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ObjectivesObstructive 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.DesignRetrospective analysis of electronic health records (EHR) over 10 years (2006-2015 inclusive).SettingUniversity of California Los Angeles (UCLA) Health System in Los Angeles, California, USA.Participants4848 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 measuresThe 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=β1×Age+β0).ResultsThe 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 (β1 days/year: all -16.9, females -18.3, males -15.9).ConclusionsHTN 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.

Obstructive sleep apnea (OSA) patients show impaired autonomic regulation, perhaps related to functional reorganization of the insula, which in healthy individuals shows sex-specific anterior and right dominance during sympathetic activation. We examined insular organization of responses to a Valsalva maneuver in OSA with functional magnetic resonance imaging (fMRI). We studied 43 newly diagnosed OSA (age mean ± SD: 46.8 ± 8.7 years; apnea-hypopnea index (AHI) ± SD: 32.1 ± 20.1 events/hour; 34 males) and 63 healthy (47.2 ± 8.8 years; 40 males) participants. Participants performed four 18-second Valsalva maneuvers (1-minute intervals, pressure ≥ 30 mmHg) 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); age and resting heart rate (HR) influences were also assessed. Right and anterior fMRI signal dominance appeared in OSA and controls, with no between-group differences. Separation by sex revealed group differences. Left ASG anterior signal dominance was lower in OSA versus control males. Left ASG and ALG anterior dominance was higher in OSA versus control females. In all right gyri, only OSA females showed greater anterior dominance than controls. Right dominance was apparent in PSG and ALG in all groups; females showed right dominance in MSG and PLG. OSA males did not show PLG right dominance. Responses were influenced substantially by HR but modestly by age. Anterior and right insular fMRI dominance appears similar in OSA versus control participants during the sympathetic phase of the Valsalva maneuver. OSA and control similarities were present in just males, but not necessarily females, which may reflect sex-specific neural injury.

Study objectivesBrain 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.MethodsWe 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

ObjectiveTo determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures.MethodsWe prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO2), and ECG for 49 patients (49 seizures) enrolled in a multicenter study of sudden unexpected death in epilepsy (SUDEP). Postictal and interictal venous blood samples were collected after a clinical seizure for measurement of serum 5-HT levels. Seizures were classified according to the International League Against Epilepsy 2017 seizure classification. We analyzed seizures with and without ICA (n = 49) and generalized convulsive seizures (GCS) with and without PCCA (n = 27).ResultsPostictal serum 5-HT levels were increased over interictal levels for seizures without ICA (p = 0.01), compared to seizures with ICA (p = 0.21). In patients with GCS without PCCA, serum 5-HT levels were increased postictally compared to interictal levels (p < 0.001), but not in patients with seizures with PCCA (p = 0.22). Postictal minus interictal 5-HT levels also differed between the 2 groups with and without PCCA (p = 0.03). Increased heart rate was accompanied by increased serum 5-HT levels (postictal minus interictal) after seizures without PCCA (p = 0.03) compared to those with PCCA (p = 0.42).ConclusionsThe data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study.

ObjectiveIctal (ICA) and postconvulsive central apnea (PCCA) have been implicated in sudden unexpected death in epilepsy (SUDEP) pathomechanisms. Previous studies suggest that serotonin reuptake inhibitors (SRIs) and benzodiazepines (BZDs) may influence breathing. The aim of this study was to investigate if chronic use of these drugs alters central apnea occurrence in patients with epilepsy.MethodsPatients with epilepsy admitted to epilepsy monitoring units (EMUs) in nine centers participating in a SUDEP study were consented. Polygraphic physiological parameters were analyzed, including video-electroencephalography (VEEG), thoracoabdominal excursions, and pulse oximetry. Outpatient medication details were collected. Patients and seizures were divided into SRI, BZD, and control (no SRI or BZD) groups. Ictal central apnea and PCCA, hypoxemia, and electroclinical features were assessed for each group.ResultsFour hundred and seventy-six seizures were analyzed (204 patients). The relative risk (RR) for ICA in the SRI group was half that of the control group (p = 0.02). In the BZD group, ICA duration was significantly shorter than in the control group (p = 0.02), as was postictal generalized EEG suppression (PGES) duration (p = 0.021). Both SRI and BZD groups were associated with smaller seizure-associated oxygen desaturation (p = 0.009; p ≪ 0.001). Neither presence nor duration of PCCA was significantly associated with SRI or BZD (p ≫ 0.05).ConclusionsSeizures in patients taking SRIs have lower occurrence of ICA, and patients on chronic treatment with BZDs have shorter ICA and PGES durations. Preventing or shortening ICA duration by using SRIs and/or BZD in patients with epilepsy may play a possible role in SUDEP risk reduction.

ObjectiveThe processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.MethodsWe retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex.ResultsSubstantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging.SignificanceSUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

ObjectiveTo precisely identify cortical regions that modulate breathing, and delineate a network of cortical structures that underpin ictal central apnea (ICA) during epileptic seizures.MethodsWe electrically stimulated multiple cortical structures in patients undergoing stereotactic EEG (SEEG) evaluation before epilepsy surgery. Structures investigated were orbitofrontal cortex, anterior and posterior cingulate and subcallosal gyri, insula, hippocampus, parahippocampal gyrus, amygdala, temporo-polar cortex, antero-mesial fusiform gyrus, and lateral and basal temporal cortices. Chest/abdominal excursions using thoracic/abdominal belts, peripheral capillary oxygen saturation, end tidal and transcutaneous carbon dioxide, and airflow were continuously monitored.ResultsNineteen consecutive adult patients (10 female) aged 18-69 years were investigated. Transient central apnea was elicited in 13/19 patients with amygdala, hippocampus head and body, anterior parahippocampal gyrus, and antero-mesial fusiform gyrus. Insula, cingulate, subcallosal, orbitofrontal, lateral, and basal temporal cortices stimulation did not induce apnea. Apnea duration was associated with stimulus duration (p < 0.001) and current intensity (p = 0.004).ConclusionsThese findings suggest a limbic/paralimbic mesial temporal breathing modulation network that includes amygdala, hippocampus, anterior parahippocampal, and antero-mesial fusiform gyri. These structures likely represent anatomical and functional substrates for ICA, a putative sudden unexpected death in epilepsy (SUDEP) breathing biomarker. Damage to such areas is known to occur in high SUDEP risk patients and SUDEP victims, and may underpin the prolonged ICA that is thought to be particularly dangerous. Furthermore, inclusive targeting of apnea-producing structures in SEEG implantations, peri-ictal breathing signal recordings, and stringent analysis of apneic sequences in seizure semiology may enhance accurate identification of symptomatogenic and seizure onset zones for epilepsy surgery.

ObjectiveTo characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy.MethodsThis was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed.ResultsWe studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy; 65 had focal epilepsy; 1 had both; and the epileptogenic zone was unknown in 2. Ictal central apnea (ICA) preceded GCS in 49 of 121 (40.4%) seizures in 23 patients, all with focal epilepsy. Postconvulsive central apnea (PCCA) occurred in 31 of 140 (22.1%) seizures in 22 patients, with generalized, focal, or unknown epileptogenic zones. In 2 patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2 per 1,000 patient-years. One patient with PCCA died of probable SUDEP during follow-up, suggesting a SUDEP incidence rate 5.1 per 1,000 patient-years. No cases of laryngospasm were detected. Rhythmic muscle artifact synchronous with breathing was present in 75 of 147 seizures and related to stertorous breathing (odds ratio 3.856, 95% confidence interval 1.395-10.663, p = 0.009).ConclusionsPCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.

PurposeWe exposed premature infants to womb-like sounds to evaluate such exposure on breathing and cardiovascular patterns. We hypothesized that these sounds would reduce apnea and intermittent hypoxemia, enhance parasympathetic outflow, and improve cardiovascular patterns.MethodsA total of 20 cases and 5 control infants at ≤32-36 weeks corrected gestational age participated in a prospective observational cohort study. Twenty-four hours of continuous ECG, respiratory and oxygen saturation data were collected in all infants. Womb-like sounds were played intermittently in 6-hour blocks. Salivary samples were collected at study beginning and end for cortisol. Apnea, intermittent hypoxemia, and bradycardia were evaluated, and heart rate variability was assessed by time domain and spectral techniques.ResultsIntermittent hypoxemia and bradycardia significantly declined after sound exposure. No significant differences in apnea, cortisol levels, or heart rate variability were evident among the study infants.ConclusionsExposing premature infants to womb-like sounds has the potential to reduce hypoxemic and bradycardic events, and be used as an intervention to stabilize breathing and cardiac control in preterm infants.

Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study.

IntroductionBrain 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.MethodsWe 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).ResultsObstructive 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.ConclusionsThe 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.

OBJECTIVE:The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. METHODS:We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO2 ), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG. RESULTS:Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P

ObjectiveReducing environmental noise benefits premature infants in neonatal intensive care units (NICU), but excessive reduction may lead to sensory deprivation, compromising development. Instead of minimal noise levels, environments that mimic intrauterine soundscapes may facilitate infant development by providing a sound environment reflecting fetal life. This soundscape may support autonomic and emotional development in preterm infants. We aimed to assess the efficacy and feasibility of external non-invasive recordings in pregnant women, endeavoring to capture intra-abdominal or womb sounds during pregnancy with electronic stethoscopes and build a womb sound library to assess sound trends with gestational development. We also compared these sounds to popular commercial womb sounds marketed to new parents.Study designIntra-abdominal sounds from 50 mothers in their second and third trimester (13 to 40 weeks) of pregnancy were recorded for 6 minutes in a quiet clinic room with 4 electronic stethoscopes, placed in the right upper and lower quadrants, and left upper and lower quadrants of the abdomen. These recording were partitioned into 2-minute intervals in three different positions: standing, sitting and lying supine. Maternal and gestational age, Body Mass Index (BMI) and time since last meal were collected during recordings. Recordings were analyzed using long-term average spectral and waveform analysis, and compared to sounds from non-pregnant abdomens and commercially-marketed womb sounds selected for their availability, popularity, and claims they mimic the intrauterine environment.ResultsMaternal sounds shared certain common characteristics, but varied with gestational age. With fetal development, the maternal abdomen filtered high (500-5,000 Hz) and mid-frequency (100-500 Hz) energy bands, but no change appeared in contributions from low-frequency signals (10-100 Hz) with gestational age. Variation appeared between mothers, suggesting a resonant chamber role for intra-abdominal space. Compared to commercially-marketed sounds, womb signals were dominated by bowel sounds, were of lower frequency, and showed more variation in intensity.ConclusionsHigh-fidelity intra-abdominal or womb sounds during pregnancy can be recorded non-invasively. Recordings vary with gestational age, and show a predominance of low frequency noise and bowel sounds which are distinct from popular commercial products. Such recordings may be utilized to determine whether sounds influence preterm infant development in the NICU.

INTRODUCTION:Obstructive sleep apnea (OSA) affects approximately 10% of adults, and alters brain gray and white matter. Psychological and physiological symptoms of the disorder are sex-specific, perhaps related to greater injury occurs in female than male patients in white matter. Our objective was to identify influences of OSA separated by sex on cortical gray matter. METHODS:We assessed cortical thickness in 48 mild-severe OSA patients (mean age±std[range] = 46.5±9.0[30.8-62.7] years; apnea-hypopnea index = 32.6±21.1[6-102] events/hour; 12 female, 36 male; OSA severity: 5 mild, 18 moderate, 25 severe) and 62 controls (mean age = 47.7±8.9[30.9-65.8] years; 22 female, 40 male). All OSA patients were recently-diagnosed via polysomnography, and control subjects screened and a subset assessed with sleep studies. We used high-resolution magnetic resonance imaging to identify OSA-related cortical thinning, based on a model with condition and sex as independent variables. OSA and OSA-by-sex interaction effects were assessed (P

ObjectiveGeneralized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms.MethodsHigh-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P

IntroductionObstructive 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.MethodsHigh-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

BackgroundCardiovascular disease varies between sexes, suggesting male-female autonomic control differences. Insular gyri help coordinate autonomic regulation and show a sex-dependent response to a sympathetic challenge.MethodsWe examined sex-related insular gyral responses to a short static handgrip exercise challenge eliciting parasympathetic withdrawal with functional magnetic resonance imaging (fMRI) during four 16-s challenges (80% maximum strength) in 23 healthy females (age; mean ± std 50 ± 8 years) and 40 males (46 ± 9 years). Heart rate (HR) and fMRI signals were compared with repeated measures ANOVA (P

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

ObjectiveObstructive sleep apnea (OSA) is accompanied by brain changes in areas that regulate autonomic, cognitive, and mood functions, which were initially examined by Gaussian-based diffusion tensor imaging measures, but can be better assessed with non-Gaussian measures. We aimed to evaluate axonal and myelin changes in OSA using axial (AK) and radial kurtosis (RK) measures.Materials and methodsWe acquired diffusion kurtosis imaging data from 22 OSA and 26 controls; AK and RK maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance.ResultsIncreased AK, indicating axonal changes, emerged in the insula, hippocampus, amygdala, dorsolateral pons, and cerebellar peduncles and showed more axonal injury over previously identified damage. Higher RK, showing myelin changes, appeared in the hippocampus, amygdala, temporal and frontal lobes, insula, midline pons, and cerebellar peduncles and showed more widespread myelin damage over previously identified injury.ConclusionsAxial kurtosis and RK measures showed widespread changes over Gaussian-based techniques, suggesting a more sensitive nature of kurtoses to injury.

ObjectiveRipples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event.MethodsWe quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ).ResultsBoth the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05).SignificanceGeneration of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway blockage, with continued diaphragmatic efforts to breathe during sleep. Brain structural changes in OSA appear in various regions, including white matter sites that mediate autonomic, mood, cognitive, and respiratory control. However, the relationships between brain white matter changes and disease severity in OSA are unclear. This study examines associations between an index of tissue integrity, magnetization transfer (MT) ratio values (which show MT between free and proton pools associated with tissue membranes and macromolecules), and disease severity (apnea-hypopnea index [AHI]) in OSA subjects. We collected whole-brain MT imaging data from 19 newly diagnosed, treatment-naïve OSA subjects (50.4 ± 8.6 years of age, 13 males, AHI 39.7 ± 24.3 events/hr], using a 3.0-Tesla MRI scanner. With these data, whole-brain MT ratio maps were calculated, normalized to common space, smoothed, and correlated with AHI scores by using partial correlation analyses (covariates, age and gender; P < 0.005). Multiple brain sites in OSA subjects, including superior and inferior frontal regions, ventral medial prefrontal cortex and nearby white matter, midfrontal white matter, insula, cingulate and cingulum bundle, internal and external capsules, caudate nuclei and putamen, basal forebrain, hypothalamus, corpus callosum, and temporal regions, showed principally lateralized negative correlations (P < 0.005). These regions showed significant correlations even with correction for multiple comparisons (cluster-level, family-wise error, P < 0.05), except for a few superior frontal areas. Predominantly negative correlations emerged between local MT values and OSA disease severity, indicating potential usefulness of MT imaging for examining the OSA condition. These findings indicate that OSA severity plays a significant role in white matter injury. © 2016 Wiley Periodicals, Inc.

UnlabelledObstructive sleep apnea syndrome (OSAS) leads to neurocognitive and autonomic deficits that are partially mediated by thalamic and putamen pathology. We examined the underlying neurochemistry of those structures using compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (JRESI), and quantified values with prior knowledge fitting. Bilaterally increased thalamic mI/Cr, putamen Glx/Cr, and Glu/Cr, and bilaterally decreased thalamic and putamen tCho/Cr and GABA/Cr occurred in OSAS vs healthy subjects (p

The insular cortex is injured in obstructive sleep apnea (OSA) and responds inappropriately to autonomic challenges, suggesting neural reorganization. The objective of this study was to assess whether the neural changes might result from γ-aminobutyric acid (GABA) and glutamate alterations. We studied 14 OSA patients [mean age ± standard deviation (SD): 47.5 ± 10.5 years; nine male; apnea-hypopnea index (AHI): 29.5 ± 15.6 events h(-1) ] and 22 healthy participants (47.5 ± 10.1 years; 11 male), using magnetic resonance spectroscopy to detect GABA and glutamate levels in insular cortices. We localized the cortices with anatomical scans, and measured neurochemical levels from anterior to mid-regions. Left and right anterior insular cortices showed lower GABA and higher glutamate in OSA versus healthy subjects [GABA left: OSA n = 6: 0.36 ± 0.10 (mean ± SD), healthy n = 5: 0.62 ± 0.18; P

Study objectivesObstructive 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.MethodsWe 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.ResultsOSA 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.ConclusionsBrain 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.

IntroductionObstructive 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.MethodsWe 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.ResultsObstructive 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.ConclusionsOur 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.

BackgroundChildhood brain tumor survivors (CBTS) often experience treatment-related neurocognitive deficits affecting quality of life (QOL), but systemic chemotherapy contributions to outcomes are unclear. Our objective was to relate brain tissue changes to neurocognitive and QOL effects after systemic myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue in CBTS.ProcedureRegional brain volumes and diffusion tensor indices were correlated with neurocognitive, behavioral, and QOL measures, and compared between 8 CBTS (mean age 8.5 years, mean age at diagnosis 32 months), and 9 healthy controls (mean 9.3 years).ResultsOverall QOL, school, and psychosocial functioning were significantly lower in patients (P < .05). Most patients scored within normative ranges on neurocognitive and behavioral assessment. Elevated mean diffusivity and decreased fractional anisotropy, indicating gray and white matter injury, respectively, appeared in memory and executive functioning areas. Low scores on Inhibition on the Neuropsychological Assessment-II were correlated with elevated mean diffusivity in prefrontal cortex.ConclusionsBrain injury, decreased QOL, and to a lesser extent, executive functioning deficits appear in CBTS treated with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue. Early cognitive and psychological assessment and intervention are warranted in this population.

Study objectivesObstructive sleep apnea (OSA) patients show brain structural injury and functional deficits in autonomic, affective, and cognitive regulatory sites, as revealed by mean diffusivity (MD) and other imaging procedures. The time course and nature of gray and white matter injury can be revealed in more detail with mean kurtosis (MK) procedures, which can differentiate acute from chronic injury, and better show extent of damage over MD procedures. Our objective was to examine global and regional MK changes in newly diagnosed OSA, relative to control subjects.MethodsTwo diffusion kurtosis image series were collected from 22 recently-diagnosed, treatment-naïve OSA and 26 control subjects using a 3.0-Tesla MRI scanner. MK maps were generated, normalized to a common space, smoothed, and compared voxel-by-voxel between groups using analysis of covariance (covariates; age, sex).ResultsNo age or sex differences appeared, but body mass index, sleep, neuropsychologic, and cognitive scores significantly differed between groups. MK values were significantly increased globally in OSA over controls, and in multiple localized sites, including the basal forebrain, extending to the hypothalamus, hippocampus, thalamus, insular cortices, basal ganglia, limbic regions, cerebellar areas, parietal cortices, ventral temporal lobe, ventrolateral medulla, and midline pons. Multiple sites, including the insular cortices, ventrolateral medulla, and midline pons showed more injury over previously identified damage with MD procedures, with damage often lateralized.ConclusionsGlobal mean kurtosis values are significantly increased in obstructive sleep apnea (OSA), suggesting acute tissue injury, and these changes are principally localized in critical sites mediating deficient functions in the condition. The mechanisms for injury likely include altered perfusion and hypoxemia-induced processes, leading to acute tissue changes in recently diagnosed OSA.

Heart failure (HF) patients show brain injury in autonomic, affective, and cognitive sites, which can change resting-state functional connectivity (FC), potentially altering overall functional brain network organization. However, the status of such connectivity or functional organization is unknown in HF. Determination of that status was the aim here, and we examined region-to-region FC and brain network topological properties across the whole-brain in 27 HF patients compared to 53 controls with resting-state functional MRI procedures. Decreased FC in HF appeared between the caudate and cerebellar regions, olfactory and cerebellar sites, vermis and medial frontal regions, and precentral gyri and cerebellar areas. However, increased FC emerged between the middle frontal gyrus and sensorimotor areas, superior parietal gyrus and orbito/medial frontal regions, inferior temporal gyrus and lingual gyrus/cerebellar lobe/pallidum, fusiform gyrus and superior orbitofrontal gyrus and cerebellar sites, and within vermis and cerebellar areas; these connections were largely in the right hemisphere (p

BackgroundApnea of Prematurity (AOP) is common, affecting the majority of infants born at

Background and purposeObstructive sleep apnea (OSA) subjects show brain injury in sites that control autonomic, cognitive, and mood functions that are deficient in the condition. The processes contributing to injury may include altered blood-brain barrier (BBB) actions. Our aim was to examine BBB function, based on diffusion-weighted pseudo-continuous arterial spin labeling (DW-pCASL) procedures, in OSA compared to controls.MethodsWe performed DW-pCASL imaging in nine OSA and nine controls on a 3.0-Tesla MRI scanner. Global mean gray and white matter arterial transient time (ATT, an index of large artery integrity), water exchange rate across the BBB (Kw, BBB function), DW-pCASL ratio, and cerebral blood flow (CBF) values were compared between OSA and control subjects.ResultsGlobal mean gray and white matter ATT (OSA vs. controls; gray matter, 1.691 ± .120 vs. 1.658 ± .109 second, P = .49; white matter, 1.700 ± .115 vs. 1.650 ± .114 second, P = .44), and CBF values (gray matter, 57.4 ± 15.8 vs. 58.2 ± 10.7 ml/100 g/min, P = .67; white matter, 24.2 ± 7.0 vs. 24.6 ± 6.7 ml/100 g/min, P = .91) did not differ significantly, but global gray and white matter Kw (gray matter, 158.0 ± 28.9 vs. 220.8 ± 40.6 min(-1) , P = .002; white matter, 177.5 ± 57.2 vs. 261.1 ± 51.0 min(-1) , P = .006), and DW-pCASL ratio (gray matter, .727 ± .076 vs. .823 ± .069, P = .011; white matter, .722 ± .144 vs. .888 ± .100, P = .004) values were significantly reduced in OSA over controls.ConclusionsOSA subjects show compromised BBB function, but intact large artery integrity. The BBB alterations may introduce neural damage contributing to abnormal functions in OSA, and suggest a need to repair BBB function with strategies commonly used in other fields.

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies.

AimsHeart failure (HF) patients show cognitive and mood impairments, including short-term memory loss and depression, that have an adverse impacting on quality of life and self-care management. Brain regions, including the hippocampus, a structure significantly involved in memory and mood, show injury in HF, but the integrity of specific hippocampal subregions is unclear.Methods and resultsTo assess regional hippocampal volume loss, we evaluated 17 HF patients (mean age ± SD, 54.4 ± 2.0 years; 12 male, left ventricular ejection fraction 28.3 ± 6.8%; New York Heart Association class II/III 94%/6%) and 34 healthy control subjects (52.3 ± 1.3 years; 24 male) using high-resolution T1-weighted magnetic resonance imaging and evaluated localized surface changes with morphometric procedures. Hippocampi were manually outlined, and volumes calculated from normalized tracings. Volume differences between groups were assessed by two-sample t-tests, and regional differences were assessed by surface morphometry. Patients with HF exhibited smaller hippocampal volumes than controls (right 3060 ± 146 mm(3) vs. 3478 ± 94 mm(3), P = 0.02; left 3021 ± 145 mm(3) vs. 3352 ± 98 mm(3), P = 0.06). Volume reductions were detected principally in CA1, an area integral to an array of learning and memory functions, as well as in mid to posterior CA3 and subiculum.ConclusionThe hippocampus shows regional volume reduction in HF, which may contribute to short-term memory loss and depression associated with the condition.

Heart failure (HF) patients show gray and white matter changes in multiple brain sites, including autonomic and motor coordination areas. It is unclear whether the changes represent acute or chronic tissue pathology, a distinction necessary for understanding pathological processes that can be resolved with diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures. We collected four DTI series from 16 HF (age 55.1 ± 7.8 years, 12 male) and 26 control (49.7 ± 10.8 years, 17 male) subjects with a 3.0-Tesla magnetic resonance imaging scanner. MD maps were realigned, averaged, normalized, and smoothed. Global and regional MD values from autonomic and motor coordination sites were calculated by using normalized MD maps and brain masks; group MD values and whole-brain smoothed MD maps were compared by analysis of covariance (covariates; age and gender). Global brain MD (HF vs. controls, units × 10(-6) mm(2) /sec, 1103.8 ± 76.6 vs. 1035.9 ± 69.4, P = 0.038) and regional autonomic and motor control site values (left insula, 1,085.4 ± 95.7 vs. 975.7 ± 65.4, P = 0.001; right insula, 1,050.2 ± 100.6 vs. 965.7 ± 58.4, P = 0.004; left hypothalamus, 1,419.6 ± 165.2 vs. 1,234.9 ± 136.3, P = 0.002; right hypothalamus, 1,446.5 ± 178.8 vs. 1,273.3 ± 136.9, P = 0.004; left cerebellar cortex, 889.1 ± 81.9 vs. 796.6 ± 46.8, P

AimsAutonomic, cognitive, and neuropsychologic deficits appear in heart failure (HF) subjects, and these compromised functions depend on cerebral cortex integrity in addition to that of subcortical and brainstem sites. Impaired autoregulation, low cardiac output, sleep-disordered-breathing, hypertension, and diabetic conditions in HF offer considerable potential to affect cortical areas by loss of neurons and glia, which would be expressed as reduced cortical thicknesses. However, except for gross descriptions of cortical volume loss/injury, regional cortical thickness integrity in HF is unknown. Our goal was to assess regional cortical thicknesses across the brain in HF, compared to control subjects.Methods and resultsWe examined localized cortical thicknesses in 35 HF and 61 control subjects with high-resolution T1-weighted images (3.0-Tesla MRI) using FreeSurfer software, and assessed group differences with analysis-of-covariance (covariates; age, gender; p

Autonomic, pain, and neuropsychologic comorbidities appear in heart failure (HF), likely resulting from brain changes, indicated as loss of structural integrity and functional deficits. Among affected brain sites, the anterior insulae are prominent in serving major regulatory roles in many of the disrupted functions commonly seen in HF. Metabolite levels, including N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (MI), could indicate the nature of anterior insula tissue injury in HF. The study aim was to assess anterior insular metabolites to determine processes mediating autonomic, pain, and neuropsychologic disruptions in HF. We performed magnetic resonance spectroscopy in bilateral anterior insulae in 11 HF and 53 controls, using a 3.0-Tesla magnetic resonance imaging scanner. Peaks for NAA at 2.02 ppm, Cr at 3.02 ppm, Cho at 3.2 ppm, and MI at 3.56 ppm were assigned, peak areas were calculated, and metabolites were expressed as ratios, including NAA/Cr, Cho/Cr, and MI/Cr. HF patients showed significantly increased Cho/Cr ratios, indicative of glial proliferation or injury, on the left anterior insula, and reduced NAA/Cr levels, suggesting neuronal loss/dysfunction, on the right anterior insula over controls. No differences in MI/Cr ratios appeared between groups. Right anterior insular neuronal loss and left glial alterations may contribute to distorted autonomic, pain, and neuropsychologic functions found in HF.

Young children with brain tumors are often treated with high-dose chemotherapy after surgery to avoid brain tissue injury associated with irradiation. The effects of systemic chemotherapy on healthy brain tissue in this population, however, are unclear. Our objective was to compare gray and white matter integrity using MRI procedures in children with brain tumors (n = 7, mean age 8.3 years), treated with surgery and high-dose chemotherapy followed by autologous hematopoietic cell rescue (AuHCR) an average of 5.4 years earlier, to age- and gender-matched healthy controls (n = 9, mean age 9.3 years). Diffusion tensor imaging data were collected to evaluate tissue integrity throughout the brain, as measured by mean diffusivity (MD), a marker of glial, neuronal, and axonal status, and fractional anisotropy (FA), an index of axonal health. Individual MD and FA maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance, with age and sex as covariates. Higher MD values, indicative of injury, emerged in patients compared with controls (p < .05, corrected for multiple comparisons), and were especially apparent in the central thalamus, external capsule, putamen, globus pallidus and pons. Reduced FA values in some regions did not reach significance after correction for multiple comparisons. Children treated with surgery and high-dose chemotherapy with AuHCR for brain tumors an average of 5.4 years earlier show alterations in white and gray matter in multiple brain areas distant from the tumor site, raising the possibility for long-term consequences of the tumor or treatment.

BackgroundSignificant alterations in autonomic nervous system (ANS) function, vasomotor reactivity, and cerebral blood flow may develop from damage to brain ANS regulatory areas in heart failure (HF). This preferentially right-sided injury occurs largely in autonomic structures perfused by the middle cerebral artery. Indications of altered, asymmetrical perfusion raise the potential for further neural damage.ObjectiveTo determine whether the extent of middle cerebral artery blood flow velocity and vasomotor reactivity is altered on one side of the brain over the other in HF versus control subjects, three ANS challenges were administered-each challenge recruited ANS regulatory areas potentially injured in HF.MethodsTranscranial Doppler ultrasonography was used to measure cerebral blood flow velocity and vasomotor reactivity in 40 HF (mean age = 52.7 years, SD = 7.5; 27 men; left ventricular ejection fraction = 26.8, SD = 8.3) and 42 control subjects (mean age = 48.3 years, SD = 6.0; 22 men) during 5% CO2 and hyperventilation, Valsalva, and orthostatic (upper body tilt) challenges.ResultsLower cerebral blood flow velocity and abnormal vasomotor reactivity (p < .01) were noted in HF middle cerebral arteries during all challenges. More right-sided flow velocity reductions appeared in HF, with laterality differences noted during CO2 and orthostatic (p < .05), but not Valsalva challenges.DiscussionDiminished cerebral blood flow velocity and altered vasomotor reactivity were associated with HF, changes being preferentially on the right side; the asymmetry was more pronounced during CO2 and orthostatic challenges. The impaired blood flow regulation may contribute to the lateralized brain pathology in ANS areas, undermining autonomic control in HF.

Study objectiveAdults 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.DesignCross-sectional study.SettingUniversity-based medical center.ParticipantsThirty-six patients with OSA, 53 controls.InterventionsNone.Measurements and resultsWe 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.ConclusionsAdults 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.

Study objectivesPatients 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.DesignCross-sectional study.SettingUniversity-based medical center.ParticipantsTwenty-three newly-diagnosed, treatment-naïve OSA and 23 age- and sex-matched control subjects.InterventionsNone.Measurements and resultsRadial 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.ConclusionsFiber 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.

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.

Obstructive sleep apnea (OSA) is accompanied by brain injury, perhaps resulting from apnea-related hypoxia or periods of impaired cerebral perfusion. Perfusion changes can be determined indirectly by evaluation of cerebral blood volume and oxygenation alterations, which can be measured rapidly and non-invasively with the global blood oxygen level dependent (BOLD) signal, a magnetic resonance imaging procedure. We assessed acute BOLD responses in OSA subjects to pressor challenges that elicit cerebral blood flow changes, using a two-group comparative design with healthy subjects as a reference. We separately assessed female and male patterns, since OSA characteristics and brain injury differ between sexes. We studied 94 subjects, 37 with newly-diagnosed, untreated OSA (6 female (age mean ± std: 52.1±8.1 yrs; apnea/hypopnea index [AHI]: 27.7±15.6 events/hr and 31 male 54.3±8.4 yrs; AHI: 37.4±19.6 events/hr), and 20 female (age 50.5±8.1 yrs) and 37 male (age 45.6±9.2 yrs) healthy control subjects. We measured brain BOLD responses every 2 s while subjects underwent cold pressor, hand grip, and Valsalva maneuver challenges. The global BOLD signal rapidly changed after the first 2 s of each challenge, and differed in magnitude between groups to two challenges (cold pressor, hand grip), but not to the Valsalva maneuver (repeated measures ANOVA, p

Abnormal autonomic function is common in pediatric diseases. Assessment of central mechanisms underlying autonomic challenges may reveal vulnerabilities antecedent to system failure. Our objective was to characterize central markers and physiological responses to a cold pressor challenge in normal children as a critical step for establishing such screening. We performed functional magnetic resonance imaging (fMRI) and collected physiological measures during cold application to the foot in 24 healthy adolescents (15.5 ± 0.4 years, 13 male). The protocol included a 120-sec baseline, 120-sec right-foot cold water immersion (4°C), and 120-sec recovery. Analyses included heart rate (HR) cross-correlations with fMRI signals. Cold application increased HR 13% 5-7 sec after onset, which remained elevated throughout the challenge. Respiratory rate transiently increased (peak 22%), then declined (nadir 12% below baseline), before normalizing at 75 sec. Cold onset rapidly increased somatosensory cortex and medullary signals, which fell after 25 sec. Right anterior insular cortex signals increased early, followed after 20 sec by the left anterior insula, with HR declining 8 sec later. Amygdalae signals also rose, but signals declined in the posterior cingulate cortex, caudate nucleus, hippocampus, and hypothalamus. Declining signals appeared late in the cerebellar fastigial nuclei (60-120 sec), and in the pons and thalamus. Somatosensory cortex, fastigial nuclei, and hypothalamic responses were principally left-sided, with bilateral responses elsewhere. Late left anterior insula responses likely underlie the HR decline; the late cerebellar pattern may modulate recovery. The laterality, timing, and amplitude of normative responses and rostral response differentiation indicate the complex integration of adolescent autonomic processing and provide indices for pathological comparisons.

Obstructive sleep apnea (OSA) is a condition characterized by upper airway muscle atonia with continued diaphragmatic efforts, resulting in repeated airway obstructions, periods of intermittent hypoxia, large thoracic pressure changes, and substantial shifts in arterial pressure with breathing cessation and resumption. The hypoxic exposure and hemodynamic changes likely induce the structural and functional deficits found in multiple brain areas, as shown by magnetic resonance imaging (MRI) procedures. Altered cerebral blood flow (CBF) may contribute to these localized deficits; thus, we examined regional CBF, using arterial spin labeling procedures, in 11 OSA (age, 49.1±12.2 years; 7 male) and 16 control subjects (42.3±10.2 years; 6 male) with a 3.0-Tesla MRI scanner. CBF maps were calculated, normalized to a common space, and regional CBF values across the brain quantified. Lowered CBF values emerged near multiple bilateral brain sites in OSA, including the corticospinal tracts, superior cerebellar peduncles, and pontocerebellar fibers. Lateralized, decreased CBF appeared near the left inferior cerebellar peduncles, left tapetum, left dorsal fornix/stria terminalis, right medial lemniscus, right red nucleus, right midbrain, and midline pons. Regional CBF values in OSA are significantly reduced in major sensory and motor fiber systems and motor regulatory sites, especially in structures mediating motor coordination; those reductions are often lateralized. The asymmetric CBF declines in motor regulatory areas may contribute to loss of coordination between upper airway and diaphragmatic musculature, and lead to further damage in the syndrome.

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

IntroductionPatients with congenital central hypoventilation syndrome (CCHS) show brain injury in areas that control chemosensory, autonomic, motor, cognitive, and emotion functions, which are deficient in the condition. Many of these abnormal characteristics are present from the neonatal period; however, it is unclear whether tissue injury underlying the characteristics progressively worsens with time. We hypothesized that several brain areas in subjects with CCHS would show increased gray matter volume loss over time.MethodsWe collected high-resolution T1-weighted images twice (4 years apart) from seven subjects with CCHS (age at first study, 16.1 ± 2.7 years; four males) and three control subjects (15.9 ± 2.1 years; three males) using a 3.0-Tesla magnetic resonance imaging (MRI) scanner, and evaluated regional gray matter volume changes with voxel-based morphometry (VBM) procedures.ResultsMultiple brain sites in CCHS, including frontal, prefrontal, insular, and cingulate cortices; caudate nuclei and putamen; ventral temporal and parietal cortices; and cerebellar cortices showed significantly reduced gray matter volume over time. Only limited brain areas, including sensory, temporal, and medullary regions, emerged with increased gray matter at the later age.DiscussionPatients with CCHS show reduced gray matter volume with age progression in autonomic, respiratory, and cognitive regulatory areas, an outcome that may contribute to deterioration of functions found in the syndrome with increasing age.

Obstructive sleep apnea (OSA) occurs in at least 10% of the population, and leads to higher morbidity and mortality; however, relationships between OSA severity and sleep or psychological symptoms are unclear. Existing studies include samples with wide-ranging comorbidities, so we assessed relationships between severity of OSA and common sleep and psychological disturbances in recently diagnosed OSA patients with minimal co-morbidities. We studied 49 newly diagnosed, untreated OSA patients without major co-morbidities such as mental illness, cardiovascular disease, or stroke; subjects were not using psychoactive medications or tobacco (mean +/- std age: 46.8+/-9.1 years; apnea/hyponea index [AHI]: 32.1+/-20.5 events/hour; female/male: 12/37; weight

Children with congenital central hypoventilation syndrome (CCHS), a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO(2) sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI) scans, with impaired responses in specific hippocampal regions, suggesting localized injury.We assessed total volume and regional variation in hippocampal surface morphology to identify areas affected in the syndrome. We studied 18 CCHS (mean age+/-std: 15.1+/-2.2 years; 8 female) and 32 healthy control (age 15.2+/-2.4 years; 14 female) children, and traced hippocampi on 1 mm(3) resolution T1-weighted scans, collected with a 3.0 Tesla MRI scanner. Regional hippocampal volume variations, adjusted for cranial volume, were compared between groups based on t-tests of surface distances to the structure midline, with correction for multiple comparisons. Significant tissue losses emerged in CCHS patients on the left side, with a trend for loss on the right; however, most areas affected on the left also showed equivalent right-sided volume reductions. Reduced regional volumes appeared in the left rostral hippocampus, bilateral areas in mid and mid-to-caudal regions, and a dorsal-caudal region, adjacent to the fimbria.The volume losses may result from hypoxic exposure following hypoventilation during sleep-disordered breathing, or from developmental or vascular consequences of genetic mutations in the syndrome. The sites of change overlap regions of abnormal functional responses to respiratory and autonomic challenges. Affected hippocampal areas have roles associated with memory, mood, and indirectly, autonomic regulation; impairments in these behavioral and physiological functions appear in CCHS.