bluuebunny/crossref_metadata_2025_split huggingface dataset:
0704 Comparative Efficacy of Tonic Motor Activation for Medication-Naïve and Dopaminergic-Treated Restless Legs Syndrome
Authors: Buchfuhrer Mark , Singh Haramandeep , Ojile Joseph , Baker Fiona , Charlesworth Jonathan 
Published: April 2024

Abstract

Introduction
Due to augmentation, exposure to dopaminergic treatment induces worsening of restless legs syndrome (RLS) and reduces response to gabapentinoid medications, frequently leading to refractory RLS. Tonic motor activation (TOMAC) is a noninvasive neurostimulation therapy indicated for refractory RLS. We tested if response to TOMAC is affected by dopaminergic treatment.

Methods
We retrospectively analyzed two clinical trials that each enrolled a mixture of adults with primary moderate-severe RLS who were medication-naïve (drug-naïve), treated with dopamine agonist medication (DA-treated), or other medication history (not analyzed here). There was no drug washout. Trial 1 (NCT04700683, mean age 55.6, 56% female) employed crossover design with 2-weeks of TOMAC and sham control in randomized order. Trial 2 (NCT05214963, mean age 56.0, 69% female) employed parallel design with participants randomized to 2-weeks of TOMAC or sham. Participants were instructed to self-administer 30-minutes of treatment when they experienced RLS symptoms. RLS severity was assessed based on change to mean International RLS Scale (IRLS) score. P-values were determined with two-factor ANOVA for treatment assignment and medication history.

Results
RLS severity improved similarly for drug-naïve and DA-treated RLS patients during TOMAC relative to sham treatment. In Trial 1, mean IRLS change during TOMAC was -4.2 points for drug-naïve (sham: 0.0 points; n=13) and -4.5 points for DA-treated (sham: -1.4; n=14) groups; treatment assignment main effect was significant (p=0.011) and there was no interaction between medication history and treatment assignment effects (p=0.679). In Trial 2, mean IRLS change during TOMAC was -6.3 points for drug-naïve (sham: -1.4; n=25) and -8.6 points for DA-treated (sham: -4.9; n=14); treatment assignment main effect was significant (p=0.010) and there was no interaction between medication history and treatment assignment effects (p=0.701). For all groups, IRLS change was &gt;3 points different for TOMAC compared to sham, the minimal clinically significant difference.

Conclusion
There was no difference in TOMAC efficacy between DA-treated and medication-naïve RLS. TOMAC treatment consistently resulted in greater RLS improvement than sham control. This differs from gabapentinoids, which have reduced effectiveness following DA treatment. These results may indicate an advantage of TOMAC over gabapentinoids for refractory RLS.

Support (if any)
Sponsored by Noctrix Health. NCT05214963 supported by NIH/NINDS R44NS117294.
0705 Detection of Periodic Limb Movements During Sleep in RLS Using Tonic Motor Activation System and Machine Learning
Authors: Rigot Stephanie , Singh Haramandeep , Baker Fiona , Ojile Joseph , Adlou Bahman , Charlesworth Jonathan 
Published: April 2024

Abstract

Introduction
Periodic limb movements during sleep (PLMS) are the most important objective correlate of restless legs syndrome (RLS) and, thus, could be beneficial for long-term monitoring and management. We aimed to develop a machine learning (ML) model to detect PLMS based on inertial measurement unit (IMU) movement sensors within an existing therapeutic device for refractory RLS – the tonic motor activation (TOMAC) system.

Methods
Twenty-two individuals with RLS completed a total of 32 nights of polysomnography (PSG) while wearing bilateral TOMAC units externally on the lower legs at the head of the fibula. Each TOMAC unit continuously recorded accelerometer and gyroscope data from a 6-axis IMU. Features including signal statistics, frequency domain characteristics, and positions were extracted from each IMU sensor in 2-second epochs throughout the night. Features were aggregated into 60-minute windows, input into a random forest ML model, and evaluated using leave-one-out cross-validation. Ground truth PLMS assessment was based on tibialis anterior EMG collected as part of PSG and technician-scored without excluding movements related to respiratory events. Classification metrics, Pearson correlations, and Bland-Altman plots were used to evaluate agreement, variability, and bias between ML model predictions and ground truth, based on ability to estimate periodic limb movement index (PLMI) for each hour and ability to screen for pathological PLMS based on the diagnostic cutoff PLMI &gt;15/hour.

Results
For calculating PLMI for each hour (n= 215 hours), ML model predictions were highly correlated with ground truth (r= 0.890) and showed minimal bias (mean ± SD= 0.11 ± 21.05). For classifying potential presence/absence of pathological PLMS, ML model predictions had high accuracy (0.907), specificity (0.958), and area under the curve (AUC, 0.841).

Conclusion
The TOMAC IMU feature-based ML model showed strong agreement with PSG-based ground truth for calculating PLMI and screening for pathological PLMS. This suggests that the therapeutic TOMAC system might also offer the possibility for long-term, in-home PLMS monitoring.

Support (if any)
Sponsored by Noctrix Health and supported by NIH/NINDS R44NS117294.
0706 Dextromethorphan for Restless Legs Syndrome: Testing the Glutamate Theory
Authors: Khalil Melissa , Dredla Brynn , Cheung Joseph , Castillo Pablo 
Published: April 2024

Abstract

Introduction
Restless legs syndrome (RLS) is a common disorder of unpleasant sensations during inactivity, an urge to move the legs, and hyperarousal. The pathophysiology is incompletely understood. Treatments are not always successful or carry side effects.

Methods
(Case Report)

Results
A 45-year-old woman presented with over a decade of RLS and sleep-onset insomnia. The diagnosis was based on the International RLS Study Group criteria. The severity was assessed by the nightly occurrence and Insomnia Severity Index (ISI) of 25. Interfering neurologic or sleep disorders, medications, and abnormal blood work were ruled out. Different dopamine agonists resulted in augmentation. Caffeine was stopped. Polysomnography revealed periodic limb movement with sleep fragmentation. Gabapentin was partially effective and poorly tolerated at high doses, but continued at 600 mg. While using Dextromethorphan (DXM) for an upper respiratory infection, the patient found dramatic improvement of her RLS symptoms. Independently, she discontinued Gabapentin, and continued DXM 30 mg for 6 months, with consistent improvement. ISI decreased to 10. Ultimately, considering its expense, DXM was tapered, and Tramadol initiated. The pathophysiology of RLS is partially understood. Studies showed abnormalities in iron regulation, low adenosine tone, enhanced glutamatergic activity, inflammation, and a genetic predisposition, as contributing factors. Alpha-2-delta calcium channel ligands inhibit the presynaptic glutamate release. Central nervous system iron deficiency may increase glutamatergic tone. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, inhibits the activation of NMDA receptor by glutamate and decreases glutamate presynaptic release. Ketamine was reported to effectively treat RLS. DXM, another NMDA receptor antagonist, has not been reported to treat RLS in the literature. Additionally, an association between inflammation and RLS was described, and limited data showed anti-inflammatory effect of DXM.

Conclusion
Patients with RLS suffer from their symptoms’ burden. Approved medications could carry side effects, or augmentation. We report a case of severe RLS with dramatic and sustained improvement with DXM.

Support (if any)
0709 Incidence, Determinants, and Impact of RLS During Pregnancy and Puerperium
Authors: Esteves Andrea , Hackethal Sandra , Riccardi Silvia , Garbazza Corrado , Manconi Mauro 
Published: April 2024

Abstract

Introduction
RLS is associated with a lower quality of life. During pregnancy, RLS is highly frequent and peaks in the third trimester. The main objective of the present study was to evaluate the impact of RLS on sleep during pregnancy and puerperium by using subjective and objective data.

Methods
This study was part of the multicenter study “Life-ON”, prospective, cohort investigation on sleep and mood changes during early pregnancy until 12 months after delivery. The presence of Restless legs Syndrome (RLS) was assessed in interview, according to essential criteria for diagnosis of RLS proposed by the International RLS Study Group (IRLSSG) during 11 visits (1 º, 2 º and 3 º trimester; and after delivery – 8 visits). Sleep was evaluated by PSG during the 2º trimester. Mood (MADRS, EPDS, HDRS-21), sleep quality (PSQI), insomnia (ISI), sleepiness (ESS) were also assessed at visits.

Results
Out of the 439 pregnant women recruited, 113 (26.037%) met the criteria for diagnosis of RLS. Together with the prevalence, the severity of RLS get worse in the third trimester. Pregnant women suffering from RLS had a worse sleep quality and insomnia then non-RLS women. A reduction in Sleep Efficiency and an increase in PLMS have also been demonstrated by polysomnography. Mood deflection was also associated with RLS; while RLS was not associated with adverse fetal outcomes and pregnancy related complications.

Conclusion
RLS is confirmed to be highly prevalent in late pregnancy. A negative impact of RLS on mood and sleep was evident from both subjective and objective tests.

Support (if any)
0711 REM Sleep Behavior Disorder Diagnostic Code Accuracy and Implications in the Outpatient Setting
Authors: Chahine Lana , Ratner Deena , Palmquist Aaron , Dholakia Gayatri , Boyce Richard , Rosano Caterina , Brooks Maria 
Published: April 2024

Abstract

Introduction
Isolated REM sleep behavior disorder (iRBD) carries increased risk for neurodegenerative parkinsonian disorders or dementia (NPD), but is difficult to accurately screen for in the community. Healthcare data offer the opportunity to identify large numbers of iRBD cases among outpatients. We aimed to determine the positive predictive value (PPV) of an RBD international classification of disorders (ICD) code for actual iRBD based on manual review of the electronic health record (EHR), examine risk of NPD diagnosis, and explore whether a statistical model developed using selected EHR data can identify individuals with RBD ICD code that have high probability for actual iRBD.

Methods
In this retrospective cohort study, an EHR search at a single healthcare system was conducted to identify outpatient cases who received ICD9 or ICD10 RBD code in 2011-2021. The EHR for each case was manually reviewed. Cases with secondary causes of RBD were excluded. Remaining cases were classified as no iRBD or actual iRBD. Incident cases of NPD were identified. PPV of presence of RBD ICD code for actual iRBD was calculated. Cumulative incidence of NPD with death as a competing event was compared in those with vs without iRBD. Least absolute shrinkage and selection operator (LASSO) regression was used to build a prediction model for iRBD and the model was validated in an independent dataset.

Results
Among 1,130 cases with RBD ICD code, 499 had secondary causes of RBD. For the remaining 628 cases, determination based on EHR review was that 168 (26.8%) did not have iRBD; PPV of RBD ICD code was 73.25%. Compared to the no iRBD group, the iRBD group had a higher risk of NPD (sub-distribution hazard ratio=10.4 (95% CI 2.5-43.1)). The LASSO prediction model for iRBD had an Area Under the Receiver Operating Characteristic Curve of 0.844 (95%CI 0.806-0.880).

Conclusion
PPV of an RBD ICD code is moderate. In the real-world setting, patients with iRBD had a high risk of diagnosis of NPD. Results indicate feasibility of using statistical models developed using EHR data to accurately predict iRBD.

Support (if any)
This work was partially funded by the University of Pittsburgh Dean’s Faculty Advancement Award (Chahine PI).
0712 Tonic Motor Activation for Restless Legs Syndrome Is Compatible with Sleep Onset and Reduces Periodic Leg Movements
Authors: Rigot Stephanie , Adlou Bahman , Kolotovska Viktoriia , Tekchandani Jatin , Charlesworth Jonathan 
Published: April 2024

Abstract

Introduction
Tonic motor activation (TOMAC) is a noninvasive neurostimulation therapy indicated for refractory restless legs syndrome (RLS). Here, we characterized the acute response to TOMAC based on objective evidence from polysomnography (PSG).

Methods
Adults with primary moderate-severe refractory RLS (n=23) were enrolled in a clinical trial (NCT05214963) that included a night of PSG with TOMAC treatment. Participants were instructed to activate TOMAC sessions to address RLS symptoms before sleep onset (bedtime session, n=8) and/or awakenings during the sleep period (mid-sleep session, n=19). When activated, TOMAC bilaterally stimulated the peroneal nerve for 30-minutes and turned off automatically. For each 30-minute TOMAC session, periodic leg movements during sleep (PLMS) were compared between the last 15min of sleep before TOMAC activation and the first 15min of sleep after TOMAC activation.

Results
Sleep initiation occurred during 75% of bedtime TOMAC sessions and 84% of mid-sleep TOMAC sessions. Mean duration from TOMAC activation to sleep was 21.9 min for bedtime sessions (median 16.1, SD 15.7) and 13.6 minutes for mid-sleep sessions (median 7.4, SD 15.4). Mean TOMAC intensity at the time of sleep onset/re-initiation was 27.2mA (SD: 5.8), similar to previous clinical trials. For mid-sleep TOMAC sessions, mean PLMS frequency reduced by 75% from 36.7/hour (SD: 68.6) before TOMAC activation to 9.1/hour (SD: 37.5, p&lt; 0.01) after TOMAC activation; this corresponded to 68% reduction relative to mean PLMS frequency during the full sleep period (28.6/hour).

Conclusion
TOMAC was compatible with sleep; both sleep onset and re-initiation were prevalent during TOMAC administration at therapeutic stimulation intensities. TOMAC was also associated with significant acute reduction in PLMS. These results motivate investigation of the longer-term effects of TOMAC on sleep architecture and PLMS.

Support (if any)
Sponsored by Noctrix Health and supported by NIH/NINDS R44NS117294.
0717 Ageism and Insomnia: Examining the Relationship Between Negative Aging Stereotypes and Insomnia in Older Adults
Authors: Boyle Julia , Fischer Ian , Bashian Hannah , Moye Jennifer , Pietrzak Robert 
Published: April 2024

Abstract

Introduction
Although insomnia symptoms (e.g., sleep disturbances, daytime complaints) are more prevalent in older age, poor sleep is not guaranteed in older adulthood. Preliminary research has found a relationship between an individual’s greater awareness of age-related changes and poor sleep; however, more research is needed to observe this relationship in insomnia and aging stereotypes. Using data from a nationally representative sample of U.S. veterans, the present study sought to characterize the relationship between negative aging stereotypes and clinical insomnia symptoms.

Methods
Participants (N=3,000) were older veterans (aged 60-99) who participated in the National Health and Resilience in Veterans Study (NHRVS). Participants reported their insomnia severity (Insomnia Severity Index [ISI]), sleep disturbance (ISI Factor 1 [items1,2,3]), and daytime dysfunction (ISI Factor 2 [items4,5,6,7]). Negative aging stereotypes were assessed using a 3-item Expectations Regarding Aging scale, which assessed negative stereotypes related to emotional, physical, and cognitive aging. Sociodemographic characteristics, mental health and medical conditions, traumatic life events, physical activity, disability, and psychotropic medication use were also assessed.

Results
Veterans who screened positive for clinical insomnia (n=213; weighted 7.1%) scored significantly higher on measures of negative stereotypes regarding emotional (p&lt;.001), physical (p=.003), and cognitive (p=.013) aging. Multivariable regression analyses revealed that, after adjusting for a broad range of sociodemographic, trauma, and health covariates, greater endorsement of negative stereotypes regarding emotional aging was associated with significantly greater odds of screening positive for clinical insomnia (OR=1.57, 95%CI=1.24-1.99, p&lt;.001), as well as higher rates of sleep disturbance (OR=1.54, 95%CI=1.28-1.86, p&lt;.001) and daytime dysfunction (OR=1.67, 95%CI=1.40-2.00, p&lt;.001). Relative to veterans who fully rejected aging stereotypes, those who somewhat and fully endorsed them were 3- and 6-times more likely to screen positive for clinical insomnia, respectively (predicted probabilities=0.10 and 0.18 vs. 0.03).

Conclusion
Negative aging stereotypes, especially emotional aging, were related to clinical insomnia symptoms in a nationally representative sample of U.S. veterans aged 60+. These findings suggest that efforts to modify aging stereotypes in older veterans may help improve overall sleep quality, or alternatively, that addressing clinical insomnia may help mitigate negative aging stereotypes. Longitudinal studies are needed to evaluate interrelationships between these measures over time.

Support (if any)
0720 A Cone Beam CT Study of Upper Airway Morphology in Perimenopausal and Postmenopausal Women
Authors: Zhang Wanxin , Gao Xuemei 
Published: April 2024

Abstract

Introduction
Menopause is accompanied by a decline in estrogen and progesterone. Several studies have demonstrated that upper airway patency decreases in women after menopause, while morphology changes are still a lack of evidence. This study aimed to explore upper airway morphology changes in perimenopausal and postmenopausal women.

Methods
This retrospective cross-sectional study included 367 consecutive Chinese female patients over 25 years old who had routinely taken large-field cone beam computed tomography in the imaging library of Peking University School and Hospital of Stomatology from October 2016 to September 2020. A total of 283 males were screened as sex controls according to the same age group. Upper airway morphology, hyoid position and facial pattern were measured. The association between perimenopausal and postmenopausal years and upper airway morphology in both sexes was analyzed.

Results
Perimenopausal women (aged 45–54 years) showed a significant decrease in the volume (3172.91mm3, 95% CI = 653.86–5691.96) and minimum cross-sectional area (37.08 mm2, 95% CI = 5.36–68.80), and a significant increase in the length (−1.96mm, 95% CI = −3.62 to −0.29) of upper airway compared to adjacent reproductive years (aged 35–44), while this difference was neither seen in other adjacent two reproductive age groups of females nor in the same age groups of males. In postmenopausal women (55 years and older), hyoid position was significantly lower (−2.74mm, 95% CI = −4.42 to −1.07) than either age group, while no similar changes were seen in men.

Conclusion
Women had smaller airway volume, reduced upper airway cross-sectional area and longer airway length in perimenopausal years, and a significantly lower hyoid position in postmenopausal years. These changes may be related to menopause itself and independent of the changes associated with aging.

Support (if any)
Clinical Research Foundation of Peking University School and Hospital of Stomatology (PKUSS-2023CRF203)
0725 Phenotyping Obstructive Sleep Apnea in Latin American Women: The Latin American Sleep Network (LATAM Sleep Net)
Authors: Labarca Gonzalo , Che Jose Luis , Henriquez-beltran Mario , Saldias Fernando , Retamal Eva , Nieto Joaquin , Perez-chada Daniel , Maquilon Cesar , Herrera Edwin , Vargas Leslie , de Castro Jorge Rey , Jorquera Jorge , Saad Romina , Bazuarto Maria Angelica , Bettancourt Eddy , Larrateguy Luis , Gutierrez Angela , Rojas Stephanie , Nunez Jimena , Zuniga Carlos 
Published: April 2024

Abstract

Introduction
Obstructive Sleep Apnea (OSA) is a major cardiovascular risk factor and has worse health outcomes. Novel OSA-driven metrics have been associated with worse outcomes. However, data on women from unrepresentative groups, such as the Hispanic/Latino population outside the USA, is scant. This study aims to quantitatively describe the clinical and novel OSA-driven phenotypes among women from Latin America.

Methods
We performed a prospective, multicenter study including women with suspected OSA from 18 sleep clinics in 8 countries (Argentina, Bolivia, Chile, Colombia, Costa Rica, Mexico, Peru, and Uruguay). We extracted the raw data from the baseline sleep study from October 2022 to December 2023. To determine 1). Sleep Apnea Specific hypoxic burden (SASHB) is defined as the total area under respiratory event-related desaturation curves; 2) Specific Heart Rate Response (ΔHR), defined as the difference between a maximum heart rate during a subject-specific search window and an event-related minimum heart rate; 3) Ventilatory burden, defined as the event-specific area under the ventilation signal, identified by amplitude changes in the nasal pressure signal; and 4) Desaturation sensitivity (i.e., the tendency to desaturate) was defined as a hypoxic burden divided by a ventilatory burden.

Results
A total of 318 women were included 26% non-OSA, 38% mild OSA, and 36% moderate to severe OSA). The average AHI3% was 16.5 ev/hr, SASHB was 43.4%min/hr; VB was 244.3 %eupnea*min/h; ΔHR was 8.2 bpm, and the desaturation sensitivity was 0.16. Among OSA patients, the AHI3% was 21.78 ev/hr; SASHB was 57.8 %min/hr; VB was 338.1 %eupnea*min/h; ΔHR was 8.14 bpm, and the desaturation sensitivity was 0.18. Based on high SASHB (≥ 60%min/hr) or high ΔHR (≥ 10 bpm), 19% and 26% of the sample are at risk of worse cardiovascular outcomes, respectively, and 7.4% of the sample reported both criteria associated with adverse outcomes.

Conclusion
Among OSA women from Latin America, OSA-physiologically driven metrics are reproducible and similar to previous publications. Further studies are needed to fully understand the clinical utility of these metrics in clinical practice. Study register ISRCTN11936746.

Support (if any)
The Chest /AASM (7868 ); NIH(1R21HL161766-01); SRS (07-SRG-22); Universidad de Concepcion(2022000589)