The Neural Basis of Aging

The initial goal of this writing project was to examine the overlap in biological phenotypes observed following 40 Hz visual and auditory stimulation and prolonged vagus nerve stimulation. Towards this end, we have come to consider that both the overlap and differences between these technologies, as well as transcranial methods using electricity, magnetism, or ultrasound, are primarily dependent upon the frequency and pattern of stimulation. We propose that the mechanism of action consists of acute or chronic activation of midbrain nuclei, especially the locus coeruleus, release of norepinephrine, dopamine, and choline, and downstream modulation of the neurogliavascular unit through astrocyte-dependent pathways in order to reduce neuroinflammation, increase blood and glymphatic flow, promote synaptic plasticity, and improve hippocampal-dependent memory. We suggest various modifications to stimulation paradigms and delivery based on this hypothesis. We review and emphasize the role of these midbrain nuclei and neuromodulators in terms of attention, learning, consciousness, and sleep, as well as across a variety of neuropsychiatric disorders. To strengthen the initial hypothesis, we also cite observations of altered gamma oscillations in patient populations from previous literature. In order to explain the significant impact of 40 Hz stimulation on Alzheimer’s disease and neurodegeneration, we attempt to provide an evolutionary and functional framework for the core role of the LC-NE-(DA) system in novelty, evolutionary drive, and management of allostatic load, its potential role in vertebrate aging, and a hypothesis for LC-NE dysfunction and depletion as the key mechanism behind the development of amyloid plaques and Alzheimer’s disease respectively.