Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review

Abstract

Despite the numerous pharmacological interventions targeting dementia, no disease-modifying therapy is available, and the prognosis remains unfavorable. A promising perspective involves tackling high-frequency gamma-band (> 30 Hz) oscillations involved in hippocampal-mediated memory processes, which are impaired from the early stages of typical Alzheimer's Disease (AD). Particularly, the positive effects of gamma-band entrainment on mouse models of AD have prompted researchers to translate such findings into humans using transcranial alternating current stimulation (tACS), a methodology that allows the entrainment of endogenous cortical oscillations in a frequency-specific manner. This systematic review examines the state-of-the-art on the use of gamma-tACS in Mild Cognitive Impairment (MCI) and dementia patients to shed light on its feasibility, therapeutic impact, and clinical effectiveness. A systematic search from two databases yielded 499 records resulting in 10 included studies and a total of 273 patients. The results were arranged in single-session and multi-session protocols. Most of the studies demonstrated cognitive improvement following gamma-tACS, and some studies showed promising effects of gamma-tACS on neuropathological markers, suggesting the feasibility of gamma-tACS in these patients anyhow far from the strong evidence available for mouse models. Nonetheless, the small number of studies and their wide variability in terms of aims, parameters, and measures, make it difficult to draw firm conclusions. We discuss results and methodological limitations of the studies, proposing possible solutions and future avenues to improve research on the effects of gamma-tACS on dementia.

Keywords: Alzheimer’s Disease; Mild Cognitive Impairment; Neurodegenerative Diseases; Neuromodulation; Non-invasive brain stimulation; Transcranial Alternating Current Stimulation.

Fig. 1

PRISMA flowchart illustrating the search and selection process of the papers included in this systematic review. In the eligibility stage, “Unfocussed” refers to reports using animal models of AD (n = 1), non-dementia samples (n = 1), tACS with non-gamma frequencies (n = 2), or sensory stimulation (n = 1)

Fig. 2

Profile plot on the effects of single-session gamma-tACS on different dementia outcomes. The plotted data represent the percentage of studies that found significant effects for each outcome ranging from 0 (i.e., the “blank” areas of the plot, which indicate that no studies found a significant effect on that outcome) to 100 (i.e., the green areas reaching the edge of the plot, which indicate that all studies found a significant effect on that outcome), N = total number of studies investigating each outcome

Fig. 3

Profile plot on the effects of multi-session gamma-tACS on different dementia outcomes. The plotted data represent the percentage of studies that report significant effects on each outcome, ranging from 0 (i.e., the “blank” areas of the plots, which indicate that no studies found a significant effect on that outcome) to 100 (i.e., the blue areas reaching the edge of the plot, which indicates that all studies found significant effects on that outcome parameter). N = total number of studies investigating each outcome

Fig. 4

The stimulation sites targeted by the reviewed studies, and the number of studies administering cognitive tasks or training during gamma-tACS. Note: Naro et al., (2016) administered gamma-tACS in several left frontal and central regions, but the most effective targets for gamma entrainment and cognitive improvement were the prefrontal regions. Sprugnoli et al., (2021) administered gamma-tACS over the right (fronto-)temporal cortex in one group and over the bitemporal cortex in the other two groups

Fig. 5

Schematic representation of hypothesized gamma-tACS effects on the AD-related neuropathological cascade, with relevant references for each target effect. Gamma-tACS (square on the left) directly affects (red arrows) brain oscillations, excitatory-inhibitory (E-I) balance, cerebral blood flow (CBF), and morpho-functional properties of microglia and astrocytes. In turn, such improvements can indirectly impact (black and red arrows) brain atrophy, amyloid-beta (Aβ) plaques, and neurofibrillary phosphorylated-tau (p-Tau) tangle formation, as well as cognitive functions. On the right side of the figure we reported the main neuropathological, markers of AD. The black (and black and red) arrows indicate the probable direction or sequence of AD neuropathological cascade