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.

Keywords: Alzheimer's disease; gamma rhythms; neuromodulation; noninvasive brain stimulation; sensory stimulation; therapeutic potential.

Figure 1.. Effects of gamma sensory stimulation on patients with Alzheimer’s disease.

A) Cognito’s light and sound goggles. B) MIT light and sound device. C) NextWave tactile stimulation chair (reference: Campbell). Abbreviations: TGF-α, transforming growth factor alpha; MIP-1β, macrophage inflammatory protein 1β; DNER, Delta and Notch-like epidermal growth factor receptor; IL5, interleukin-5; TWEAK, tumor necrosis factor-related weak inducer of apoptosis; DMN, default mode network; ADCS-ADL, Alzheimer’s Disease Cooperative Study activities of daily living inventory; SLUMS, Saint Louis University Mental Status.

Figure 2.. Effects of 40 Hz tACS and TMS on patients with Alzheimer’s disease.

A) Schematic of (Transcranial Alternating Current Stimulation) tACS and (Transcranial Magnetic Stimulation) TMS devices. tACS involves the application of sinusoidal alternating electric currents between two scalp electrodes. It is capable of operating at various frequencies and can influence neural activity in the immediate vicinity of the stimulating electrode, leading to compensatory adjustments in interconnected neural networks [49]. TMS, on the other hand, employs magnetic fields to generate electrical currents within specific brain regions. Through repetitive TMS, sequences of magnetic pulses can be directed at a targeted area of the brain, thereby inducing cortical oscillations at designated frequencies [49]. B) Reported effects of 40 Hz tACS and TMS treatments on AD patients. Abbreviations: pTau, phosphorylated tau; [₁₈F]-FTP, [18F]-Flortaucipir tau tracer; Aβ, amyloid-beta; RAVLT, Rey auditory verbal learning test; FNAT, face-name association task, WMS-IV, Wechsler Memory Scale-IV; TMT, Trail Making Test; ADAS-Cog, Alzheimer’s disease assessment scale cognitive section; MMSE, mini-mental state examination; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; PET, positron emission tomography.

Figure 3.. Mechanisms underlying the beneficial effects of gamma stimulation in AD

Schematic showing known and hypothetical mechanisms mediating the clinical effects of 40Hz stimulation. A) Sensory stimulation is transduced in the sensory organs and the signals progress through the canonical sensory pathways. Note that sensory processing is highly parallelized (indicated by parallel black arrows), hence 40hz stimulation not only is relayed to cortex via thalamus (e.g. Schneider et al for uni-modal visual stimulation [65]) but also travels via parallel pathways to multiple subcortical regions and can influence other modalities via regions such as the thalamic reticular nucleus. B) Hypothetical involvement of subcortical circuits that process sensory stimulation in parallel to cortical signaling. C) A region that responds to 40 Hz stimulation (e.g. amyloid reduction, neuroprotection) may do so due to direct subthreshold synaptic currents (e.g. evoking hemodynamic changes or synaptic plasticity, changes in neuronal firing) or due to non-local events (e.g. global increase in CSF flow, neuromodulators). Abbreviations: CSF, cerebrospinal fluid.