Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Posttraumatic stress symptoms across the deployment cycle: A latent transition analysis.

Our objective was to examine symptom-level changes in the course in posttraumatic stress disorder (PTSD) across the deployment cycle among combat-exposed Marines, and to determine the degree to which combat exposure and post-deployment stressor exposure predicted PTSD symptom profile transitions. We examined PTSD symptoms in a cohort of U.S. Marines (N = 892) recruited for the Marine Resiliency Study (MRS). Marines deployed as one battalion infantry unit to Afghanistan in 2010 and were assessed pre-deployment and one, five, and eight months post-deployment. We employed latent transition analysis (LTA) to examine Marines' movement across PTSD symptom profiles, determined by latent class analysis (LCA). LCAs revealed a 3-class solution one month pre-deployment, a 4-class solution at five months post-deployment, and a 3-class solution at eight months post-deployment. LTA revealed notable movement between classes over time, which depended chiefly on pre-deployment symptom presentation. Marines who reported few pre-deployment symptoms either maintained these low levels or returned to low levels by eight months. Marines who reported a moderate number of symptoms at pre-deployment had variable outcomes; 50% had reductions by eight months, and those who reported numbing symptoms at five months post-deployment tended to report more symptoms at eight months. Marines who reported more PTSD symptoms prior to deployment retained more symptoms eight months post-deployment. Combat exposure and post-deployment stressor exposure predicted profile transitions. Examining transitions between latent class membership over time revealed prognostic information about Marines' eight-month PTSD outcomes. The extent of pre-deployment PTSD symptoms was particularly informative of likely PTSD outcomes.

The structure of PTSD in active-duty marines across the deployment cycle.

OBJECTIVE: There has been significant debate about the optimal factor structure of posttraumatic stress disorder (PTSD). In military and veteran samples, most available studies have employed self-report measures, assessed PTSD cross-sectionally, used treatment-seeking samples, and assessed symptoms years after deployment. We extend previous studies by comparing the factor structure of clinician-assessed and self-report Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) PTSD in a nontreatment seeking sample at 4 time points spanning the deployment cycle. METHOD: The data source for this study was the Marine Resiliency Study (MRS), a longitudinal study of 4 battalion cohorts of active-duty male Marines deployed to Iraq and Afghanistan between 2008 and 2012. We examined the fourth cohort (N = 892), which was evaluated 1 month predeployment, and 1, 5, and 8 months postdeployment. RESULTS: Confirmatory factor analyses (CFA) revealed that the 5-factor solution best fit the data across all time points, and across both interview and self-report assessments. CONCLUSION: The temporal consistency and convergence demonstrated by our analyses underscores the validity of the 5-factor model among service members exposed to warzone stressors. In particular, the findings suggest that diagnostic criteria for PTSD may benefit from disaggregating hyperarousal symptoms in military samples.

Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans.

We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress.

PTSD symptom presentation across the deployment cycle.

BACKGROUND: Symptom-level variation in posttraumatic stress disorder (PTSD) has not yet been examined in the early post-deployment phase, but may be meaningful etiologically, prognostically, and clinically. METHODS: Using latent class analysis (LCA), we examined PTSD symptom heterogeneity in a cohort of participants from the Marine Resiliency Study (MRS), a longitudinal study of combat Marines deployed to Iraq and Afghanistan (N=892). Typologies of PTSD symptom presentation were examined at one month pre-deployment and again one, five, and eight months post-deployment. RESULTS: Heterogeneity in PTSD symptom presentation was evident at each assessment point, and the degree of symptom heterogeneity (i.e., the number of classes identified) differed by time point. Symptom patterns stabilized over time from notable symptom fluctuations during the early post-deployment period to high, medium, and low symptom severity by eight months post-deployment. Hypervigilance and exaggerated startle were frequently endorsed by participants in the initial month post-deployment. Flashbacks, amnesia, and foreshortened future were infrequently endorsed. Greater combat exposure, lifespan trauma, and avoidant coping generally predicted worse outcomes. LIMITATIONS: Data were self-report and may have limited generalizability due to our lack of women and inclusion of only combat Marines. Attrition and re-ranging of data resulted in significant missing data and affected the representativeness of the sample. CONCLUSIONS: Symptom-level variability is highest in the month following deployment and then stabilizes over time. Should post-deployment assessments occur too soon, they may capture common and transient early post-deployment reactions, particularly anxious arousal.

The relationship between course of PTSD symptoms in deployed U.S. Marines and degree of combat exposure.

Large cohort studies suggest that most military personnel experience minimal posttraumatic stress disorder (PTSD) symptoms following warzone deployment, an outcome often labeled resilience. Very low symptom levels, however, may be a marker for low exposure, not resilience, which requires relatively high-magnitude or high-frequency stress exposure as a precondition. We used growth mixture modeling (GMM) to examine the longitudinal course of lifetime PTSD symptoms following combat exposure by disaggregating deployed U.S. Marines into upper, middle, and lower tertiles of combat exposure. All factor models fit the data well; Tucker-Lewis Index (TLI) and comparative fit index (CFI) values ranged from .91 to .97. Three distinct trajectories best explained the data within each tertile. The upper tertile comprised True Resilience (73.2%), New-Onset Symptoms (18.3%), and Pre-existing Symptoms (8.5%) trajectories. The middle tertile also comprised True Resilience (74.5%), New-Onset Symptoms (16.1%), and Pre-existing Symptoms (9.4%) trajectories. The lower tertile comprised Artifactual Resilience (86.3%), Pre-existing Symptoms (7.6%), and New-Onset Symptoms (6.1%) trajectories. True Resilience involved a clinically significant symptom increase followed by a return to baseline, whereas Artifactual Resilience involved consistently low symptoms. Conflating artifactual and true resilience may inaccurately create the expectation of persistently low symptoms regardless of warzone exposure.

Posttraumatic stress in deployed Marines: prospective trajectories of early adaptation.

We examined the course of PTSD symptoms in a cohort of U.S. Marines (N = 867) recruited for the Marine Resiliency Study (MRS) from a single infantry battalion that deployed as a unit for 7 months to Afghanistan during the peak of conflict there. Data were collected via structured interviews and self-report questionnaires 1 month prior to deployment and again at 1, 5, and 8 months postdeployment. Second-order growth mixture modeling was used to disaggregate symptom trajectories; multinomial logistic regression and relative weights analysis were used to assess the role of combat exposure, prior life span trauma, social support, peritraumatic dissociation, and avoidant coping as predictors of trajectory membership. Three trajectories best fit the data: a low-stable symptom course (79%), a new-onset PTSD symptoms course (13%), and a preexisting PTSD symptoms course (8%). Comparison in a separate MRS cohort with lower levels of combat exposure yielded similar results, except for the absence of a new-onset trajectory. In the main cohort, the modal trajectory was a low-stable symptoms course that included a small but clinically meaningful increase in symptoms from predeployment to 1 month postdeployment. We found no trajectory of recovery from more severe symptoms in either cohort, suggesting that the relative change in symptoms from predeployment to 1 month postdeployment might provide the best indicator of first-year course. The best predictors of trajectory membership were peritraumatic dissociation and avoidant coping, suggesting that changes in cognition, perception, and behavior following trauma might be particularly useful indicators of first-year outcomes.

Does mental health stigma change across the deployment cycle?

OBJECTIVES: Prior research on mental health stigma in military personnel has been cross-sectional. We prospectively examined the course of perceived mental health stigma in a cohort of deployed U.S. combat Marines. METHODS: Participants (N = 768) were assessed 1 month before a 7-month deployment to Afghanistan, and again at 1, 5, and 8 months postdeployment. We also examined three predictors of the course of stigma: post-traumatic stress disorder symptom severity, vertical and horizontal unit cohesion, and mental health treatment utilization while deployed. RESULTS: Perceptions of stigma remained largely stable across the deployment cycle, with latent growth curve analyses revealing a statistically significant but small decrease in stigma over time. Lower post-traumatic stress disorder symptoms and greater perceived vertical and horizontal support predicted decreases in stigma over time, whereas mental health treatment utilization in theater did not predict the course of stigma. CONCLUSIONS: Perceived stigma was low and largely stable over time.

Benevolent sexist beliefs predict perceptions of speakers and recipients of a term of endearment.

This study examined how endorsement of benevolent sexist ideologies predicts perceptions of requesters who use a term of endearment and of the female addressees who comply with their requests. Undergraduate women who previously completed the Benevolent Sexism Scale as part of the Ambivalent Sexism Inventory were randomly assigned to one of four groups. They watched one of four videos in which a female addressee responded to a request that either included or did not include the term of endearment "hon"; the requester was either male or female. Participants then rated both actors' social likeability. Among participants who watched a woman respond to a female requester who addressed her with the term "hon," benevolent sexism scores predicted liking for the female responder and disliking of the female requester. Findings reflect the dissatisfaction of women who are high in benevolent sexism with women who act outside of traditional gender role expectations.