Thalamic altered spontaneous activity and connectivity in obstructive sleep apnea syndrome.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) syndrome is a sleep disorder characterized by excessive snoring, repetitive apneas, and nocturnal arousals, that leads to fragmented sleep and intermittent nocturnal hypoxemia. Morphometric and functional brain alterations in cortical and subcortical structures have been documented in these patients via magnetic resonance imaging (MRI), even if correlational data between the alterations in the brain and cognitive and clinical indexes are still not reported. METHODS: We examined the impact of OSA on brain spontaneous activity by measuring the fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional MRI data of 20 drug-naïve patients with OSA syndrome and 20 healthy controls matched for age, gender, and body mass index. RESULTS: Patients showed a pattern of significantly abnormal subcortical functional activity as compared to controls, with increased activity selectively involving the thalami, specifically their intrinsic nuclei connected to somatosensory and motor-premotor cortical regions. Using these nuclei as seed regions, the subsequent functional connectivity analysis highlighted an increase in patients' thalamocortical connectivity at rest. Additionally, the correlation between fALFF and polysomnographic data revealed a possible link between OSA severity and fALFF of regions belonging to the central autonomic network. CONCLUSIONS: Our results suggest a hyperactivation in thalamic diurnal activity in patients with OSA syndrome, which we interpret as a possible consequence of increased thalamocortical circuitry activation during nighttime due to repeated arousals.

Optimization of Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea With Ultrasound Assessment of Tongue Movement.

BACKGROUND: Hypoglossal nerve stimulation (HGNS) is an Food and Drug Administration-approved therapy for obstructive sleep apnea. Initial programming of HGNS is based on the observation of anterior tongue movement, which may not reflect opening at the retroglossal airway. We developed an ultrasonographic technique to assess the base of tongue movement with HGNS to be used to optimize the initial voltage settings. STUDY QUESTION: This study aimed to investigate the use of ultrasound to assess tongue movement with HGNS and related this measure to the apnea hypopnea index (AHI) on subsequent home sleep apnea testing or in-laboratory polysomnography with therapy. STUDY DESIGN: Seventeen subjects (n = 17) implanted with HGNS were enrolled at least 1 month postimplantation. Ultrasonographic measures were then used to optimize HGNS voltage to produce observable base of tongue protrusion without producing discomfort. Responders were defined as a reduction in AHI > 50% and an AHI of <20 events/h. RESULTS: There were 17 subjects, 11 men and 6 women, with age = 64.6 ± 9.8 years, body mass index = 27.9 ± 2.7 kg/m2, and pretreatment AHI = 36.5 ± 14.4/h, T-90% = 10.7 ± 14.8%. The mean hyoid bone excursion (HBE) in responders = 1.0 ± 0.13 cm versus 0.82 ± 0.12 cm in nonresponders (P = 0.017). HBE was correlated with AHI during HGNS treatment (coef. -0.54, P = 0.03). Best subsets regression analysis using treatment-based AHI as the dependent variable and age, body mass index, baseline AHI, HBE, and HGNS voltage as independent variables showed that HBE (coef. -44.6, P = 0.044) was the only independent predictor of response. Receiver operator curve analysis showed that HBE > 0.85 cm had a sensitivity of 83.3% and specificity of 80.0% with a positive likelihood ratio of 4.17 to predict responder status. CONCLUSION: We demonstrated that ultrasound assessment of HBE during HGNS programming is a useful tool to optimize therapy.

Clinical Radiographic Predictors of Response to Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

OBJECTIVE: To determine if clinically acquired cephalometric measurements, specifically soft palate size, can predict hypoglossal nerve stimulation outcomes. STUDY DESIGN: Combined prospective cohort study and retrospective review. SETTING: US sleep otolaryngology training program. METHODS: Adults with obstructive sleep apnea and apneahypopnea index greater than 15 events/h who underwent hypoglossal nerve stimulation. Eligible subjects had diagnostic preoperative sleep studies and full-night efficacy postoperative studies for analysis. Lateral neck x-rays were obtained as part of routine clinical care and measured for key cephalometric variables by trained head and neck radiologists. Continuous variables were compared using the Student t test, while χ2 testing was used for categorical variables. RESULTS: Fifty-one patients met all study criteria. On average, patients were white, middle aged, and overweight. Following hypoglossal nerve stimulation, the overall cohort achieved a significant apnea-hypopnea index reduction from 36.7 events/h to 20.6 events/h (P < .01) and a response rate of 47% (defined as apnea-hypopnea index reduction >50% and apnea-hypopnea index <20 events/h). On average, therapy responders had significantly thinner soft palates than nonresponders (13.4 ± 3.8 mm vs 16.0 ± 3.4 mm, P = .045). CONCLUSIONS: Patient-specific anatomic factors, specifically soft palate thickness, may help identify optimal candidates for hypoglossal nerve stimulation. A larger, prospective study including both anatomic and physiologic variables is required to validate these findings.

Ultrasound Localization and Percutaneous Electrical Stimulation of the Hypoglossal Nerve and Ansa Cervicalis.

OBJECTIVE: Hypoglossal nerve stimulation for obstructive sleep apnea (OSA) can be effective for appropriately selected patients, but current patient selection criteria are complex and still result in a proportion of nonresponders. Ansa cervicalis stimulation of the infrahyoid cervical strap muscles has recently been proposed as a new form of respiratory neurostimulation (RNS) therapy for OSA treatment. We hypothesized that percutaneous stimulation of both nerves in humans with temporary electrodes would make testing of the physiologic response to different RNS strategies possible. STUDY DESIGN: Nonrandomized acute physiology study. SETTING: Tertiary care hospital. METHODS: Fifteen participants with OSA underwent ultrasonography and placement of percutaneous electrodes proximal to the medial division of the hypoglossal nerve and the branch of the ansa cervicalis innervating the sternothyroid muscle (ACST). Procedural success was documented in each participant, as were any failures or procedural complication. RESULTS: The hypoglossal nerve was successfully localized in 15 of 15 (100%) participants and successfully stimulated in 13 of 15 (86.7%). The ACST was successfully localized in 15 of 15 (100%) participants and successfully stimulated in 14 of 15 (93.3%). Stimulation failure of the hypoglossal nerve was due to suboptimal electrode placement in 1 participant and electrode displacement in the other 2 cases. No complications occurred. CONCLUSIONS: The hypoglossal nerve and ACST can be safely stimulated via percutaneous electrode placement. Larger trials of percutaneous stimulation may help to identify responders to different RNS therapies for OSA with temporary or permanent percutaneous electrodes. Techniques for electrode design, nerve localization, and electrode placement are described.

Anatomic predictors of response and mechanism of action of upper airway stimulation therapy in patients with obstructive sleep apnea.

Study Objectives: Upper airway stimulation has been shown to be an effective treatment for some patients with obstructive sleep apnea. However, the mechanism by which hypoglossal nerve stimulation increases upper airway caliber is not clear. Therefore, the objective of this study was to identify the mechanism of action of upper airway stimulation. We hypothesized that, with upper airway stimulation, responders would show greater airway opening in the retroglossal (base of the tongue) region, greater hyoid movement toward the mandible, and greater anterior motion in the posterior, inferior region of the tongue compared with nonresponders. Methods: Seven participants with obstructive sleep apnea who had been successfully treated with upper airway stimulation (responders) and six participants who were not successfully treated (nonresponders) underwent computed tomography imaging during wakefulness with and without hypoglossal nerve stimulation. Responders reduced their apnea-hypopnea index (AHI) by 22.63 ± 6.54 events per hour, whereas nonresponders had no change in their AHI (0.17 ± 14.04 events per hour). We examined differences in upper airway caliber, the volume of the upper airway soft tissue structures, craniofacial relationships, and centroid tongue and soft palate movement between responders and nonresponders with and without hypoglossal nerve stimulation. Results: Our data indicate that compared with nonresponders, responders had a smaller baseline soft palate volume and, with stimulation, had (1) a greater increase in retroglossal airway size; (2) increased shortening of the mandible-hyoid distance; and (3) greater anterior displacement of the tongue. Conclusions: These results suggest that smaller soft palate volumes at baseline and greater tongue movement anteriorly with stimulation improve the response to upper airway stimulation.

Treatment of obstructive sleep apnoea-hypopnea syndrome by mandible advanced device reduced neuron apoptosis in frontal cortex of rabbits.

Objective: To investigate effects of mandible advanced device (MAD) therapy for obstructive sleep apnoea-hypopnea syndrome (OSAHS) on the neuron apoptosis and acetylcholine esterase activity in frontal cortex. Materials and methods: Thirty male New Zealand white rabbits were randomly divided into three groups (n = 10 in each group): group OSAHS, group MAD, and control group. Hydrophilic polyacrylamide gel was injected into soft palate of the animals to induce OSAHS in group OSAHS and group MAD. The group MAD animals wore MAD to relief the obstructiveness. The control group was not given any treatment. Computed tomography (CT) examination of the upper airway and polysomnography (PSG) recordings were performed in supine position. All rabbits were induced to sleep in a supine position for 4 to 6 hours every day and were observed for consecutive 8 weeks. The frontal cortices of three groups were dissected and the neuron apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry. Acetylcholine esterase (AchE) activity in the frontal cortex was measured by spectrophotometry. Results: The group OSAHS exhibited high neuron apoptosis rate and low AchE activity than those of group MAD and control group. The blood oxygen saturation was negatively correlated with neuronal apoptosis rate and positively correlated with AchE activity. Applying MAD in OSAHS animals significantly improve the neuronal damage and function deficits by apnoea-hypoxia caused by narrowed upper airway. Conclusion: This study provided evidence that MAD therapy for OSAHS can significantly decrease neuronal apoptosis and increase AchE activity in the frontal cortex.

Sonographic evaluation of tongue motions during upper airway stimulation for obstructive sleep apnea-a pilot study.

INTRODUCTION: The objective was to evaluate the feasibility of sonographic evaluation of functional tongue motion as a tool to evaluate postoperative outcomes in human subjects using breathing-synchronized stimulation of the hypoglossal nerve-a novel therapy option for patients with obstructive sleep apnea (OSA). MATERIAL AND METHODS: Sixteen patients with OSA (n = 16, age 60.4 ± 10.2, BMI 28.7 ± 2.4, AHI 35.0 ± 11.8) underwent sonographic evaluation of tongue motion after initiation of therapy with the Inspire II Upper Airway Stimulation system. Sonographic examination was performed in four different planes (A = floor of the mouth frontal, B = base of the tongue horizontal, C = floor of the mouth parallel to mandible, and D = floor of the mouth median sagittal) in an attempt to visualize tongue surface, tongue and hyoid motion, and the distance of protrusion. RESULTS: Identification of the tongue surface was achieved in all cases in planes B, C, and D and 81 % of patients in plane A. Tongue motion was evident on the right (implant) side in 63 % in plane A and 75 % in plane B. Distance of protrusion was measured in plane B at 1.04 cm (±0.51), in plane C at 1.08 cm (±0.47), and in plane D at 0.96 cm (±0.45). Hyoid protrusion was measured in plane C or D and was 0.57 cm (±0.39). Significant correlations among the three planes were observed, but there was no correlation to the reduction of apnea-hypopnea index. CONCLUSION: The results indicate feasibility of sonography to identify tongue and hyoid motions during upper airway stimulation. Useful sonographic planes and landmarks, which allow visualization of dynamic effects of upper airway stimulation, could be established. The evaluation of the tongue in a horizontal (B) and in a sagittal plane (D) appears to be superior to the other investigated planes. The approximate tongue protrusion needed to generate a significant reduction of AHI and ODI was 1 cm.

Morphometry analysis of basal ganglia structures in children with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) affects both adults and children, likely mediated by the deficits of various brain regions. The association between structural alterations in the brain and OSA syndrome have been reported in adult patients, but the corresponding evidence for OSA children is still limited. OBJECTIVE: The proposed study aimed to investigate the structural alterations in the brain of children with OSA, with focus on basal ganglia structures. METHODS: We recruited 25 OSA children (aged 10.3±1.5 years) and 30 healthy children (aged 10.1±1.8 years) with T1-weighted brain MRI and performed automatic segmentation of their brains. The shape alterations of the basal ganglia structures for OSA syndrome was determined by comparison of the OSA group and control group with surface-based shape analysis. RESULTS: Differences in the morphometry of the left thalamus and the left pallidum were found between the OSA group and control group. Compared to the control group, the OSA group presented significant atrophy in the ventral posterior nucleus and the medial dorsal nucleus of the left thalamus, while regional dilation was found in both the internal and external segments of the left pallidum. CONCLUSION: These findings identified the association between the structural deficits of the thalamus and OSA syndrome in children, which was consistent with the existing findings in OSA adults. In addition, the present study provided new insights to the distinctive pattern of structural changes of the pallidum in pediatric OSA when compared to adult OSA.

Accelerated Echo Planer J-resolved Spectroscopic Imaging of Putamen and Thalamus in Obstructive Sleep Apnea.

UNLABELLED: Obstructive 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 < 0.05). Increased right thalamic Glx/Cr, Glu/Cr, Gln/Cr, Asc/Cr, and decreased GPC/Cr and decreased left thalamic tNAA/Cr, NAA/Cr were detected. The right putamen showed increased mI/Cr and decreased tCho/Cr, and the left, decreased PE/Cr ratio. ROC curve analyses demonstrated 60-100% sensitivity and specificity for the metabolite ratios in differentiating OSAS vs. CONTROLS: Positive correlations were found between: left thalamus mI/Cr and baseline oxygen saturation (SaO2); right putamen tCho/Cr and apnea hypopnea index; right putamen GABA/Cr and baseline SaO2; left putamen PE/Cr and baseline SaO2; and left putamen NAA/Cr and SaO2 nadir (all p < 0.05). Negative correlations were found between left putamen PE/Cr and SaO2 nadir. These findings suggest underlying inflammation or glial activation, with greater alterations accompanying lower oxygen saturation. These metabolite levels may provide biomarkers for future neurochemical interventions by pharmacologic or other means.

Upper Airway Collapsibility Assessed by Negative Expiratory Pressure while Awake is Associated with Upper Airway Anatomy.

STUDY OBJECTIVES: There is a growing interest to develop a simple method to characterize the mechanisms leading to upper airway collapse in order to guide treatment options in patients with obstructive sleep apnea (OSA). Critical closing pressure (Pcrit) during sleep is able to predict the anatomical component of OSA. However, Pcrit is a laborious method that is only used for research purposes. The application of negative expiratory pressure (NEP) is a simple method to assess upper airway collapsibility that can be easily performed during wakefulness. We hypothesized that NEP will be, similarly to Pcrit, associated with upper airway anatomy assessed by computed tomography (CT) scan. METHODS: Patients under investigation for OSA underwent polysomnography, CT of the upper airway, NEP while awake, and Pcrit during sleep. NEP was performed with -5 cm H2O in supine position using a nasal mask. Pcrit was measured during sleep induced by low doses of midazolam. RESULTS: Twenty-eight male subjects were studied (age 45 ± 13 y, body mass index 29.4 ± 4.9 kg/m2, apnea-hypopnea index (AHI) 30 ± 26, range 2 to 86 events/h). NEP and Pcrit were similarly associated with tongue area (r = 0.646 and r = 0.585), tongue volume (r = 0.565 and r = 0.613) and pharyngeal length (r = 0.580 and r = 0.611), respectively (p < 0.05 for all comparisons). NEP and Pcrit were also significantly correlated with AHI (r = 0.490 and r = 0.531). NEP and Pcrit were significantly higher in patients with severe OSA than the remaining population. CONCLUSIONS: NEP is a simple and promising method that is associated with the anatomical component of upper airway collapsibility. NEP may be valuable to select patients for noncontinuous positive airway pressure alternative therapies for OSA.