Sex-specific hippocampus volume changes in obstructive sleep apnea.

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 ±â€¯SD: 46.3 ±â€¯8.8 years; mean AHI ±â€¯SD: 34.1 ±â€¯21.5 events/h;50 male) and 59 healthy age-matched control (46.8 ±â€¯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 ±â€¯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.

Altered resting-state hippocampal and caudate functional networks in patients with obstructive sleep apnea.

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.

Epiglottis cross-sectional area and oropharyngeal airway length in male and female obstructive sleep apnea patients.

INTRODUCTION: Obstructive sleep apnea (OSA) is a male-predominant condition, characterized by repeated upper-airway collapse with continued diaphragmatic efforts during sleep, and is accompanied by severe physiological consequences. Multiple morphological aspects, including epiglottis cross-sectional area (CSA) and oropharyngeal airway length (OPAL), can contribute to airway collapsibility in the condition. This study focused on the effects of OSA severity, sex, and race on OPA dimensions. MATERIALS AND METHODS: Two high-resolution T1-weighted image series were collected from 40 mild-to-severe OSA subjects (age 46.9±9 years, body mass index 30.4±5.4 kg/m2, Apnea-Hypopnea Index score 32.8±22.5, 28 males) and 54 control subjects (47±9 years, 24.7±3.8 kg/m2, 32 males) using a 3 T magnetic resonance-imaging scanner. Caucasian, Asian, African-American, and "other" subjects constituted the study pool. Both image series were realigned and averaged, and reoriented to a common space. CSA and OPAL were measured, normalized for subject height, and compared between sexes and disease-severity levels in OSA and control subjects. RESULTS: Significantly reduced epiglottis CSA appeared only in severe OSA vs controls (P=0.009). OPAL increased significantly with OSA severity vs controls (mild, P=0.027; moderate, P<0.001; severe, P<0.001). OSA males showed increased CSA and greater OPAL than OSA females, which may underlie the increased proportion of affected males with higher apnea-hypopnea index scores. However, no significant differences appeared between CSA and OPAL measures for male and female controls, suggesting that airway morphology may not be the sole contributor for airway collapse. No ethnic or racial differences appeared for CSA or OPAL measures. CONCLUSION: Sex-based reductions in epiglottis CSA and increased OPAL in OSA subjects may enhance airway-collapse vulnerability, more so with greater disease severity, and partially underlie male vs female susceptibility to the sleep disorder.

Disrupted functional brain network organization in patients with obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) subjects show impaired autonomic, affective, executive, sensorimotor, and cognitive functions. Brain injury in OSA subjects appears in multiple sites regulating these functions, but the integrity of functional networks within the regulatory sites remains unclear. Our aim was to examine the functional interactions and the complex network organization of these interactions across the whole brain in OSA, using regional functional connectivity (FC) and brain network topological properties. METHODS: We collected resting-state functional magnetic resonance imaging (MRI) data, using a 3.0-Tesla MRI scanner, from 69 newly diagnosed, treatment-naïve, moderate-to-severe OSA (age, 48.3 ± 9.2 years; body mass index, 31 ± 6.2 kg/m(2); apnea-hypopnea index (AHI), 35.6 ± 23.3 events/h) and 82 control subjects (47.6 ± 9.1 years; body mass index, 25.1 ± 3.5 kg/m(2)). Data were analyzed to examine FC in OSA over controls as interregional correlations and brain network topological properties. RESULTS: Obstructive sleep apnea subjects showed significantly altered FC in the cerebellar, frontal, parietal, temporal, occipital, limbic, and basal ganglia regions (FDR, P < 0.05). Entire functional brain networks in OSA subjects showed significantly less efficient integration, and their regional topological properties of functional integration and specialization characteristics also showed declined trends in areas showing altered FC, an outcome which would interfere with brain network organization (P < 0.05; 10,000 permutations). Brain sites with abnormal topological properties in OSA showed significant relationships with AHI scores. CONCLUSIONS: Our findings suggest that the dysfunction extends to resting conditions, and the altered FC and impaired network organization may underlie the impaired responses in autonomic, cognitive, and sensorimotor functions. The outcomes likely result from the prominent structural changes in both axons and nuclear structures, which occur in the condition.

Aberrant Insular Functional Network Integrity in Patients with Obstructive Sleep Apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is accompanied by tissue injury to the insular cortices, areas that regulate autonomic pain, dyspnea, and mood, all of which are affected in the syndrome. Presumably, the dysregulation of insular-related functions are mediated by aberrant functional connections with other brain regions; however, the integrity of the functional connectivity (FC) to other sites is undescribed. Our aim was to examine resting-state FC of the insular cortices to other brain areas in OSA, relative to control subjects. METHODS: We collected resting-state functional magnetic resonance imaging (MRI) data from 67 newly diagnosed, treatment-naïve OSA and 75 control subjects using a 3.0-Tesla MRI scanner. After standard processing, data were analyzed for the left and right insular FC. RESULTS: OSA subjects showed complex aberrant insular FC to several brain regions, including frontal, parietal, cingulate, temporal, limbic, basal ganglia, thalamus, occipital, cerebellar, and brainstem regions. Areas of altered FC in OSA showed linear relationships with magnitudes of sleep related and neuropsychologic-related variables, whereas control subjects showed no such relationships with those measures. CONCLUSIONS: Brain functional connections from insular sites to other brain regions in OSA subjects represent abnormal autonomic, affective, sensorimotor, and cognitive control networks that may affect both impaired parasympathetic and sympathetic interactions, as well as abnormal sensorimotor integration, affected in the condition. The functional changes likely result from the previously reported structural changes in OSA subjects, as demonstrated by diverse neuroimaging studies.

Abnormal myelin and axonal integrity in recently diagnosed patients with obstructive sleep apnea.

STUDY OBJECTIVES: Patients with obstructive sleep apnea (OSA) show significant white matter injury; whether that injury represents myelin or axonal damage is unclear. The objective was to examine myelin and axonal changes in patients with newly diagnosed OSA over control subjects. DESIGN: Cross-sectional study. SETTING: University-based medical center. PARTICIPANTS: Twenty-three newly-diagnosed, treatment-naïve OSA and 23 age- and sex-matched control subjects. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Radial and axial diffusivity maps, calculated from diffusion tensor imaging data (3.0 Tesla MRI scanner), indicating diffusion perpendicular (myelin status) or parallel (axonal status) to fibers, respectively, were normalized, smoothed, and compared between groups (analysis of covariance; covariate: age). Global brain radial and axial diffusivity values, and global brain volume with myelin and axonal changes were determined, and region-of-interest analyses performed in areas of significant differences between groups based on voxel-based procedures. Global radial and axial diffusivity values were significantly reduced in OSA versus control subjects (radial, P = 0.004; axial, P = 0.019), with radial (myelin) diffusivity reduced more than axial (axonal), and more left-sided reduction for both measures. Localized declines for myelin and axonal measures appeared in the dorsal and ventral medulla, cerebellar cortex and deep nuclei, basal ganglia, hippocampus, amygdala, corpus callosum, insula, cingulate and medial frontal cortices, and other cortical areas (P < 0.005), all regions mediating functions affected in OSA. CONCLUSIONS: Fiber injury appears in critical medullary respiratory regulatory sites, as well as cognitive and autonomic control areas. Myelin is more affected in newly diagnosed OSA than axons, and primarily on the left side, possibly from the increased myelin sensitivity to hypoxia and asymmetric perfusion.

Insular cortex metabolite changes in obstructive sleep apnea.

STUDY OBJECTIVE: Adults with obstructive sleep apnea (OSA) show significant autonomic and neuropsychologic deficits, which may derive from damage to insular regions that serve those functions. The aim was to assess glial and neuronal status from anterior insular metabolites in OSA versus controls, using proton magnetic resonance spectroscopy (PMRS), and thus to provide insights for neuroprotection against tissue changes, and to reduce injury consequences. DESIGN: Cross-sectional study. SETTING: University-based medical center. PARTICIPANTS: Thirty-six patients with OSA, 53 controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We performed PMRS in bilateral anterior insulae using a 3.0-Tesla magnetic resonance imaging scanner, calculated N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), myo-inositol/creatine (MI/Cr), and MI/NAA metabolite ratios, and examined daytime sleepiness (Epworth Sleepiness Scale, ESS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), and neuropsychologic status (Beck Depression Inventory II [BDI-II] and Beck Anxiety Inventory [BAI]). Body mass index, BAI, BDI-II, PSQI, and ESS significantly differed between groups. NAA/ Cr ratios were significantly reduced bilaterally, and left-sided MI/Cr and MI/NAA ratios were increased in OSA over controls. Significant positive correlations emerged between left insular MI/Cr ratios and apnea-hypopnea index values, right insular Cho/Cr ratios and BDI-II and BAI scores, and negative correlations appeared between left insular NAA/Cr ratios and PSQI scores and between right-side MI/Cr ratios and baseline and nadir change in O2 saturation. CONCLUSIONS: Adults with obstructive sleep apnea showed bilaterally reduced N-acetylaspartate and left-side increased myo-inositol anterior insular metabolites, indicating neuronal damage and increased glial activation, respectively, which may contribute to abnormal autonomic and neuropsychologic functions in the condition. The activated glial status likely indicates increased inflammatory action that may induce more neuronal injury, and suggests separate approaches for glial and neuronal protection.

Brain putamen volume changes in newly-diagnosed patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by cognitive, motor, autonomic, learning, and affective abnormalities. The putamen serves several of these functions, especially motor and autonomic behaviors, but whether global and specific sub-regions of that structure are damaged is unclear. We assessed global and regional putamen volumes in 43 recently-diagnosed, treatment-naïve OSA (age, 46.4 ± 8.8 years; 31 male) and 61 control subjects (47.6 ± 8.8 years; 39 male) using high-resolution T1-weighted images collected with a 3.0-Tesla MRI scanner. Global putamen volumes were calculated, and group differences evaluated with independent samples t-tests, as well as with analysis of covariance (covariates; age, gender, and total intracranial volume). Regional differences between groups were visualized with 3D surface morphometry-based group ratio maps. OSA subjects showed significantly higher global putamen volumes, relative to controls. Regional analyses showed putamen areas with increased and decreased tissue volumes in OSA relative to control subjects, including increases in caudal, mid-dorsal, mid-ventral portions, and ventral regions, while areas with decreased volumes appeared in rostral, mid-dorsal, medial-caudal, and mid-ventral sites. Global putamen volumes were significantly higher in the OSA subjects, but local sites showed both higher and lower volumes. The appearance of localized volume alterations points to differential hypoxic or perfusion action on glia and other tissues within the structure, and may reflect a stage in progression of injury in these newly-diagnosed patients toward the overall volume loss found in patients with chronic OSA. The regional changes may underlie some of the specific deficits in motor, autonomic, and neuropsychologic functions in OSA.

Heart rate responses to autonomic challenges in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by structural alterations and dysfunction in central autonomic regulatory regions, which may impair dynamic and static cardiovascular regulation, and contribute to other syndrome pathologies. Characterizing cardiovascular responses to autonomic challenges may provide insights into central nervous system impairments, including contributions by sex, since structural alterations are enhanced in OSA females over males. The objective was to assess heart rate responses in OSA versus healthy control subjects to autonomic challenges, and, separately, characterize female and male patterns. We studied 94 subjects, including 37 newly-diagnosed, untreated OSA patients (6 female, age mean ± std: 52.1 ± 8.1 years; 31 male aged 54.3 ± 8.4 years), and 57 healthy control subjects (20 female, 50.5 ± 8.1 years; 37 male, 45.6 ± 9.2 years). We measured instantaneous heart rate with pulse oximetry during cold pressor, hand grip, and Valsalva maneuver challenges. All challenges elicited significant heart rate differences between OSA and control groups during and after challenges (repeated measures ANOVA, p<0.05). In post-hoc analyses, OSA females showed greater impairments than OSA males, which included: for cold pressor, lower initial increase (OSA vs. control: 9.5 vs. 7.3 bpm in females, 7.6 vs. 3.7 bpm in males), OSA delay to initial peak (2.5 s females/0.9 s males), slower mid-challenge rate-of-increase (OSA vs. control: -0.11 vs. 0.09 bpm/s in females, 0.03 vs. 0.06 bpm/s in males); for hand grip, lower initial peak (OSA vs. control: 2.6 vs. 4.6 bpm in females, 5.3 vs. 6.0 bpm in males); for Valsalva maneuver, lower Valsalva ratio (OSA vs. control: 1.14 vs. 1.30 in females, 1.29 vs. 1.34 in males), and OSA delay during phase II (0.68 s females/1.31 s males). Heart rate responses showed lower amplitude, delayed onset, and slower rate changes in OSA patients over healthy controls, and impairments may be more pronounced in females. The dysfunctions may reflect central injury in the syndrome, and suggest autonomic deficiencies that may contribute to further tissue and functional pathologies.

Sex differences in white matter alterations accompanying obstructive sleep apnea.

STUDY OBJECTIVES: Females with obstructive sleep apnea (OSA) show different psychological and physiological symptoms from males, which may be associated with sex-related variations in neural injury occurring with the disorder. To determine whether male- or female-specific brain injury is present in OSA, we assessed influences of sex on white matter changes in the condition. DESIGN: Two-group factorial. SETTING: University medical center. PATIENTS OR PARTICIPANTS: 80 subjects total, with newly diagnosed, untreated OSA groups of 10 female (age mean ± SE: 52.6 ± 2.4 years, AHI 22.5 ± 4.1 events/h) and 20 male (age 48.9 ± 1.7, AHI 25.5 ± 2.9) patients, and 20 female (age 50.3 ± 1.7) and 30 male (age 49.2 ± 1.4) healthy control subjects. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Brain fiber integrity was assessed with fractional anisotropy (FA), a diffusion tensor imaging-derived measure. Sleep quality, daytime sleepiness, depression, and anxiety were assessed with questionnaires. We identified regions of differing injury in male versus female OSA patients by assessing brain regions with significant interaction effects of OSA and sex on FA. Areas of sex-specific, OSA-related FA reductions appeared in females relative to males, including in the bilateral cingulum bundle adjacent to the mid hippocampus, right stria terminalis near the amygdala, prefrontal and posterior-parietal white matter, corpus callosum, and left superior cerebellar peduncle. Females with OSA showed higher daytime sleepiness, anxiety and depression levels, and reduced sleep quality. CONCLUSIONS: Sex differences in white matter structural integrity appeared in OSA patients, with females more affected than males. These female-specific structural changes may contribute to or derive from neuropsychological and physiological symptom differences between sexes.

Altered global and regional brain mean diffusivity in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common and progressive disorder accompanied by severe cardiovascular and neuropsychological sequelae, presumably induced by brain injury resulting from the intermittent hypoxia and cardiovascular processes accompanying the syndrome. However, whether the predominant brain tissue pathology is acute or chronic in newly-diagnosed, untreated OSA subjects is unclear; this assessment is essential for revealing pathological processes. Diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures can detect and differentiate acute from chronic pathology and may be useful to reveal processes in the condition. We collected four DTI series from 23 newly-diagnosed, treatment-naïve OSA and 23 control subjects, using a 3.0-Tesla magnetic resonance imaging scanner. Mean diffusivity maps were calculated from each series, realigned, averaged, normalized to a common space, and smoothed. Global brain MD values for each subject were calculated using normalized MD maps and a global brain mask. Mean global brain MD values and smoothed MD maps were compared between groups by using analysis of covariance (covariate: age). Mean global brain MD values were significantly reduced in OSA compared with controls (P = 0.01). Multiple brain sites in OSA, including medullary, cerebellar, basal ganglia, prefrontal and frontal, limbic, insular, cingulum bundle, external capsule, corpus callosum, temporal, occipital, and corona radiata regions showed reduced regional MD values compared with controls. The results suggest that global brain MD values are significantly reduced in OSA, with certain regional sites especially affected, presumably a consequence of axonal, glial, and other cell changes in those areas. The findings likely represent acute pathological processes in newly-diagnosed OSA subjects.

Neural alterations associated with anxiety symptoms in obstructive sleep apnea syndrome.

BACKGROUND: Neuropsychological comorbidities, including anxiety symptoms, accompany obstructive sleep apnea (OSA); structural and functional brain alterations also occur in the syndrome. The objective was to determine whether OSA patients expressing anxiety symptoms show injury in specific brain sites. METHODS: Magnetic resonance T2-relaxometry was performed in 46 OSA and 66 control subjects. Anxiety symptoms were evaluated using the Beck Anxiety Inventory (BAI); subjects with BAI scores >9 were classified anxious. Whole brain T2-relaxation maps were compared between anxious and nonanxious groups using analysis of covariance (covariates, age and gender). RESULTS: Sixteen OSA and seven control subjects showed anxiety symptoms, and 30 OSA and 59 controls were nonanxious. Significantly higher T2-relaxation values, indicating tissue injury, appeared in anxious OSA versus nonanxious OSA subjects in subgenu, anterior, and mid-cingulate, ventral medial prefrontal and bilateral insular cortices, hippocampus extending to amygdala and temporal, and bilateral parietal cortices. Brain injury emerged in anxious OSA versus nonanxious controls in bilateral insular cortices, caudate nuclei, anterior fornix, anterior thalamus, internal capsule, mid-hippocampus, dorsotemporal, dorsofrontal, ventral medial prefrontal, and parietal cortices. CONCLUSIONS: Anxious OSA subjects showed injury in brain areas regulating emotion, with several regions lying outside structures affected by OSA alone, suggesting additional injurious processes in anxious OSA subjects.

Neural alterations and depressive symptoms in obstructive sleep apnea patients.

STUDY OBJECTIVES: Depressive symptoms are common in obstructive sleep apnea (OSA) patients, and brain injury occurs with both OSA and depression independently. The objective was to determine whether brain alterations in OSA bear relationships to depressive symptoms. DESIGN: Cross-sectional study. SETTING: University-based medical center. PARTICIPANTS: 40 treatment-naive OSA subjects and 61 control subjects without diagnosed psychopathology. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Whole-brain maps of T2 relaxation time, a measure sensitive to injury, were calculated from magnetic resonance images, transformed to common space, and smoothed. Control and OSA groups were classified by Beck Depression Inventory (BDI)-II scores (> or =12 symptomatic, <10 asymptomatic for depressive symptoms). The OSA group separated into 13 symptomatic (mean +/- SD: BDI-II 21 +/- 8; age 47.6 +/- 11; apnea hypopnea index [AHI] 28.3 +/- 17), and 27 asymptomatic (4 +/- 3; 47.5 +/- 8; 31.5 +/- 16) subjects. The control group included 56 asymptomatic (BDI-II 2.5 +/- 2.6; age 47.3 +/- 9) subjects. Asymptomatic OSA subjects exhibited higher AHI. T2 maps were compared between groups (ANCOVA), with age and gender as covariates. Injury appeared in symptomatic vs asymptomatic OSA subjects in the mid- and anterior cingulate, anterior insular, medial pre-frontal, parietal, and left ventrolateral temporal cortices, left caudate nucleus, and internal capsule. Relative to asymptomatic controls, symptomatic OSA patients showed damage in the bilateral hippocampus and caudate nuclei, anterior corpus callosum, right anterior thalamus, and medial pons. CONCLUSIONS: Neural injury differed between OSA patients with and without depressive symptoms. Depressive symptoms may exacerbate injury accompanying OSA, or introduce additional damage in affective, cognitive, respiratory, and autonomic control regions.

Brain structural changes in obstructive sleep apnea.

STUDY OBJECTIVES: Determine whether obstructive sleep apnea (OSA) subjects show indications of axonal injury. DESIGN: We assessed fiber integrity in OSA and control subjects with diffusion tensor imaging (DTI). We acquired four whole-brain DTI series from each subject. The four series were realigned, and the diffusion tensor calculated at each voxel. Fractional anisotropy (FA), a measure of fiber integrity, was derived from the diffusion tensor, resulting in a whole brain FA "map." The FA maps were spatially normalized, smoothed, and compared using voxel-based statistics to determine differences between OSA and control groups, with age as a covariate (P < 0.05, corrected for multiple comparisons). SETTING: University medical center. SUBJECTS: We studied 41 patients with untreated OSA (mean age +/- SD: 46.3 +/- 8.9 years; female/male: 7/34) with apnea-hypopnea index 15 to 101 (mean +/- SD: 35.7 +/- 18.1 events/hour), and 69 control subjects (mean age +/- SD: 47.5 +/- 8.79 years; female/male: 25/44). MEASUREMENTS AND RESULTS: Multiple regions of lower FA appeared within white matter in the OSA group, and included fibers of the anterior corpus callosum, anterior and posterior cingulate cortex and cingulum bundle, right column of the fornix, portions of the frontal, ventral prefrontal, parietal and insular cortices, bilateral internal capsule, left cerebral peduncle, middle cerebellar peduncle and corticospinal tract, and deep cerebellar nuclei. CONCLUSIONS: White matter is extensively affected in OSA patients; the alterations include axons linking major structures within the limbic system, pons, frontal, temporal and parietal cortices, and projections to and from the cerebellum.

Reduced mammillary body volume in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) patients show compromised emotional and cognitive functions, including anterograde memory deficits. While some memory inadequacies in OSA may result from earlier-described structural deficits in the hippocampus, mammillary body injury also could contribute, since these structures receive projections from the hippocampus via the fornix, project heavily to the anterior thalamus, and have been implicated in other conditions with memory deficiencies, such as Korsakoff's syndrome. However, volume loss in mammillary bodies has not been reported in OSA, likely a consequence of logistic difficulties in size assessment. We evaluated mammillary body volumes in 43 OSA (mean age+/-S.D., 46.9+/-9.2 years; mean apnea-hypopnea-index+/-S.D., 31.2+/-19.9 events/h) and 66 control subjects (age, 47.3+/-8.9 years). Two high-resolution T1-weighted image volumes were collected on a 3.0 T magnetic resonance scanner, averaged to improve signal-to-noise, and reoriented (without warping) into a common space. Brain sections containing both mammillary bodies were oversampled, and the bodies were manually traced and volumes calculated. OSA patients showed significantly reduced left, right, and combined mammillary body volumes compared with control subjects, after partitioning for age, gender, and head size (multivariate linear model, p<0.05). Left-side mammillary bodies showed greater volume reduction than the right side. Diminished mammillary body volume in OSA patients may be associated with memory and spatial orientation deficits found in the syndrome. The mechanisms contributing to the volume loss are unclear, but may relate to hypoxic/ischemic processes, possibly assisted by nutritional deficiencies in the syndrome.

Regional brain response patterns to Cheyne-Stokes breathing.

Cheyne-Stokes breathing (CSB) results from impaired integration of sensory information with respiratory motor output; however, regions mediating the disturbed control are unknown. We examined functional magnetic resonance imaging signals during CSB within sleep to determine affected areas. Two male patients with severe obstructive sleep apnea were scanned while asleep over multiple sessions during which they exhibited CSB. Significant signal increases coincident with apneic periods emerged bilaterally in the cerebellar cortex, hippocampus, mediodorsal thalamus, frontal cortex and precentral gyrus. Signals declined bilaterally in the anterior cingulate cortex and postcentral gyrus. The reduced activation in primary sensory cortex and increased signals prior to breathing onset in the motor cortex are consistent with loss of sensory stimulation by airflow, and with anticipatory action of the motor cortex prior to initiation of breathing. Hippocampal and anterior cingulate cortex participation likely reflect previously-demonstrated roles for initiating inspiratory efforts and resolving sensory information and motor action, respectively.

fMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects.

Obstructive sleep apnea (OSA) patients exhibit altered sympathetic outflow, which may reveal mechanisms underlying the syndrome. We used functional MRI (fMRI) in 16 control and 10 OSA subjects who were free of cardiovascular or mood-altering drugs to examine neural responses to a forehead cold pressor challenge, which elicits respiratory slowing, bradycardia, and enhanced sympathetic outflow. The magnitude of cold-induced bradycardia was smaller, and respiratory slowing showed greater intersubject variability and reached a nadir later in OSA patients. Both groups showed similar signal changes to cold stimulation in multiple brain sites. However, signal increases emerged in OSA over controls in anterior and posterior cingulate and cerebellar and frontal cortex, whereas signals markedly declined in the ventral thalamus, hippocampus, and insula rather than rising as in controls. Anomalous responses often paralleled changes in breathing and heart rate. Medullary, midbrain areas and lentiform and cerebellar dentate nuclei also showed lower signals in OSA cases. Cold pressor physiological responses are modified in OSA and may result from both diminished and exaggerated responses in multiple brain structures.

Brain responses associated with the Valsalva maneuver revealed by functional magnetic resonance imaging.

The Valsalva maneuver, a test frequently used to evaluate autonomic function, recruits discrete neural sites. The time courses of neural recruitment relative to accompanying cardiovascular and breathing patterns are unknown. We examined functional magnetic resonance imaging signal changes within the brain to repeated Valsalva maneuvers and correlated these changes with physiological trends. In 12 healthy subjects (age, 30-58 yr), a series of 25 volumes (20 gradient echo echo-planar image slices per volume) was collected using a 1.5-Tesla scanner during a 60-s baseline and 90-s challenge period consisting of three Valsalva maneuvers. Regions of interest were examined for signal intensity changes over baseline and challenge conditions in cardiorespiratory-related regions. In addition, whole brain correlations between signal intensity and heart rate and airway load pressure were performed on a voxel-by-voxel basis. Significant signal changes, correlated with the time course of load pressure and heart rate, emerged within multiple areas, including the amygdala and hippocampus, insular and lateral frontal cortices, dorsal pons, dorsal medulla, lentiform nucleus, and fastigial and dentate nuclei of the cerebellum. Signal intensities peaked early in the Valsalva maneuver within the hippocampus and amygdala, later within the dorsal medulla, pons and midbrain, and deep cerebellar nuclei, and last within the lentiform nuclei and the lateral prefrontal cortex. The ventral pontine signals increased during the challenge, but not in a fashion correlated to load pressure or heart rate. Sites showing little or no correlation included the vermis and medial prefrontal cortex. These data suggest an initiating component arising in rostral brain areas, a later contribution from cerebellar nuclei, basal ganglia, and lateral prefrontal cortex, and a role for the ventral pons in mediating longer term processes.

Brain morphology associated with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by repeated occurrences of hypoxic, hypercapnic, and transient blood pressure elevation episodes that may damage or alter neural structures. Underdeveloped structures or pre-existing damage in brain areas may also contribute to the genesis of the syndrome. Brain morphology in 21 patients with OSA and in 21 control subjects was assessed using high-resolution T1-weighted magnetic resonance imaging. Three-dimensional brain images were obtained with voxels of approximately 1 mm3. Images were spatially normalized and segmented into gray matter, white matter, and cerebrospinal fluid. For each segment, regional volumetric differences were determined relative to age, handedness, and group (patients with OSA versus control subjects), using voxel-based morphometry, with OSA effects weighted by disease severity. A significant age effect on total gray matter was found in control subjects but not in patients with OSA. Diminished regional and often unilateral gray matter loss was apparent in multiple sites of the brain in patients with OSA, including the frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum. Unilateral loss in well-perfused structures suggests onset of neural deficits early in the OSA syndrome. The gray matter loss occurs within sites involved in motor regulation of the upper airway as well as in areas contributing to cognitive function.