Quantitative Analysis of Factors of Attrition in a Double-blind rTMS Study for Alzheimer Treatment.

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 This study was conducted on the 28 withdrawn cases from a 7-month study investigating the short-term and long-term therapeutic effects of rTMS for Alzheimer disease among 156 participants across 3 sites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.

Can Brain Volume-Driven Characteristic Features Predict the Response of Alzheimer's Patients to Repetitive Transcranial Magnetic Stimulation? A Pilot Study.

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.

Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial.

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 â€‹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 REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02908815.

Gray and White Matter Voxel-Based Morphometry of Alzheimer's Disease With and Without Significant Cerebrovascular Pathologies.

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.

Evaluating the Diagnostic Value of Electrovestibulography (EVestG) in Alzheimer's Patients with Mixed Pathology: A Pilot Study.

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.

Measuring anxiety disorder in bipolar disorder using EVestG: broad impact of medication groups.

Objectives: Anxiety 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. Methods: In 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. Findings: For 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. Novelty: This 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.

Does Resting Motor Threshold correlate with severity of Alzheimer's disease?

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.

Verification EVestG recordings are vestibuloacoustic signals.

Introduction: Neural dysfunction is associated with aberrant nerve firing; thus, electrodiagnosis has the potential for objective diagnosis and quantification of neural dysfunction. Electrical stimulation alters nerve firing and may also have treatment potential. This article outlines some findings related to electrodiagnosis and electrical stimulation of the ear. The quasi-synchronous firing of many vestibuloacoustic nerve fibers can produce an extracellular potential defined as a field potential (FP). Electrovestibulography (EVestG) is a method to record vestibuloacoustic signals and detect the associated FPs. A clear picture of the muscle-, EEG-, saccade-related, or other artefactual origins, and the physiologic basis of FPs recorded with EVestG, is evolving. EVestG was applied to demonstrate the effect of electrical stimulation on spontaneous FPs in the ear canal. Methods: Bilateral EVestG recordings were conducted on 14 guinea pigs before and after stimulation with 3-0.5 mA ipsilateral anodal electrical pulses before and after ablation via unilateral Scarpa's ganglionectomy to elucidate the origin of the EVestG recorded spontaneous FPs. Results: Anodal electrical stimulation suppresses the recorded activity. There was a significant reduction of the level of recorded signal observed following anodal stimulation on the ablated but not the intact side. Conclusion: Electrical stimulation of the external auditory canal reduces spontaneous electrical activity in the ear canal, some of which is due to central nervous system activity. The EVestG recorded FPs have a major vestibuloacoustic component.

The Effect of Transcranial Alternating Current Stimulation With Cognitive Training on Executive Brain Function in Individuals With Dementia: Protocol for a Crossover Randomized Controlled Trial.

BACKGROUND: Although memory and cognitive declines are associated with normal brain aging, they may also be precursors to dementia. OBJECTIVE: We aim to offer a novel approach to prevent or slow the progress of neurodegenerative dementia, or plausibly, improve the cognitive functions of individuals with dementia. METHODS: We will recruit and enroll 75 participants (older than 50 years old with either mild cognitive impairment or probable early or moderate dementia) for this double-blind randomized controlled study to estimate the efficacy of active transcranial alternating current stimulation with cognitive treatment (in comparison with sham transcranial alternating current stimulation). This will be a crossover study; a cycle consists of sham or active treatment for a period of 4 weeks (5 days per week, in two 30-minute sessions with a half-hour break in between), and participants are randomized into 2 groups, with stratification by age, sex, and cognitive level (measured with the Montreal Cognitive Assessment). Outcomes will be assessed before and after each treatment cycle. The primary outcomes are changes in Wechsler Memory Scale Older Adult Battery and Alzheimer Disease Assessment Scale scores. Secondary outcomes are changes in performance on tests of frontal lobe functioning (verbal fluency), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), mood changes (Montgomery-Åsberg Depression Rating Scale), and short-term recall (visual 1-back task). Exploratory outcome measures will also be assessed: static and dynamic vestibular response using electrovestibulography, neuronal changes using functional near-infrared spectroscopy, and change in spatial orientation using virtual reality navigation. RESULTS: As of February 10, 2022, the study is ongoing: 7 patients have been screened, and all were deemed eligible for and enrolled in the study; 4 participants have completed baseline assessments. CONCLUSIONS: We anticipate that transcranial alternating current stimulation will be a well-tolerated treatment, with no serious side effects and with considerable short- and long-term cognitive improvements. TRIAL REGISTRATION: Clinicaltrials.gov NCT05203523; https://clinicaltrials.gov/show/NCT05203523. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37282.

Comparing Vestibular Responses to Linear and Angular Whole-Body Accelerations in Real and Immersive Environments.

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.

An unbiased algorithm for objective separation of Alzheimer's, Alzheimer's mixed with cerebrovascular symptomology, and healthy controls from one another using electrovestibulography (EVestG).

Diagnosis of Alzheimer's disease (AD) from AD with cerebrovascular disease pathology (AD-CVD) is a rising challenge. Using electrovestibulography (EVestG) measured signals, we develop an automated feature extraction and selection algorithm for an unbiased identification of AD and AD-CVD from healthy controls as well as their separation from each other. EVestG signals of 24 healthy controls, 16 individuals with AD, and 13 with AD-CVD were analyzed within two separate groupings: One-versus-One and One-versus-All. A multistage feature selection process was conducted over the training dataset using linear support vector machine (SVM) classification with 10-fold cross-validation, k nearest neighbors/averaging imputation, and exhaustive search. The most frequently selected features that achieved highest classification performance were selected. 10-fold cross-validation was applied via a linear SVM classification on the entire dataset. Multivariate analysis was run to test the between population differences while controlling for the covariates. Classification accuracies of ≥ 80% and 78% were achieved for the One-versus-All classification approach and AD versus AD-CVD separation, respectively. The results also held true after controlling for the effect of covariates. AD/AD-CVD participants showed smaller/larger EVestG averaged field potential signals compared to healthy controls and AD-CVD/AD participants. These characteristics are in line with our previous study results.

Egocentric spatial orientation differences between Alzheimer's disease at early stages and mild cognitive impairment: a diagnostic aid.

Alzheimer's disease (AD) is a growing global crisis. Egocentric spatial orientation deteriorates with age and more significantly with AD. A simple and quick virtual reality (VR) localization and target finding technique is presented as a diagnostic aid to screen mild cognitive impairment (MCI) from AD. Spatial orientation data from 93 individuals (65 AD at a mild stage, 20 MCI, and 8 other dementia types) based on VR localization of a target on a landmark-less cubic 3-story building were analyzed. We hypothesize AD and MCI groups' performances are significantly different. AD and MCI spatial performances were statistically significantly (p < 0.001) different. These results plus the longitudinal tracking of three patients who developed AD over a period of 5 years suggest the proposed spatial tests may be used as a quick and simple clinical diagnostic aid to separate AD at early to mild stages from MCI.

Baseline Prediction of rTMS efficacy in Alzheimer patients.

Repetitive transcranial magnetic stimulation (rTMS) with extensive 2-6-week protocols are applied to improve cognition and/or slow the cognitive decline seen in Alzheimer's Disease (AD). To date, there are no means to predict the response of a patient to rTMS treatment at baseline. Electrovestibulography (EVestG) biomarkers can be used to predict, at baseline, the efficacy of rTMS when applied to AD individuals. In a population of 27 AD patients (8 with significant cerebrovascular symptomatology, labelled ADcvd) EVestG signals were measured before and after rTMS treatment, and then compared with 16 age-matched healthy controls. MoCA was measured at baseline, whilst ADAS-Cog was the primary outcome measure. AD severity and comorbid cerebrovascular disease were treated as covariates. Using ADAS-Cog total score change, 13/27 AD/ADcvd patients improved with rTMS and 14/27 showed no-improvement. Leave-one-out-cross-validated linear-discriminant-analysis using two EVestG features yielded a blind accuracy of 75% for separating the improved and non-improved populations. Three-way separation of improved/non-improved/control accuracy was 91.9% using MoCA (67% alone) and one EVestG feature (66% alone). AD severity affects the rTMS treatment efficacy. The effect of existing significant cerebrovascular symptomatology on the efficacy of rTMS treatment remains unresolved. Baseline EVestG features can be predictive of the efficacy of rTMS treatment.

Postural Sway Characteristics Are Affected by Alzheimer's Disease.

The vestibular system, responsible for balance, is affected by Alzheimer's disease (AD). In this paper, linear and non-linear balance features were used to assess the postural stability of 13 AD individuals at mild stages in comparison with 16 healthy controls. Utilizing two accelerometers, the anterior-posterior (AP) and medial-lateral (ML) sways were recorded from the T2 vertebrae and lateral malleolus of participants standing on a solid and soft foam surface under both eyes-open and eyes-closed conditions. From the recorded signals, four features were extracted and used for statistical analysis: Number of Position Changes (NPC), Number of Non-Zero Accelerations (NNZA), Katz, and Higuchi fractal dimensions (KFD and HFD, respectively). The results show: 1) postural stability is significantly worse for the eyes-closed compared to eyes-open condition (P<0.05 for all features except HFD) as well as whilst standing on soft foam compared to the solid surface (P<0.05 for all features) in both groups; 2) balance perturbations were larger for AP sway than ML on both solid and foam surfaces in both groups (P<0.05 for NPC and NNZA); and 3) stationary balance is significantly poorer for AD individuals compared to controls (P<0.05 for all features). These observations show that both linear and non-linear characteristics of postural stability data have the potentials to be used as objective diagnostic aids for the detection of AD.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial.

BACKGROUND: Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large, multisite, randomized, placebo-controlled, double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer disease. OBJECTIVE: The objectives of this paper are to report on recruitment, adherence, and adverse events (AEs) to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size. METHODS: The specific requirements of the analytic protocol are to (1) ensure the double-blind nature of the data while doing the analysis, (2) estimate the predictive probabilities of success (PPoSs), (3) estimate the numbers needed to treat, (4) re-estimate the initial required sample size. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian PPoS to predict the success rate and determine whether the study should continue. RESULTS: The enrollment has been slowed significantly due to the COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious AE. Only 2 patients dropped out of the study due to their intolerability to rTMS pulses. CONCLUSIONS: Overall, the study with the same protocol is going as expected with no serious AE or any major protocol deviation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31183.

Physiological separation of Alzheimer's disease and Alzheimer's disease with significant levels of cerebrovascular symptomology and healthy controls.

Most dementia patients with a mixed dementia (MxD) diagnosis have a mix of Alzheimer's disease (AD) and vascular dementia. Electrovestibulography (EVestG) records vestibuloacoustic afferent activity. We hypothesize EVestG recordings of AD and MxD patients are different. All patients were assessed with the Montreal cognitive assessment (MoCA) and Hachinski ischemic scale (HIS) (> 4 HIS score < 7 is representative of MxD cerebrovascular symptomology). EVestG recordings were made from 26 AD, 21 MxD and 44 healthy (control) participants. Features were derived from the EVestG recordings of the average field potential and field potential interval histogram to classify the AD, MxD and control groups. Multivariate analysis was used to test the features' significance. Using a leave-one-out cross-validated linear discriminant analysis with 3 EVestG features yielded accuracies > 80% for separating pairs of AD/MxD/control. Using the MoCA assessment and 2 EVestG features, a best accuracy of 81 to 91% depending on the classifier was obtained for the 3-way identification of AD, MxD and controls. EVestG measures provide a physiological basis for identifying AD from MxD. EVestG measures are hypothesized to be partly related to channelopathies and changes in the descending input to the vestibular periphery. Four of the five AD or MxD versus control features used had significant correlations with the MoCA. This supports assertions that the pathologic changes associated with AD impact the vestibular system and further are suggestive that the postulated physiological changes behind these features have an association with cognitive decline severity.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Alzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia. OBJECTIVE: The objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment. METHODS: We have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention. RESULTS: As of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect. CONCLUSIONS: This protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples. TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25144.

A Novel Program to Improve Cognitive Function in Individuals With Dementia Using Transcranial Alternating Current Stimulation (tACS) and Tutored Cognitive Exercises.

The effects of cognitive exercises on the healthy aging population is controversial. Transcranial alternating current stimulation (tACS) is considered a promising tool for modulating brain oscillation. Research is lacking on its long-lasting cognitive/therapeutic effect. This is the first pilot study to explore the effect of a regimen of cognitive exercises with and without tACS on older adults with dementia. The study groups were 28 individuals (age 56-83 years) enrolled into two groups: Exr Group, who received cognitive exercises only and the Exr + tACS Group who received tACS at 40 Hz simultaneously with cognitive exercises for a period of 4 consecutive weeks, 5 days/week, two 30 min-sessions/day; all the training sessions were tutored. The cognitive exercises were applied using the MindTriggers app. They were assessed at pre and post intervention and also one month after the end of trial (follow-up) with an independent assessment (WMS-IV) as the primary outcome measure. The results show significant cognitive improvement at post-intervention in both groups, while the Exr + tACS protocol lead to superior cognitive improvement at follow-up session. The most important outcomes of this study are: 1) The tutored repeated practice of the MindTriggers app exercises does significantly improve the cognitive functions of older adults with dementia and that that improvement lasts for at least one month after the end of the intervention, and 2) The application of tACS increases the positive effects of cognitive exercises with the positive effect lasting an even longer period of time than exercises alone; in other words we speculate that it may lead to long-term potentiation.

Correlation between Ocular and Vestibular Abnormalities and Convergence Insufficiency in Post-Concussion Syndrome.

The vestibular and oculomotor/visual systems are commonly affected in post-concussion syndrome (PCS). Convergence insufficiency (CI) is the most common ocular abnormality after concussion. Electrovestibulography (EVestG) is a relatively new non-invasive method that measures the peripheral vestibular responses; it has shown abnormal vestibular responses in a PCS. Here, we report the results of investigating the correlation between the vestibular and oculomotor systems in PCS population using EVestG and CI measures. Forty-eight PCS patients were tested using EVestG, out of which 20 also completed the Rivermead post-concussion questionnaire (RPQ). An EVestG feature (Field Potential (FP)-area) was extracted from the stationary part of the EVestG signals. A neuro-ophthalmologist (author BM) measured participants' CI at near vision using cross-cover examination and a prism-bar. Results indicate: (1) vestibular abnormality (i.e. FP-area) and CI values are significantly correlated in PCS (R = 0.68, p < .01), and (2) there are significant correlations between severity of concussion (i.e. RPQ3) and CI (R = 0.70, p < .01) and between RPQ3 and FP-area (R = -0.56, p < .02). To the best of our knowledge, this is the first study that objectively demonstrates a significant positive correlation between the CI and vestibular systems' abnormality. These findings are scientifically important as they help localise the pathology of PCS, and are clinically valuable as they help physicians in their decision-making about PCS diagnosis and rehabilitation strategies.