Sensory gamma frequency stimulation in cognitively healthy and AD individuals safely induces highly coordinated 40 hz neural oscillation: A preliminary study of non‐invasive sensory stimulation for treating Alzheimer’s disease

Abstract

Background Our lab previously showed that 40 Hz sensory stimulation can modulate neural oscillations, ameliorate Alzheimer’s disease (AD) pathology, and improve cognition in AD mouse models (Iaccarino, Singer et al., Nature, 2016; Martorell, Paulson et al., Cell, 2019; Adaikkan et al., Neuron, 2019). To determine the safety and feasibility of 40 Hz sensory stimulation as a potential therapeutic for AD, human subjects, including AD patients, were exposed to various stimulation modalities and their electrophysiological responses were studied. Method We developed a device that delivers light and sound at desired frequencies for human use. Cognitively healthy (24 males, 22 females; age range 20‐75) and AD subjects (7 males, 10 females; age range 55‐88) were stimulated with our device while their scalp electroencephalogram (EEG) was recorded. Epilepsy patients with intracranial electrodes (1 male, 1 female; age 19) were also exposed to our device for sensory stimulation while recording the intracranial EEG (iEEG). The EEG signals were screened for interictal/ictal spikes and analyzed to evaluate spectral characteristics. Result The EEG signals from cognitively healthy and AD subjects as well as epilepsy patients did not show any interictal/ictal spikes during or after the stimulation. In all subject groups, our sensory stimulation increased the spectral power and coherence at 40 Hz, with the concurrent visual and auditory stimulation leading to more widespread and coordinated 40 Hz oscillations than visual or auditory stimulation alone. iEEG signals showed that our sensory stimulation can entrain deeper brain regions. An hour‐long continuous 40 Hz stimulation using concurrent visual and auditory stimuli in healthy older subjects showed 40 Hz power and coherence both increasing over time. Following the hour‐long stimulation, gamma power and coherence were elevated compared to the pre‐stimulation levels. Conclusion Our non‐invasive sensory stimulation at gamma frequency safely induces highly coordinated 40 Hz oscillations in cognitively healthy and AD subjects. This serves as a preliminary study for a placebo‐controlled, randomized control trial to test the effect of our sensory stimulation on AD. The application of non‐invasive techniques to modulate gamma oscillations in the human brain is a novel and potentially very powerful disease modifying therapeutic for the treatment of dementia.

Gamma Entrainment Improves Synchronization Deficits in Dementia Patients

“…How can the entrainment of gamma band oscillatory activity lead to the therapeutic effects reported for AD [27][28][29][30]33,34 ? One mechanism which may help explain these effects is the principle of neuroplasticity, which states that the synaptic links between neurons experiencing synchronized activity strengthen over time.…”

“…Second, the hippocampus acts as a gamma generator 50 , and since the gamma quality is affected by AD 4 , direct gamma entrainment may prove more effective in repairing the cycle. Recent studies have reported improvements on patients using gamma entrainment 30,34 . In a study based on stimulating PV cells of the hippocampus invasively via optogenetics in a mouse model of AD, rehabilitated theta-gamma coupling and gamma power were reported along with better performance in an object and place recognition task 23 .…”

“…Interventions based on stimulating neural populations in the gamma band have been recently proposed and are under examination on animal models of AD 22,[27][28][29] and in limited human studies [30][31][32][33][34][35][36] . These approaches aim to reinvigorate the functionality of the brain networks through synchronized pumping of rhythmic energy via one or multiple sensory modalities.…”

Gamma oscillations and application of 40‐Hz audiovisual stimulation to improve brain function

“…Audiovisual combined stimulation induced more coordinated gamma oscillations that affect several brain regions more broadly and deeply than either visual or auditory stimulation alone (Suk et al, 2020). An animal experiment showed that amyloid beta plaques were generally reduced throughout the cerebral cortex under audiovisual combined stimulation at 40 Hz (Martorell et al, 2019).…”

Gamma Oscillations in Alzheimer’s Disease and Their Potential Therapeutic Role

“…While patients’ gamma brain activity or possible changes on AD pathology were not assessed, this study provided solid evidence regarding the efficacy of gamma-based treatment in AD. More recently, Suk et al (2020) developed a light and noise delivery device and stimulated at 40 Hz cognitively healthy, AD, and epileptic patients while their electrophysiological responses were recorded. The concurrent audiovisual stimulation was proved safe in all subject groups, including the epileptic patients, while induced highly coordinated 40 Hz oscillations.…”