Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients

Abstract

Pathological proteins contributing to Alzheimer's disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT03556280.

Keywords: Alzheimer’s disease; actigraphy; activities of daily living; sensory-evoked gamma oscillation; sleep.

FIGURE 1

CONSORT flow diagram and study design. Current analysis included patients receiving treatment during eyes-closed condition and completed the 6-month trial, including all patients in the treatment and sham groups. Patients not included in this report are currently receiving therapy during the eyes-open condition in the on-going trial.

FIGURE 2

Cumulative distribution of rest and active durations based on 14,736 h of nighttime actigraphy data recorded from all participated patients (n = 22). The cumulative distributions of nighttime rest periods (displayed in blue) show exponential distribution, whereas active periods (displayed in black) show power law distribution. Solid lines show the best straight-line fits: rest durations can be fitted by a straight line in log-linear scale (A), and active durations can be fitted with a straight line in log-log scale (B). X axis display the nighttime durations; Y axis show the cumulative distributions. The current actigraphy data analysis revealed similar nighttime rest/activity dynamics to nighttime sleep/wake dynamics based on polysomnography data analysis (Lo et al., 2013).

FIGURE 3

Actigraphy recordings from a single patient demonstrating the effects of gamma sensory stimulation therapy on nighttime active and rest periods. (A–E) Five consecutive nights prior to treatment, (F–J) five consecutive nights during treatment period. Level of continuous activity is shown by the black tracing; median filtered activity levels are indicated by green (A–E) and brown (F–J) curves. The applied analysis identified nighttime active and rest periods: denoted sleep periods are marked by horizontal light blue bars, and the longest movement periods during nights are indicated by the dark blue bars. Compared to the pre-treatment period, fewer and shorter movement periods are observed. X-axis shows the time of day, Y-axis shows the activity level (in log scale).

FIGURE 4

Gamma sensory stimulation therapy reduced duration of active periods during nighttime. Changes in durations of active periods in treatment group is shown in red and sham group is shown in blue from the first 12 weeks to the last 12 weeks of the therapy (A). Active durations were normalized by dividing duration of each active period by the duration of the corresponding nighttime period (B). Changes observed in the treatment group (red) indicate a significant reduction in duration of active periods, indicating an improvement in sleep quality, while the opposite can be assessed in the sham group (blue).

FIGURE 5

Gamma sensory stimulation therapy results in maintenance of daytime activities assessed by Activities of Daily Living (ADCS-ADL) Score. Relative changes in daytime activities are shown between weeks 1–12 and weeks 13–24 in the treatment (red; n = 14) and sham (blue; n = 8) groups. Changes in daytime activities showed a significant (p < 0.035) improvement in the treatment group and a significant (p < 0.001) decline in the sham group.