Study on the effect of 40 Hz non-invasive light therapy system. A protocol for a randomized, double-blinded, placebo-controlled clinical trial.

Introduction: With no cure or effective treatment, the prevalence of patients with Alzheimer's disease (AD) is expected to intensify, thereby increasing the social and financial burden on society. Light-based 40 Hz brain stimulation is considered a novel treatment strategy for patients with AD that may alleviate some of this burden. The clinical trial ALZLIGHT will utilize a novel Light Therapy System (LTS). The LTS uses Invisible Spectral Flicker for non-invasive induction of 40 Hz neural activity. This protocol describes a trial evaluating the efficacy and safety of a light-based 40 Hz brain stimulation in patients with mild-to-moderate AD. Methods: 62 patients with mild-to-moderate AD will participate in a randomized, double-blinded, placebo-controlled, parallel-group, and single-center trial. The participants will partake in an enrollment period of 1 month, an intervention period of 6 months, and a 1.5-month post-interventional follow-up period. Prior to the baseline measurement (week 0), the patients will be randomized to either active or placebo intervention from baseline (week 0) to post-intervention follow-up (week 26). Discussion: This protocol describes a randomized, double-blinded, placebo-controlled clinical trial that may increase the understanding of the effect of gamma oscillations in the human brain and how it could be utilized as a novel and important tool for the treatment of AD. The effect is measured through a large, multidisciplinary assessment battery.Clinical trial registration:www.ClinicalTrials.gov, (NCT05260177). Registered on March 2, 2022.

Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study.

BACKGROUND: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer's disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. OBJECTIVE: To investigate the safety, feasibility, and exploratory measures of efficacy. METHODS: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. RESULTS: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. CONCLUSION: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Lack of amygdala habituation to negative emotional faces in alcohol use disorder and the relation to adverse childhood experiences.

Aberrant limbic circuit reactivity to negative stimuli might be related to alterations in emotion processing and regulation in alcohol use disorder (AUD). The current study tested for the first time in AUD the hypothesis of aberrant amygdala habituation to repeated aversive stimuli-a robust and reliable neuroimaging marker for emotion processing. We explored the link between deficits in habituation to adverse childhood experience (ACE), a common risk factor for impaired emotion regulation and AUD. AUD individuals (N = 36) and healthy controls (HC; N = 26) participated in an observational case-control functional magnetic resonance imaging (fMRI) study. An established habituation index was used to investigate processing of aversive emotional faces of the amygdala. AUD individuals showed an overall deficit in amygdala habituation (right: t = 4.26, pFWE = 0.004; left: t = 4.79, pFWE ≤ 0.001). Amygdala habituation was significantly related to increased exposure to ACE in HC (t = 3.88, pFWE = 0.012), whereas this association was not observed in AUD individuals (T = 1.80, pFWE = 0.662). Further, a significant association between higher alcohol consumption and reduced amygdala habituation (right: R2  = -0.356, F = 8.736, p = 0.004; left: R2  = -0.309, F = 6.332, p = 0.015) was observed. We found novel evidence for neural alterations in emotion processing in AUD individuals, indexed by deficient amygdala habituation to negative emotional content. We replicated a prior report on a link between ACE and amygdala habituation, a well-established environmental risk factor for mental disorders and emotion dysregulation, in our control sample. Additionally, deficient amygdala habituation related to the amount of alcohol consumption in the overall sample might indicate a short-term substance effect.