Device-related outcomes following hypoglossal nerve stimulator implantation.

STUDY OBJECTIVES: Hypoglossal nerve stimulation (HGNS) has been widely used to treat obstructive sleep apnea in selected patients. Here we evaluate rates of revision and explant related to HGNS implantation and assess types of adverse events contributing to revision and explant. METHODS: Post-market surveillance data for HGNS implanted between January 1, 2018 and March 31, 2022, were collected. Event rates and risk were calculated using the post-market surveillance event counts and sales volume over the same period. Indications were categorized for analysis. Descriptive statistics were reported and freedom from explant or revision curves were grouped by year of implantation. RESULTS: Of the 20,881 HGNS implants assessed, rates of explant and revision within the first year were 0.723% and 1.542%, respectively. The most common indication for explant was infection (0.378%) and for revision was surgical correction (0.680%). Of the 5,820 devices with three-year post-implantation data, the rate of explant was 2.680% and of revision was 3.557%. During this same interval, elective removal (1.478%) was the most common indication, and for revisions, surgical correction (1.134%). CONCLUSIONS: The efficacy of HGNS is comparable in the real world setting to published clinical trial data. Rates of explant and revision are low, supporting a satisfactory safety profile for this technology.

Relationship of Nocturnal Insomnia Symptoms and Outcomes After Hypoglossal Nerve Stimulation.

Objective: In patients undergoing hypoglossal nerve stimulation (HGNS), we examined the Insomnia Severity Index (ISI) to understand how baseline sleep onset insomnia (SOI), sleep maintenance insomnia (SMI), and early morning awakening (EMA) affected postsurgical outcomes. Study Design: Observational. Setting: Multicenter registry. Methods: We included patients from the Adherence and Outcomes of Upper Airway Stimulation for Obstructive Sleep Apnea International Registry (ADHERE) with a baseline ISI from 2020 to 2023. Regression analysis examined the association of ISI question scores for SOI, SMI, and EMA and outcomes: Apnea-Hypopnea Index (AHI) reduction, device usage, changes in the Epworth Sleepiness Scale (ESS) and overall ISI score, final visit (FV) completion, and satisfaction. Results: No relationship was noted between insomnia subtypes and AHI reduction or FV completion. In the subgroup of patients with baseline moderate/severe insomnia, patients with major impairment for SOI used their device 64 min/day longer than those with minimal impairment. Among all patients, those with baseline major impairment for SOI had a 2.3 points greater improvement in ISI from baseline to FV compared to patients with minimal impairment, while patients with baseline major impairment for SMI had a 2.0 and 3.5 points greater improvement in the ESS and ISI than those with minimal impairment. Patients with EMA and moderate/severe baseline insomnia had decreased odds of being satisfied after surgery. Conclusion: In ADHERE, nocturnal symptoms of insomnia did not limit HGNS efficacy or therapy use. Conversely, those with worse insomnia subtype impairments at baseline had improved outcomes related to adherence, sleepiness, and insomnia at the FV.

Defining the Shape of the Mylohyoid Muscle: A Morphometric Imaging Study.

OBJECTIVES: Implantable hypoglossal nerve stimulation (HNS) therapy is an evolving therapeutic alternative for patients with refractory obstructive sleep apnea (OSA). The muscular anatomy of this region has implications for surgical access through this zone as well as positioning and anchoring of hardware in this area. The purpose of this study was to radiologically describe the topography of the mylohyoid muscle and adjacent structures across a wide age spectrum. METHODS: We retrospectively evaluated computed tomography scans of the neck in 102 patients who were imaged for reasons unrelated to the floor of mouth or submental space. Patients with prior surgery or pathology in the area of interest were excluded. Fourteen relevant muscle measurements were made on a midline sagittal image and a coronal image positioned at the midpoint between the hyoid bone and the mandible. RESULTS: We included 49 men and 53 women with an average age of 44 years (range 19-70). The average mylohyoid length was 42 mm; the average distance between the anterior digastric bellies was 17 mm. The average angle of the central mylohyoid was 174° in the sagittal plane and 164° in the coronal plane. Several measurements were significantly correlated with patient age, including the angle measurements and the distance between the digastric muscles. Aberrant digastric anatomy was common. CONCLUSIONS: The mylohyoid muscle has multiple radiologically distinct segments with predictable curvatures. An understanding of submental muscular anatomy, along with its variability between patients, may be beneficial to the development of bilateral implantable neurostimulation technology for the treatment of refractory OSA. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:2970-2975, 2024.

Hypoglossal Nerve Stimulation Therapy for Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of disrupted breathing during sleep. The most effective treatment for OSA is positive pressure ventilation; however, this treatment can be complicated by adherence difficulties. An array of alternative OSA therapies have emerged, including positional therapy, nasal exhalation devices, oral appliances, and various nasal, pharyngeal, and skeletal surgical treatments. One of the newest options, hypoglossal nerve stimulation (HNS) therapy, represents a hybrid medical and surgical treatment. This therapy involves an FDA-approved surgically implanted neuromodulation system that is activated by the patient each night to augment upper airway dilator muscle activity and improve airflow. The implanted components comprise a pulse generator, an electrode on the distal portion of the hypoglossal nerve, and a respiratory sensing lead that allows for synchronization of electrical impulses with the patient's respiratory cycle. Using a representative patient case, the authors describe HNS therapy, including its indications, patient selection, surgical procedure, long-term outpatient management, and outcomes data.

Evaluating Targeted Therapeutic Response With Predictive Blood-Based Biomarkers in Patients With Chronic Mild Traumatic Brain Injury.

Chronic consequences of mild traumatic brain injury (mTBI) are heterogeneous, but may be treatable with targeted medical and rehabilitation interventions. A biological signature for the likelihood of response to therapy (i.e., "predictive" biomarkers) would empower personalized medicine post-mTBI. The purpose of this study was to correlate pre-intervention blood biomarker levels and the likelihood of response to targeted interventions for patients with chronic issues attributable to mTBI. Patients with chronic symptoms and/or disorders secondary to mTBI >3 months previous (104 days to 15 years; n = 74) were enrolled. Participants completed pre-intervention assessments of symptom burden, comprehensive clinical evaluation, and blood-based biomarker measurements. Multi-domain targeted interventions for specific symptoms and impairments across a 6-month treatment period were prescribed. Participants completed a follow-up testing after the treatment period. An all-possible model's backward logistic regression was built to identify predictors of improvement in relation to blood biomarker levels before intervention. The minimum clinically important difference (MCID) of the change score (post-intervention subtracted from pre-intervention) for the Post-Concussion Symptom Scale (PCSS) to identify treatment responders from non-responders was the primary outcome. The MCID for total PCSS score was 10. The model to predict change in PCSS score over the 6-month intervention was significant (R2 = 0.09; p = 0.01) and identified ubiquitin C-terminal hydrolase L1 (odds ratio [OR] = 2.53; 95% confidence interval [CI], 1.18-5.46; p = 0.02) and hyperphosphorylated tau (p-tau; OR = 0.70; 95% CI, 0.51-0.96; p = 0.03) as significant predictors of symptom improvement beyond the PCSS MCID. In this cohort of chronic TBI subjects, blood biomarkers before rehabilitation intervention predicted the likelihood of response to targeted therapy for chronic disorders post-TBI.

Long-Term Generator Replacement Experience in Hypoglossal Nerve Stimulator Therapy Recipients With CPAP-Intolerant Obstructive Sleep Apnea.

OBJECTIVE: In the last decade, hypoglossal nerve stimulation (HNS) has emerged as a therapeutic alternative for patients with obstructive sleep apnea. The original clinical trial cohorts are entering the phase of expected battery depletion (8-12 years). This study aimed to examine the surgical experience with implantable pulse generator (IPG) replacements and the associated long-term therapy outcomes. STUDY DESIGN: Retrospective analysis of patients from the original clinical trial databases (STAR, German post-market) who were followed in the ongoing ADHERE registry. SETTING: International multicenter HNS registry. METHODS: The ADHERE registry and clinical trial databases were cross-referenced to identify the serial numbers of IPGs that were replaced. Data collection included demographics, apnea-hypopnea index (AHI), therapy use, operative times, and adverse events. RESULTS: Fourteen patients underwent IPG replacement 8.3 ± 1.1 years after their initial implantation. Body mass index was unchanged between the original implant and IPG replacement (29 ± 4 vs 28 ± 2 kg/m2 , p = .50). The mean IPG replacement operative time was shorter than the original implant (63 ± 50 vs 154 ± 58 minutes, p < .002); however, 2 patients required stimulation lead replacement which significantly increased operative time. For patients with available AHI and adherence data, the mean change in AHI from baseline to latest follow-up (8.7 ± 1.1 years after de novo implant) was -50.06%, and the mean therapy use was 7.2 hours/night. CONCLUSION: IPG replacement surgery was associated with low complications and shorter operative time. For patients with available outcomes data, adherence and efficacy remained stable after 9 years of follow-up.

Association of Plasma Biomarkers with Sleep Outcomes and Treatment Response After Mild Traumatic Brain Injury.

Sleep disturbances occur in up to 70% of patients with mild traumatic brain injury (mTBI). Modern mTBI management recommends targeted treatment for the patient's unique clinical manifestations (i.e., obstructive sleep apnea, insomnia). The purpose of this study was to evaluate the association of plasma biomarkers with symptom reports, overnight sleep evaluations, and response to treatment for sleep disturbances secondary to mTBI. This study is a secondary analysis of a prospective multiple interventional trial of patients with chronic issues related to mTBI. Pre- and post-intervention assessments were conducted, including overnight sleep apnea evaluation, the Pittsburgh Sleep Quality Index (PSQI), and blinded analysis of blood biomarkers. Bivariate Spearman correlations were conducted for pre-intervention plasma biomarker concentrations and 1) PSQI change scores and 2) pre-intervention sleep apnea outcomes (i.e., oxygen saturation measures). A backward logistic regression model was built to evaluate the association of pre-intervention plasma biomarkers with improvement in PSQI over the treatment period (p < 0.05). Participants were 36.3 ± 8.6 years old and 6.1 ± 3.8 years from their index mTBI. Participants reported subjective improvements (PSQI = -3.7 ± 3.8), whereas 39.3% (n = 11) had improved PSQI scores beyond the minimum clinically important difference (MCID). PSQI change scores correlated with von Willebrand factor (vWF; ρ = -0.50; p = 0.02) and tau (ρ = -0.53; p = 0.01). Hyperphosphorylated tau correlated with average saturation (ρ = -0.29; p = 0.03), lowest desaturation (ρ = -0.27; p = 0.048), and baseline saturation (ρ = -0.31; p = 0.02). The multi-variate model (R 2 = 0.33; p = 0.001) retained only pre-intervention vWF as a predictor (odds ratio = 3.41; 95% confidence interval, 1.44-8.08; p = 0.005) of improving PSQI scores beyond the MCID. vWF had good discrimination (area under the curve = 0.83; p = 0.01), with an overall accuracy of 77%, sensitivity of 46.2%, and specificity of 90.0%. Validation of vWF as a potential predictive biomarker of sleep improvement post-mTBI could optimize personalized management and healthcare utilization.

Will nasal airway surgery improve my sense of smell? A prospective observational study.

BACKGROUND: The effect of nasal airway surgery on olfaction has not been well established. The goal of this study is to assess changes in olfaction after septoplasty with inferior turbinate reduction through both objective and patient-reported measures. METHODS: Prospective, observational study was conducted of patients with nasal airway obstruction presenting between July 2017 and October 2019 who underwent septoplasty with inferior turbinate reduction. Nasal airflow was characterized with the Nasal Obstruction Symptom Evaluation (NOSE) scale and an 11-point ease-of-breathing (EOB) Likert scale, and olfaction with an 11-point olfactory Likert scale and the 40-item University of Pennsylvania Smell Identification Test (UPSIT), pre- and postoperatively. Pearson correlations were used to assess the relationship between measures of nasal obstruction and olfaction. RESULTS: Among 80 patients, mean NOSE scores improved from 67.4 preoperatively to 19.6 postoperatively (p < 0.001). EOB Likert scores improved from a mean of 3.9/10 to 8.1/10 after surgery (p < 0.001). Olfactory Likert scores improved from a baseline of 6.1/10 preoperatively to 7.9/10 after surgery (p < 0.001). No statistically significant difference was noted in UPSIT testing pre- versus postoperatively. A moderate correlation was noted between the degree of change in NOSE scores and improved olfactory Likert scores (r = 0.51, p < 0.001), and similarly between the degree of change in EOB Likert scores and improved olfactory Likert scores (r = 0.55, p < 0.0001). CONCLUSIONS: Based on our data, subjective tests of olfaction may improve with nasal airway surgery in some patients. Changes in olfaction best correlate with the extent to which surgery can improve subjective nasal obstructive symptoms.

Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea?

STUDY OBJECTIVES: Untreated obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness, decreased quality of life, and cardiovascular disease. Positive airway pressure is the first-line therapy for OSA; however, adherence is difficult. Upper airway stimulation is a Food and Drug Administration-approved treatment of OSA. The objective of this study was to evaluate for a difference in treatment efficacy and adherence of upper airway stimulation therapy for OSA between individuals who are White and non-White using data from the ADHERE registry. METHODS: ADHERE registry is a multicenter prospective study of real-world experience of upper airway stimulation for treatment of OSA in the United States and Europe. Propensity score matching was used to create a balanced dataset between the White and non-White groups. t-Tests at a significance level of 5% were used to compare numeric values between groups. RESULTS: There were 2,755 participants of the ADHERE registry: 27 were excluded due to not having a race identified, 125 participants identified as non-White, 2,603 identify as White, and 27 did not provide race information. Propensity score matching was used to select 110 participants, with 55 White and 55 non-White for the noninferiority analysis. We did not find a difference in adherence, treatment apnea-hypopnea index, changes in Epworth Sleepiness Scale score, or clinical global impression after intervention score between White and non-White individuals. CONCLUSIONS: Our study found that there was no statistically significant difference in adherence or efficacy with upper airway stimulation therapy between White and non-White individuals. However, the percent of non-White people implanted is low, which suggests a need to expand access to this therapy for non-White populations with OSA who cannot tolerate positive airway pressure therapy. CITATION: Khan M, Stone A, Soose RJ, et al. Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea? J Clin Sleep Med. 2022;18(9):2167-2172.

Factors affecting obstructive sleep apnea patients' use of upper airway stimulation treatment.

STUDY OBJECTIVES: Upper airway stimulation (UAS) is an alternative treatment for obstructive sleep apnea that must be activated nightly. Although the implanted device offsets the mask- or pressure-related side effects often associated with continuous positive airway pressure therapy, some UAS recipients do not use the therapy consistently. This study qualitatively explored factors associated with UAS usage in obstructive sleep apnea patients. METHODS: Semistructured interviews were conducted with 24 obstructive sleep apnea patients who received UAS treatment. Twelve patients were categorized as high users with mean usage of ≥ 4 hours/night and 12 were categorized as low users with < 4 hours/night or nonuse. Interviews explored patients' experiences regarding barriers and facilitators to UAS use and their advice for new UAS recipients. Demographic and clinical data including the Insomnia Severity Index and Generalized Anxiety Disorder Scale were collected. RESULTS: Compared to high users, low users had higher levels of insomnia (mean Insomnia Severity Index: 3.6 vs 15.2, respectively) and anxiety (mean Generalized Anxiety Disorder Scale: 3.4 vs 6.9). High users reported more positive experiences with UAS treatment, such as improvements in symptoms and convenience of treatment, as facilitators of use. Low users tended to focus on the negative aspects of treatment, particularly stimulation-related discomfort and associated sleep disturbance. CONCLUSIONS: Insomnia with or without anxiety contributes to differing patient-reported experiences in high vs low user groups, with increased insomnia symptoms among low users. Improved understanding of the specific barrier and facilitators of UAS adherence may drive better long-term use and more personalized management strategies, including concomitant insomnia treatment. CLINICAL TRIALS REGISTRATION: Registry: ClinicalTrials.gov; Name: Stimulation Therapy for Apnea: Reporting Thoughts (START); URL: https://clinicaltrials.gov/ct2/show/NCT04768543; Identifier: NCT04768543. CITATION: Luyster FS, Ni Q, Lee K, et al. Factors affecting obstructive sleep apnea patients' use of upper airway stimulation treatment. J Clin Sleep Med. 2022;18(9):2207-2215.

Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea.

Importance: Patients with Down syndrome have a high incidence of persistent obstructive sleep apnea (OSA) and limited treatment options. Upper airway hypoglossal stimulation has been shown to be effective for adults with OSA but has not yet been evaluated for pediatric populations. Objective: To evaluate the safety and effectiveness of upper airway stimulation for adolescent patients with Down syndrome and severe OSA. Design, Setting, and Participants: This prospective single-group multicenter cohort study with 1-year follow-up was conducted between April 1, 2015, and July 31, 2021, among a referred sample of 42 consecutive adolescent patients with Down syndrome and persistent severe OSA after adenotonsillectomy. Intervention: Upper airway stimulation. Main Outcomes and Measures: The prespecified primary outcomes were safety and the change in apnea-hypopnea index (AHI) from baseline to 12 months postoperatively. Polysomnographic and quality of life outcomes were assessed at 1, 2, 6, and 12 months postoperatively. Results: Among the 42 patients (28 male patients [66.7%]; mean [SD] age, 15.1 [3.0] years), there was a mean (SD) decrease in AHI of 12.9 (13.2) events/h (95% CI, -17.0 to -8.7 events/h). With the use of a therapy response definition of a 50% decrease in AHI, the 12-month response rate was 65.9% (27 of 41), and 73.2% of patients (30 of 41) had a 12-month AHI of less than 10 events/h. The most common complication was temporary tongue or oral discomfort, which occurred in 5 patients (11.9%). The reoperation rate was 4.8% (n = 2). The mean (SD) improvement in the OSA-18 total score was 34.8 (20.3) (95% CI, -42.1 to -27.5), and the mean (SD) improvement in the Epworth Sleepiness Scale score was 5.1 (6.9) (95% CI, -7.4 to -2.8). The mean (SD) duration of nightly therapy was 9.0 (1.8) hours, with 40 patients (95.2%) using the device at least 4 hours a night. Conclusions and Relevance: Upper airway stimulation was able to be safely performed for 42 adolescents who had Down syndrome and persistent severe OSA after adenotonsillectomy with positive airway pressure intolerance. There was an acceptable adverse event profile with high rates of therapy response and quality of life improvement. Trial Registration: ClinicalTrials.gov Identifier: NCT02344108.

Cluster analysis of upper airway stimulation adherence patterns and implications on clinical care.

STUDY OBJECTIVES: Upper airway stimulation (UAS) therapy is effective for a subset of obstructive sleep apnea (OSA) patients with continuous positive airway pressure (CPAP) intolerance. While overall adherence is high, some patients have suboptimal adherence, which limits efficacy. Our goal was to identify therapy usage patterns during the first 3 months of therapy to enable targeted strategies for improved adherence. METHODS: Therapy data was retrieved from 2098 patients for three months after device activation. Data included mean and standard deviation (SD) of hours of use, therapy pauses, hours from midnight the therapy was turned ON and OFF, percentage of missing days, and stimulation amplitude. Cluster analysis was performed using Gaussian mixture models that categorized patients into six main groups. RESULTS: The six groups and their prevalence can be summarized as Cluster 1A: Excellent Use (34%); Cluster 1B: Excellent Use with variable timing (23%); Cluster 2A: Good Use with missing days and late therapy ON (16%), Cluster 2B: Good Use with missing days, late therapy ON, and early therapy OFF (12%); Cluster 3A: Variable Use with frequent missing days (8%); Cluster 3B: Variable Use with frequent pauses (7%). Most patients (85%) are excellent or good users with mean therapy use >6 hours per night. CONCLUSIONS: Cluster analysis of early UAS usage patterns identified six distinct groups that may enable personalized interventions for improved long-term management. Differentiation of the patient clusters may have clinical implications with regard to sleep hygiene education, therapy discomfort, comorbid insomnia, and other conditions that impact adherence.

Impulse Configuration in Hypoglossal Nerve Stimulation in Obstructive Sleep Apnea: The Effect of Modifying Pulse Width and Frequency.

OBJECTIVES: Hypoglossal nerve stimulation is an effective treatment option for obstructive sleep apnea (OSA) in positive airway pressure therapy failure. Nonetheless, data regarding the functional effect of modifying stimulation parameters within each electrode configuration are limited. MATERIALS AND METHODS: In a retrospective study of 76 patients with 12 months or more follow-up, functional tongue protrusion thresholds were compared for pulse width and frequency configurations of 90 µsec 33 Hz vs 120 µsec 40 Hz. The number of tolerated voltage amplitude steps between sensation, functional, and subdiscomfort thresholds were assessed for both settings as well as impedances. RESULTS: The overall cohort showed improvement in OSA metrics: median apnea-hypopnea index from 30.0/hour to 18.6/hour and Epworth Sleepiness Scale from 13.5 to 7.6. For both bipolar and unipolar electrode configurations, the stimulation amplitude required for functional tongue protrusion was significantly reduced when the pulse width and frequency were converted from 90 µsec 33 Hz to 120 µsec 40 Hz (p < 0.001). Nevertheless, the number of voltage amplitude steps from sensation, functional, to subdiscomfort thresholds did not differ between the two settings. The ratio of automatically derived impedances between bipolar and unipolar electrode configurations was relevantly correlated with the ratio of functional thresholds at these parameters. CONCLUSION: Changing the stimulation parameters may lower the voltage requirements while maintaining the same effect on tongue protrusion. Changing these stimulation parameters does not affect the range of tolerated impulse steps between functional and subdiscomfort thresholds. Future technical appliances could help estimate functional thresholds at different electrode configurations for each patient by automatically measuring impedances.

Impact of Body Mass Index and Discomfort on Upper Airway Stimulation: ADHERE Registry 2020 Update.

OBJECTIVES/HYPOTHESIS: To provide the ADHERE registry Upper Airway Stimulation (UAS) outcomes update, including analyses grouped by body mass index (BMI) and therapy discomfort. STUDY DESIGN: Prospective observational study. METHODS: ADHERE captures UAS outcomes including apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), therapy usage, patient satisfaction, clinician assessment, and safety over a 1-year period. BMI ≤32 kg/m2 (BMI32 ) and 32 < BMI ≤35 kg/m2 (BMI35 ) group outcomes were examined. RESULTS: One thousand eight hundred forty-nine patients enrolled in ADHERE, 1,019 reached final visit, 843 completed the visit. Significant changes in AHI (-20.9, P < .0001) and ESS (- 4.4, P < .0001) were demonstrated. Mean therapy usage was 5.6 ± 2.2 hr/day. Significant therapy use difference was present in patients with reported discomfort versus no discomfort (4.9 ± 2.5 vs. 5.7 ± 2.1 hr/day, P = .01). Patients with discomfort had higher final visit mean AHI versus without discomfort (18.9 ± 18.5 vs. 13.5 ± 13.7 events/hr, P = .01). Changes in AHI and ESS were not significantly different. Serious adverse events reported in 2.3% of patients. Device revision rate was 1.9%. Surgical success was less likely in BMI35 versus BMI32 patients (59.8% vs. 72.2%, P = .02). There was a significant therapy use difference: 5.8 ± 2.0 hr/day in BMI32 versus 5.2 ± 2.2 hr/day in BMI35 (P = .028). CONCLUSIONS: Data from ADHERE demonstrate high efficacy rates for UAS. Although surgical response rate differs between BMI32 and BMI35 patient groups, the AHI and ESS reduction is similar. Discomfort affects therapy adherence and efficacy. Thus, proper therapy settings adjustment to ensure comfort is imperative to improve outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2616-2624, 2021.

Improving outcomes of hypoglossal nerve stimulation therapy: current practice, future directions, and research gaps. Proceedings of the 2019 International Sleep Surgery Society Research Forum.

Hypoglossal nerve stimulation (HGNS) has evolved as a novel and effective therapy for patients with moderate-to-severe obstructive sleep apnea. Despite positive published outcomes of HGNS, there exist uncertainties regarding proper patient selection, surgical technique, and the reporting of outcomes and individual factors that impact therapy effectiveness. According to current guidelines, this therapy is indicated for select patients, and recommendations are based on the Stimulation Therapy for Apnea Reduction or STAR trial. Ongoing research and physician experiences continuously improve methods to optimize the therapy. An understanding of the way in which airway anatomy, obstructive sleep apnea phenotypes, individual health status, psychological conditions, and comorbid sleep disorders influence the effectiveness of HGNS is essential to improve outcomes and expand therapy indications. This article presents discussions on current evidence, future directions, and research gaps for HGNS therapy from the 10th International Surgical Sleep Society expert research panel. CITATION: Suurna MV, Jacobowitz O, Chang J, et al. Improving outcomes of hypoglossal nerve stimulation therapy: current practice, future directions and research gaps. Proceedings of the 2019 International Sleep Surgery Society Research Forum. J Clin Sleep Med. 2021;17(12):2477-2487.

B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma.

Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.

Targeted Intervention Improves Symptoms and Impairments in Patients With Mild Traumatic Brain Injury With Chronic Symptom: A Prospective, Multiple Interventional Research Trial.

BACKGROUND: Mild traumatic brain injury (mTBI) and its potential long-term consequences is a primary concern for the US military. The purpose of the study is to evaluate if participants improved in anxiety/mood symptoms, sleep quality, and vestibular/ocular symptoms following a 6-month active intervention, and to explore the effect of targeted treatment for those with specific symptoms/impairments (e.g., psychological, sleep, ocular, vestibular). MATERIALS AND METHODS: A multidisciplinary clinical team adjudicated participants (n=72, 35.8±8.6 years old, 19% female) to have one of the following primary clinical trajectories: psychological (PSYCH; n=34), sleep (SLEEP; n=25) and vestibular/ocular (VESTIB/OCULAR; n=18). Participants returned for follow-up assessment 6 months later. Assessments included the Post-Concussion Symptom Scale [PCSS], Generalized Anxiety Disorder-7 [GAD-7], Pittsburgh Sleep Quality Index [PSQI], and Dizziness Handicap Inventory [DHI]. Change in concussion symptoms and primary outcome for the given trajectory (i.e., PSYCH=GAD-7, SLEEP=PSQI, VESTIB/OCULAR=DHI) was assessed. RESULTS: Following the 6-month intervention, participants reduced PCSS Score (-14.5±2.4; p<.001; η2=0.34), GAD-7 (-3.1±0.5; p<.001; η2=0.34), PSQI (-2.7±0.5; p<.001; η2=0.34) and DHI (-9.2±2.0; p<.001; η2=0.23). PSYCH (n=34) reduced PCSS score (-17.9±3.6; p<.001; η2=0.45) and GAD-7 (-3.1±0.7; p<.001; η2=0.38). SLEEP (n=25) reduced PCSS score (-8.8±4.4; p=.06; η2=0.15) and PSQI (-3.6±0.9; p<.001; η2=0.45) scores. VESTIB/OCULAR (n=18) reduced PCSS score (-16.7±4.8; p=.03; η2=0.45), and DHI (-15.7±5.5; p=.012; η2=0.35). CONCLUSIONS: Large effects were observed for concussion, anxiety, sleep, and dizziness symptom reduction over 6-month treatment. Each primary outcome demonstrated a larger treatment effect for the given trajectory than the overall sample, indicating that targeted treatment can reduce symptom burden in patients with mTBI with chronic symptoms.

Symptom-Dependent Changes in MEG-Derived Neuroelectric Brain Activity in Traumatic Brain Injury Patients with Chronic Symptoms.

Neuroelectric measures derived from human magnetoencephalographic (MEG) recordings hold promise as aides to diagnosis and treatment monitoring and targeting for chronic sequelae of traumatic brain injury (TBI). This study tests novel MEG-derived regional brain measures of tonic neuroelectric activation for long-term test-retest reliability and sensitivity to symptoms. Resting state MEG recordings were obtained from a normative cohort, Cambridge Centre for Ageing and Neuroscience (CamCAN), baseline: n = 619; mean 16-month follow-up: n = 253) and a chronic symptomatic TBI cohort, Targeted Evaluation, Action and Monitoring of Traumatic Brain Injury (TEAM-TBI), baseline: n = 64; mean 6-month follow-up: n = 39). For the CamCAN cohort, MEG-derived neuroelectric measures showed good long-term test-retest reliability for most of the 103 automatically identified stereotypic regions. The TEAM-TBI cohort was screened for depression, somatization, and anxiety with the Brief Symptom Inventory and for insomnia with the Insomnia Severity Index. Linear classifiers constructed from the 103 regional measures from each TEAM-TBI cohort member distinguished those with and without each symptom, with p < 0.01 for each-i.e., the tonic regional neuroelectric measures of activation are sensitive to the presence/absence of these symptoms. The novel regional MEG-derived neuroelectric measures obtained and tested in this study demonstrate the necessary and sufficient properties to be clinically useful-i.e., good test-retest reliability, sensitivity to symptoms in each individual, and obtainable using automatic processing without human judgement or intervention.

Model-based analysis of implanted hypoglossal nerve stimulation for the treatment of obstructive sleep apnea.

STUDY OBJECTIVES: Individuals with obstructive sleep apnea (OSA), characterized by frequent sleep disruptions from tongue muscle relaxation and airway blockage, are known to benefit from on-demand electrical stimulation of the hypoglossal nerve. Hypoglossal nerve stimulation (HNS) therapy, which activates the protrusor muscles of the tongue during inspiration, has been established in multiple clinical studies as safe and effective, but the mechanistic understanding for why some stimulation parameters work better than others has not been thoroughly investigated. METHODS: In this study, we developed a detailed biophysical model that can predict the spatial recruitment of hypoglossal nerve fascicles and axons within these fascicles during stimulation through nerve cuff electrodes. Using this model, three HNS programming scenarios were investigated including grouped cathode (---), single cathode (o-o), and guarded cathode bipolar (+-+) electrode configurations. RESULTS: Regardless of electrode configuration, nearly all hypoglossal nerve axons circumscribed by the nerve cuff were recruited for stimulation amplitudes <3 V. Within this range, monopolar configurations required lower stimulation amplitudes than the guarded bipolar configuration to elicit action potentials within hypoglossal nerve axons. Further, the spatial distribution of the activated axons was more uniform for monopolar versus guarded bipolar configurations. CONCLUSIONS: The computational models predicted that monopolar HNS provided the lowest threshold and the least sensitivity to rotational angle of the nerve cuff around the hypoglossal nerve; however, this setting also increased the likelihood for current leakage outside the nerve cuff, which could potentially activate axons in unintended branches of the hypoglossal nerve. CLINICAL TRIAL REGISTRATION: NCT01161420.