Background: Obstructive Sleep Apnea (OSA) is one of the most prevalent sleep disorders associated with cardiovascular complications, cognitive impairments, and reduced quality of life. Early and accurate diagnosis is essential. The present gold standard, polysomnography, is expensive and resource-intensive. This work develops a non-invasive machine-learning-based framework to classify four OSA severity groups (non, mild, moderate, and severe) using tracheal breathing sounds (TBSs) and anthropometric variables. Methods: A total of 199 participants were recruited, and TBS were recorded whilst awake (wakefulness) using a suprasternal microphone. The workflow included the following steps: signal preprocessing (segmentation, filtering, and normalization), multi-domain feature extraction representing spectral, temporal, nonlinear, and morphological features, adaptive feature normalization, and a three-stage feature selection that combined univariate filtering, Shapley Additive Explanations (SHAP)-based ranking, and recursive feature elimination (RFE). The classification included training ensemble learning models via bootstrap aggregation and validating them using stratified k-fold cross-validation (CV), while preserving the OSA severity and anthropometric distributions. Results: The proposed framework performed well in discriminating among OSA severity groups. TBS features, combined with anthropometric ones, increased classification performance and reliability across all severity classes, providing proof for the efficacy of non-invasive audio biomarkers for OSA screening. Conclusions: TBS-based model's features, coupled with anthropometric information, offer a promising alternative or supplement to PSG for OSA severity detection. The approach provides scalability and accessibility to extend screening and potentially enables earlier detection of OSA, compared to cases that might remain undiagnosed without screening.

Electrovestibulography (EVestG) has shown promise in diagnosis and separating of patients with Alzheimer’s disease (AD) with different levels of cerebrovascular disease (CVD). This exploratory sub-study investigates one of the main EVestG biomarkers in detecting neurophysiological changes associated with real versus sham transcranial alternating current stimulation (tACS) combined with cognitive exercises as a treatment for patients with AD. The extracted feature, the averaged action potential (AP) area, was compared between baseline, post-intervention, and 2-month post-follow-up assessments. Results indicate real tACS paired with cognitive exercises produced more consistent neurophysiological shifts toward healthy pattern compared to that of sham stimulation paired with cognitive exercises. Further, the AP-area changes in the two subgroups of low and high CVD amongst the AD participants showed different patterns in the real tACS group, implying different mechanism of tACS depending on the CVD level of the patients. These results congruent with prior diagnostic studies suggest AP-area can monitor the physiological effects of tACS as a treatment for patients with AD and mixed AD-CVD.

In this pilot study, we introduce a novel approach for the upper airway acoustic modelling aimed at developing a patient-specific transfer function of the upper airway. We modelled the upper airway as an acoustic filter, and hypothesized the parameters of such model would correlate with the anatomical features. The method involved generating a signal with known frequency characteristics at the mouth while recording the output at the suprasternal notch. Five distinct protocols were tested, and a consistency study was conducted to identify the most suitable protocol. The protocols varied in terms of input sound type and breathing maneuvers. Ten healthy subjects participated in this pilot study over three days with four recordings per day. The results indicated that the most consistent protocol utilizing white noise as the input sound while the participant breathed passively. The standard error of the difference between the detected peak frequencies was less than 10

Background and Objectives: Transcranial alternating current stimulation (tACS) at 40 Hz has shown potential to enhance cognitive function. However, research on its combination with cognitive exercises, particularly its long-term effects in a dementia population, remains limited. This study investigated the effects of 40 Hz tACS paired with simultaneous cognitive exercises on cognition, neuropsychiatric symptoms, and the depression status of individuals with dementia in a sham-controlled, double-blind crossover design. Materials and Methods: A total of 42 participants with dementia were randomized into two groups: (1) the R1S2 group received 40 Hz real tACS with cognitive exercises, followed by a ≥8-week washout period, and then sham tACS with cognitive exercises; (2) the S1R2 group received the reversed sequence. tACS was applied at 1.5 mA peak-to-peak with electrodes over the left dorsolateral prefrontal cortex and contralateral supraorbital area. Participants received two 30 min stimulation sessions per day, 5 days per week, for 4 consecutive weeks, paired with cognitive exercises using the MindTriggers app (2.9.1). The primary outcome was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the secondary outcomes included the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Neuropsychiatric Inventory Questionnaire (NPI-Q). All outcome measures were assessed before and after each treatment block. Results: Real tACS paired with cognitive exercises significantly improved ADAS-Cog scores post-treatment compared to pre-treatment (p-value = 0.019), whereas sham tACS did not. Furthermore, real tACS produced significant long-term improvements approximately 2–3 months post-treatment in ADAS-Cog scores compared to sham (p-value = 0.048). Both real (p-value = 0.003) and sham (p-value = 0.015) tACS significantly reduced NPI-Q scores post-treatment. MADRS scores significantly improved (p-value = 0.007) post-treatment for real tACS but not sham. Conclusions: The 40 Hz tACS paired with cognitive exercises improves cognition, neuropsychiatric symptoms, and depression post-treatment in dementia, with sustained cognitive effects. The findings highlight its potential as a non-invasive therapeutic intervention for dementia.

The efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for Alzheimer’s disease (AD) is uncertain at baseline. Herein, we aimed to investigate whether radiomic features from the pre-treatment MRI data could predict rTMS efficacy for AD treatment. Out of 110 participants with AD in the active (n = 75) and sham (n = 35) rTMS treatment groups having T1-weighted brain MRI data, we had two groups of responders (active = 55 and sham = 24) and non-responders (active = 20 and sham = 11). We extracted histogram-based radiomic features from MRI data using 3D Slicer software; the most important features were selected utilizing a combination of a two-sample t-test, correlation test, least absolute shrinkage, and selection operator. The support vector machine classified rTMS responders and non-responders with a cross-validated mean accuracy/AUC of 81.9

Alzheimer’s disease (AD) is the most common type of dementia, and AD individuals often present significant cerebrovascular disease (CVD) symptomology. AD with significant levels of CVD is frequently labeled mixed dementia (or sometimes AD-CVD), and the differentiation of these two neuropathologies (AD, AD-CVD) from each other is challenging, especially at early stages. In this study, we compared the gray matter (GM) and white matter (WM) volumes in AD (n = 83) and AD-CVD (n = 37) individuals compared with those of cognitively healthy controls (n = 85) using voxel-based morphometry (VBM) of their MRI scans. The control individuals, matched for age and sex with our two dementia groups, were taken from the ADNI. The VBM analysis showed widespread patterns of significantly lower GM and WM volume in both dementia groups compared to the control group ( P < .05, family-wise error corrected). While comparing with AD-CVD, the AD group mainly demonstrated a trend of lower volumes in the GM of the left putamen and right hippocampus and WM of the right thalamus (uncorrected P < .005 with cluster threshold, K = 10). The AD-CVD group relative to AD tended to present lower GM and WM volumes, mainly in the cerebellar lobules and right brainstem regions, respectively (uncorrected P < .005 with cluster threshold, K = 10). Although finding a discriminatory feature in structural MRI data between AD and AD-CVD neuropathologies is challenging, these results provide preliminary evidence that demands further investigation in a larger sample size.

Repetitive transcranial magnetic stimulation (rTMS) is used clinically to treat major depression and has more recently been applied as a potential treatment for Alzheimer’s disease (AD). Given that the rTMS treatment protocols for AD are similar to those used for depression, we investigated whether the AD participants’ cognition change after rTMS was, in part, due to a change in depressive level. Twenty-eight participants of an rTMS treatment study for AD participated in this study. We collected cognitive measures to partition them into 2 groups of subjects with marked or moderate responses (n = 13) and those with responses of small or none (n = 15). Besides, we recorded pre and post Electrovestibulography (EVestG) signals, and 2 EVestG features targeting depression were calculated from the averaged field potential curve (FP ave ) and low-frequency modulation of the recorded firing pattern (33-interval histogram [IH33]), respectively. We then compared these features in the above-mentioned cognitive-wise response groups. The FP ave and IH33 depression-related features showed no substantial difference between pre- and post-treatment in either group in response to rTMS treatment. The change in these EVestG depression features of the AD participants was also poorly correlated with Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change with treatment. This study’s results demonstrate that cognitive improvement post rTMS is not predominantly a result of an improvement in depression.

We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer's disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham rTMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. The rTMS pulses (20 ​Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied serially to the left and right dorsolateral prefrontal cortex using neuro-navigation. We compared the primary outcome measure's (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment up to two months post-treatment with either sham or active coils. The results show both short and long-term benefits of active rTMS treatment but also show similar benefits for sham coil treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil's potential to induce a low-level current in the brain.Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02908815

Attrition is a particular concern in studies examining the efficacy of a treatment for Alzheimer disease. Analyzing reasons for withdrawal in Alzheimer studies is crucial to ruling out attrition bias, which can undermine a study's validity. In contrast, attrition in studies using repetitive transcranial magnetic stimulation (rTMS) has received much less attention. Our goal was to identify any commonalities between participants who withdrew for the same reasons. Three independent coders rated each response concerning the reasons for withdrawal, and frequency tables were generated to characterize the participants within each category. This study was conducted on the 28 withdrawn cases from a 7-month study investigating the short-term and long-term therapeutic effects of rTMS for Alzheimer disease among 156 participants across 3 sites of the study. Seven reasons for withdrawal were identified, with health and medical changes being the most commonly reported reason (7 participants). Personal issues involving family or caregivers were the next most common (5 participants), and the remaining 5 categories consisted of 3 participants each. Although the limited sample size prevented the use of inferential statistics, our findings highlight the need for more transparent reporting of attrition rates and withdrawal reasons by rTMS researchers.

This study is a post-hoc examination of baseline MRI data from a clinical trial investigating the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for patients with mild–moderate Alzheimer’s disease (AD). Herein, we investigated whether the analysis of baseline MRI data could predict the response of patients to rTMS treatment. Whole-brain T1-weighted MRI scans of 75 participants collected at baseline were analyzed. The analyses were run on the gray matter (GM) and white matter (WM) of the left and right dorsolateral prefrontal cortex (DLPFC), as that was the rTMS application site. The primary outcome measure was the Alzheimer’s disease assessment scale—cognitive subscale (ADAS-Cog). The response to treatment was determined based on ADAS-Cog scores and secondary outcome measures. The analysis of covariance showed that responders to active treatment had a significantly lower baseline GM volume in the right DLPFC and a higher GM asymmetry index in the DLPFC region compared to those in non-responders. Logistic regression with a repeated five-fold cross-validated analysis using the MRI-driven features of the initial 75 participants provided a mean accuracy of 0.69 and an area under the receiver operating characteristic curve of 0.74 for separating responders and non-responders. The results suggest that GM volume or asymmetry in the target area of active rTMS treatment (DLPFC region in this study) may be a weak predictor of rTMS treatment efficacy. These results need more data to draw more robust conclusions.

Alzheimer's disease (AD) is often mixed with cerebrovascular disease (AD-CVD). Heterogeneity of dementia etiology and the overlapping of neuropathological features of AD and AD-CVD make feature identification of the two challenging. Separation of AD from AD-CVD is important as the optimized treatment for each group may differ. Recent studies using vestibular responses recorded from electrovestibulography (EVestG (TM)) have offered promising results for separating these two pathologies. An EVestG measurement records responses to several different physical stimuli (called tilts). In previous research, the number of EVestG features from different tilts was selected based on physiological intuition to classify AD from AD-CVD. As the number of potential characteristic features from all tilts can be very large, in this study, we used an algorithm based on principal component analysis (PCA) to rank the most effective vestibular stimuli for differentiating AD from AD-CVD. Analyses were performed on the EVestG signals of 28 individuals with AD and 24 with AD-CVD. The results of this study showed that tilts simulating the otolithic organs (utricle and saccule) generated the most characteristic features for separating AD from AD-CVD.

ObjectivesAnxiety disorder is present in approximately half of all bipolar disorder (BD) patients. There are neurologic bases for the comorbidity of balance (vestibular) disorders and anxiety. Our objective is to use electrovestibulography (EVestG), which is predominantly a measure of vestibular neural activity to not only quantitatively detect and measure comorbid anxiety disorder but also to quantitatively measure the impacts of anti-depressant, anti-psychotic, and mood stabilizer medication groups on anxiety measures in BD patients.MethodsIn a population of 50 (24 with anxiety disorder) depressive phase BD patients, EVestG signals were measured. Participants were labeled depression-wise as anxious or non-anxious using standard questionnaires. Analyses were conducted on the whole dataset as well as on matched (age/gender/MADRS) and “modeled medication-free” subsets. Modulations of the low-frequency EVestG firing pattern data were measured.FindingsFor BD, the main anxious minus non-anxious difference was the presence of an increase in spectral power proximal to 8–9 Hz, which was best attenuated by mood stabilizers.NoveltyThis is the first study to use an oto-acoustic physiological measure to quantify anxiety disorder in BD wherein it appears to manifest as a peak proximal to 8–9 Hz which we hypothesize as likely linked to hippocampal theta.

Background and Objectives: Diagnosis of dementia subtypes caused by different brain pathophysiologies, particularly Alzheimer’s disease (AD) from AD mixed with levels of cerebrovascular disease (CVD) symptomology (AD-CVD), is challenging due to overlapping symptoms. In this pilot study, the potential of Electrovestibulography (EVestG) for identifying AD, AD-CVD, and healthy control populations was investigated. Materials and Methods: A novel hierarchical multiclass diagnostic algorithm based on the outcomes of its lower levels of binary classifications was developed using data of 16 patients with AD, 13 with AD-CVD, and 24 healthy age-matched controls, and then evaluated on a blind testing dataset made up of a new population of 12 patients diagnosed with AD, 9 with AD-CVD, and 8 healthy controls. Multivariate analysis was run to test the between population differences while controlling for sex and age covariates. Results: The accuracies of the multiclass diagnostic algorithm were found to be 85.7% and 79.6% for the training and blind testing datasets, respectively. While a statistically significant difference was found between the populations after accounting for sex and age, no significant effect was found for sex or age covariates. The best characteristic EVestG features were extracted from the upright sitting and supine up/down stimulus responses. Conclusions: Two EVestG movements (stimuli) and their most informative features that are best selective of the above-populations’ separations were identified, and a hierarchy diagnostic algorithm was developed for three-way classification. Given that the two stimuli predominantly stimulate the otholithic organs, physiological and experimental evidence supportive of the results are presented. Disruptions of inhibition associated with GABAergic activity might be responsible for the changes in the EVestG features.

Abstract Background- We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer’s disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham TMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. Methods - The rTMS pulses (20 Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied to the bilateral dorsolateral prefrontal cortex bilaterally using neuro-navigation. We compared the primary outcome measure’s (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Results- Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment with either sham or active coils. Conclusion- The results do not support the benefit of active rTMS versus sham for cognitive treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil’s potential to induce a low-level current in the brain.

Abstract Background- We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer’s disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham TMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. Methods - The rTMS pulses (20 Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied to the bilateral dorsolateral prefrontal cortex bilaterally using neuro-navigation. We compared the primary outcome measure’s (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Results- Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment with either sham or active coils. Conclusion- The results do not support the benefit of active rTMS versus sham for cognitive treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil’s potential to induce a low-level current in the brain.

The vestibular end organs differ in terms of anatomical and physiological characteristics. Sensory modalities' stimuli including visual stimuli and vestibular sensation can influence these organs differently. This paper explores differences between vestibular responses to axial tilts in physical and virtual environments. Four passive whole-body movements (linear: up-down, and angular: yaw, pitch, and roll) were applied to twenty-seven healthy participants once using a hydraulic chair (physical) and once visually using a head-mounted display (virtual). Electrovestibulography (EVestG) was used as the outcome measure to investigate the magnitude of vestibular-response-change in both ears for physical and virtual stimuli. Three features including average action potential (AP) area, AP amplitude, and mean detected firing rate change were used as indices of response. The results show that for both physical and virtual stimuli (1) generally the pitch and roll tilts produce the largest EVestG changes compared to other tilts (2) roll and pitch tilt responses are not significantly different from each other and (3) right side and left side roll tilts' responses are not significantly different. The findings indicate although visually- and physically-induced vestibular responses are different in terms of afferent activity, visual stimuli can still result in distinct responses when exposed to different axial tilts.

Conflicting results have emerged from studies examining the potential of resting motor threshold (RMT) as a neurophysiological marker for Alzheimer's disease (AD) diagnosis and progression. In this study, we estimated the strength of the association between RMT measurements and severity of cognitive impairment in a relatively large sample (N=128) of clinical trial participants with mild (Clinical Dementia Rating - CDR=1) to moderate (CDR=2) AD. RMT for each participant was determined by applying single-pulse transcranial magnetic stimulation repeated at varying intensities over left and right sides of the primary motor cortex. RMT is the minimum intensity that evoked a visible contralateral involuntary finger twitch and RMT asymmetry is the absolute difference between the left and right RMT measurements. Cognitive impairment was measured with the Montreal Cognitive Assessment (MoCA) and the Alzheimer Disease Assessment Scale - Cognitive (ADAS-Cog) scores. Although the left and right RMT was lower in CDR 2 than in CDR 1 participants, neither RMT nor RMT asymmetry correlated significantly with cognitive test scores. In conclusion, our study in a large sample size does not support the idea that RMT is a sensitive marker of cognitive decline/severity in AD. Clinical Relevance- This study provides evidence that RMT may not be useful for AD progression monitoring.