 5.5; P = 0.002), GAD-7 (OSA = 4.8 ± 5.0, control = 2.1 ± 3.9; P = 0.02), PHQ-9 (OSA = 6.9 ± 6.1, control = 2.6 ± 3.8; P = 0.003) and ESS (OSA = 8.1 ± 5.3, control = 5.0 ± 3.3; P = 0.03). Similar OSA-vs-control differences appeared in males, but females only showed significant differences in PHQ-9 and ESS, not PSS or GAD-7. PSS correlated strongly with GAD-7 and PHQ-9 across groups (R = 0.62-0.89), and moderately with ESS. Perceived stress is high in OSA, and closely related to anxiety and depressive symptoms. The findings support testing stress reduction in OSA.

Objectives: Obstructive sleep apnoea (OSA) is a risk factor for hypertension (HTN), but the clinical progression of OSA to HTN is unclear. There are also sex differences in prevalence, screening and symptoms of OSA. Our objective was to estimate the time from OSA to HTN diagnoses in females and males., Design: Retrospective analysis of electronic health records (EHR) over 10 years (2006-2015 inclusive)., Setting: University of California Los Angeles (UCLA) Health System in Los Angeles, California, USA., Participants: 4848 patients: females n=2086, mean (SD) age=52.8 (13.2) years; males n=2762, age=53.8 (13.5) years. These patients were selected from 1.6 million with diagnoses in the EHR who met these criteria: diagnoses of OSA and HTN; in long-term care defined by ambulatory visits at least 1 year prior and 1 year subsequent to the first OSA diagnosis; no diagnosis of OSA or HTN at intake; and a sleep study performed at UCLA., Primary and Secondary Outcome Measures: The primary outcome measure in each patient was time from the first diagnosis of OSA to the first diagnosis of HTN (OSA to HTN days). Since HTN and OSA are progressive disorders, a secondary measure was the relationship between OSA to HTN time and age (OSA to HTN=β 1 ×Age+β 0 )., Results: The median (lower and upper quartiles) days from OSA to HTN were: all -532 (-1439, -3); females -610 (-1579, -42); and males -451 (-1358, 0). Older age in both sexes was associated with less time to a subsequent HTN diagnosis or more time from a prior HTN diagnosis (β 1 days/year: all -16.9, females -18.3, males -15.9)., Conclusions: HTN was on average diagnosed years prior to OSA, with a longer separation in females. Our findings are consistent with underscreening of OSA, more so in females than males. Undiagnosed OSA may delay treatment for the sleep disorder and perhaps affect the development and progression of HTN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objectives: Cardiovascular comorbidities in obstructive sleep apnea (OSA) are difficult to treat, perhaps due to autonomic dysfunction. We assessed beat-to-beat blood pressure (BP) variability (BPV) in OSA while considering other markers derived from electrocardiogram and continuous BP signals., Methods: We studied 66 participants (33 participants with OSA: respiratory event index [mean ± SEM]: 21.1 ± 2.7 events/h; 12 females, aged 51.5 ± 2.4 years; body mass index: 32.8 ± 1.4 kg/m²; 33 healthy controls: 20 females; aged 45.3 ± 2.4 years; body mass index: 26.3 ± 0.7 kg/m²). We collected 5-minute resting noninvasive beat-to-beat BP and electrocardiogram values. From BP, we derived systolic, diastolic, and mean BP values, and calculated variability as standard deviations (systolic BPV, diastolic BPV, BPV). We also calculated diastole-to-systole time (time to peak). From the electrocardiogram, we derived QRS markers and calculated heart rate and heart rate variability. We performed a multivariate analysis of variance based on sex and group (OSA vs control), with Bonferroni-corrected post hoc comparisons (P ≤ .05) between groups. We calculated correlations of BPV with biological variables., Results: Multivariate analysis of variance showed effects of diastolic BPV and BPV in OSA; post hoc comparisons revealed high diastolic BPV and BPV only in female participants with OSA vs controls. QRS duration was higher in OSA, with post hoc comparisons showing the effect only in males. BPV correlated positively with heart rate variability in controls but not in participants with OSA. BPV correlated positively with time to peak in females with OSA and OSA combined, whereas there was no BPV-time-to-peak correlation in healthy participants., Conclusions: The findings show sex-specific autonomic dysfunction reflected in beat-to-beat BP in OSA. The higher BPV may reflect poor baroreflex control or vascular damage in OSA, which are potential precursors to cardiovascular complications., (© 2021 American Academy of Sleep Medicine.)

Study Objectives: Brain regulation of autonomic function in obstructive sleep apnea (OSA) is disrupted in a sex-specific manner, including in the insula, which may contribute to several comorbidities. The insular gyri have anatomically distinct functions with respect to autonomic nervous system regulation; yet, OSA exerts little effect on the organization of insular gyral responses to sympathetic components of an autonomic challenge, the Valsalva. We further assessed neural responses of insular gyri in people with OSA to a static handgrip task, which principally involves parasympathetic withdrawal., Methods: We measured insular function with blood oxygen level dependent functional MRI. We studied 48 newly-diagnosed OSA (age mean±std:46.5±9 years; AHI±std:32.6±21.1 events/hour; 36 male) and 63 healthy (47.2±8.8 years;40 male) participants. Subjects performed four 16s handgrips (1 min intervals, 80% subjective maximum strength) during scanning. fMRI time trends from five insular gyri-anterior short (ASG); mid short (MSG); posterior short (PSG); anterior long (ALG); and posterior long (PLG)-were assessed for within-group responses and between-group differences with repeated measures ANOVA (p<0.05) in combined and separate female-male models; age and resting heart-rate (HR) influences were also assessed., Results: Females showed greater right anterior dominance at the ASG, but no differences emerged between OSA and controls in relation to functional organization of the insula in response to handgrip. Males showed greater left anterior dominance at the ASG, but there were also no differences between OSA and controls. The males showed a group difference between OSA and controls only in the ALG. OSA males had lower left activation at the ALG compared to control males. Responses were mostly influenced by HR and age; however, age did not impact the response for right anterior dominance in females., Conclusions: Insular gyri functional responses to handgrip differ in OSA vs controls in a sex-based manner, but only in laterality of one gyrus, suggesting anterior and right-side insular dominance during sympathetic activation but parasympathetic withdrawal is largely intact, despite morphologic injury to the overall structure., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Obstructive sleep apnea (OSA) patients show hippocampal-related autonomic and neurological symptoms, including impaired memory and depression, which differ by sex, and are mediated in distinct hippocampal subfields. Determining sites and extent of hippocampal sub-regional injury in OSA could reveal localized structural damage linked with OSA symptoms., Methods: High-resolution T1-weighted images were collected from 66 newly-diagnosed, untreated OSA (mean age ± SD: 46.3 ± 8.8 years; mean AHI ± SD: 34.1 ± 21.5 events/h;50 male) and 59 healthy age-matched control (46.8 ± 9.0 years;38 male) participants. We added age-matched controls with T1-weighted scans from two datasets (IXI, OASIS-MRI), for 979 controls total (426 male/46.5 ± 9.9 years). We segmented the hippocampus and analyzed surface structure with "FSL FIRST" software, scaling volumes for brain size, and evaluated group differences with ANCOVA (covariates: total-intracranial-volume, sex; P < .05, corrected)., Results: In OSA relative to controls, the hippocampus showed small areas larger volume bilaterally in CA1 (surface displacement ≤0.56 mm), subiculum, and uncus, and smaller volume in right posterior CA3/dentate (≥ - 0.23 mm). OSA vs. control males showed higher bilateral volume (≤0.61 mm) throughout CA1 and subiculum, extending to head and tail, with greater right-sided increases; lower bilateral volumes (≥ - 0.45 mm) appeared in mid- and posterior-CA3/dentate. OSA vs control females showed only right-sided effects, with increased CA1 and subiculum/uncus volumes (≤0.67 mm), and decreased posterior CA3/dentate volumes (≥ - 0.52 mm). Unlike males, OSA females showed volume decreases in the right hippocampus head and tail., Conclusions: The hippocampus shows lateralized and sex-specific, OSA-related regional volume differences, which may contribute to sex-related expression of symptoms in the sleep disorder. Volume increases suggest inflammation and glial activation, whereas volume decreases suggest long-lasting neuronal injury; both processes may contribute to dysfunction in OSA.

Introduction: Brain structural injury and metabolic deficits in the hippocampus and caudate nuclei may contribute to cognitive and emotional deficits found in obstructive sleep apnea (OSA) patients. If such contributions exist, resting-state interactions of these subcortical sites with cortical areas mediating affective symptoms and cognition should be disturbed. Our aim was to examine resting-state functional connectivity (FC) of the hippocampus and caudate to other brain areas in OSA relative to control subjects, and to relate these changes to mood and neuropsychological scores., Methods: We acquired resting-state functional magnetic resonance imaging (fMRI) data from 70 OSA and 89 healthy controls using a 3.0-Tesla magnetic resonance imaging scanner, and assessed psychological and behavioral functions, as well as sleep issues. After standard fMRI data preprocessing, FC maps were generated for bilateral hippocampi and caudate nuclei, and compared between groups (ANCOVA; covariates, age and gender)., Results: Obstructive sleep apnea subjects showed significantly higher levels of anxiety and depressive symptoms over healthy controls. In OSA subjects, the hippocampus showed disrupted FC with the thalamus, para-hippocampal gyrus, medial and superior temporal gyrus, insula, and posterior cingulate cortex. Left and right caudate nuclei showed impaired FC with the bilateral inferior frontal gyrus and right angular gyrus. In addition, altered limbic-striatal-cortical FC in OSA showed relationships with behavioral and neuropsychological variables., Conclusions: The compromised hippocampal-cortical FC in OSA may underlie depression and anxious mood levels in OSA, while impaired caudate-cortical FC may indicate deficits in reward processing and cognition. These findings provide insights into the neural mechanisms underlying the comorbidity of mood and cognitive deficits in OSA., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)