Audiovisual gamma stimulation for the treatment of neurodegeneration

Abstract

Alzheimer's disease (AD) is the most common type of neurodegenerative disease and a health challenge with major social and economic consequences. In this review, we discuss the therapeutic potential of gamma stimulation in treating AD and delve into the possible mechanisms responsible for its positive effects. Recent studies reveal that it is feasible and safe to induce 40 Hz brain activity in AD patients through a range of 40 Hz multisensory and noninvasive electrical or magnetic stimulation methods. Although research into the clinical potential of these interventions is still in its nascent stages, these studies suggest that 40 Hz stimulation can yield beneficial effects on brain function, disease pathology, and cognitive function in individuals with AD. Specifically, we discuss studies involving 40 Hz light, auditory, and vibrotactile stimulation, as well as noninvasive techniques such as transcranial alternating current stimulation and transcranial magnetic stimulation. The precise mechanisms underpinning the beneficial effects of gamma stimulation in AD are not yet fully elucidated, but preclinical studies have provided relevant insights. We discuss preclinical evidence related to both neuronal and nonneuronal mechanisms that may be involved, touching upon the relevance of interneurons, neuropeptides, and specific synaptic mechanisms in translating gamma stimulation into widespread neuronal activity within the brain. We also explore the roles of microglia, astrocytes, and the vasculature in mediating the beneficial effects of gamma stimulation on brain function. Lastly, we examine upcoming clinical trials and contemplate the potential future applications of gamma stimulation in the management of neurodegenerative disorders.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid

“…We found that 40 Hz multisensory audio-visual stimulation increased 40 Hz local field potential power in frontal cortex areas of 6-month-old 5XFAD mice (Extended Data Fig. 1a–c ), as expected on the basis of prior reports in mice 6 and humans 8 , 16 . In separate cohorts of 6-month-old 5XFAD mice, 40 Hz stimulation attenuated amyloid burden compared with no stimulation, 8 Hz stimulation and 80 Hz stimulation controls (Fig.…”

“…In humans and mice, sensory stimuli at specific frequencies can be used to promote neural activity corresponding to the sensory stimulation 15 . Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions, including the prefrontal cortex 6 , 7 , 16 , and we and others found that noninvasive 40 Hz sensory stimulation attenuates amyloid burden in Alzheimer’s disease model mice 8 . In particular, multisensory 40 Hz stimulation (that is, combined light and sound stimulation) attenuates amyloid burden throughout the cortex, including the prefrontal cortex 6 .…”

“… The glymphatic movement of fluid through the brain removes metabolic waste 1 – 4 . Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease 5 – 8 . Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease.…”

Visually Evoked 40 Hz Gamma Activity Enhanced by Transcranial Electrical Stimulation

“…Pulsed TES combined with periodic VS modulated gamma activity more strongly than the visual modality alone. This finding is highly relevant given the widespread interest in gamma stimulation to causally investigate associated cognitive functions such as memory (Hanslmayr et al, 2019), the role of gamma activity in general brain health (Başar, 2013), and new therapeutic avenues for neurodegenerative conditions, including Alzheimer’s Disease (Blanco-Duque et al, 2023). The present study opens the door for future research targeting higher neuronal frequencies with multimodal TES, VS, and EEG based on the optimised parameters determined here – i.e., occipital-central TES sites and matching stimulation frequencies.…”

“…By modulating gamma activity, both VS and TES at this frequency are promising approaches to causally investigate memory functions (Hanslmayr et al, 2019) and to intervene against cognitive decline in dementia (Guan et al, 2022;Nissim et al, 2023;Shu et al, 2024;Strüber & Herrmann, 2020;Traikapi & Konstantinou, 2021). If multisensory stimulation yields larger effects than one modality alone (Blanco-Duque et al, 2023), combining sensory and electrical modalities is also likely to increase effects, but this approach is untested. To examine how VS and TES might interact, it is necessary to measure brain activity concurrently.…”