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.

Gamma frequency sensory stimulation in mild probable Alzheimer’s dementia patients: Results of feasibility and pilot studies

“…Disturbances in daily activity rhythms accelerate the progression from MCI to AD, and a diagnosis of MCI or AD is associated with accelerated worsening of the disturbances [ 50 ]. Our findings of significantly increased day-to-day regularity of activity patterns (IS) over four months in the active group but not the control group are consistent with findings that GENUS light and sound can intervene to improve daily rhythms that ordinarily degrade with age and in AD [ 31 , 73 ]. Sleep may also be affected by combined GENUS stimulation.…”

Cognitive tasks propagate the neural entrainment in response to a visual 40 Hz stimulation in humans

“…This seems to suggest that visual gamma entrainment fundamentally differs from the steady-state responses induced by lower stimulation frequencies, which is in line with theories stating that steady-state responses to higher frequencies have a different cortical distribution compared to those elicited by lower frequencies (Vialatte et al, 2010 ; Wu, 2016 ). A recent paper (Cimenser et al, 2021 ) suggests that the lower frequencies in the gamma range propagate to the larger scalp areas compared to the higher frequencies (including 40 Hz). The authors of this paper however, did not use a task and it is still not clear whether the propagation of the entrainment in combination with a task is different in 40 Hz stimulation from other gamma frequencies.…”

Translational approaches to influence sleep and arousal

“…Accordingly, methods which increase neural activity during wakefulness, such as TMS, may increase slow-wave activity in subsequent sleep ( Huber et al, 2007 ). In a recent study, 40 Hz visual and auditory stimulation benefitted sleep in a small sample of Alzheimer’s disease patients ( Cimenser et al, 2021 ). Similar stimulation improved pathology in Alzheimer’s disease mouse models ( Addaikkan et al, 2019 ; Iacarino et al, 2016 ; Martorell et al, 2019 ).…”

“…One possible way that 40 Hz stimulation may improve pathology and cognition is by improving sleep. In a small recent clinical study 14 patients with mild to moderate AD showed improved sleep as assessed by actigraphy measures following 1 h of 40 Hz sensory stimulation/day for 6 months versus 8 sham control subjects ( Cimenser et al, 2021 ). Furthermore, in contrast to the sham stimulation control group which declined in their ability to carry out daily living activities, the stimulation group maintained their ability to function.…”