Modulation of Cross-Frequency Theta-Gamma Coupling Via Gamma Transcranial Alternating Current Stimulation in Healthy Adults
Modulation of Cross-Frequency Theta-Gamma Coupling Via Gamma Transcranial Alternating Current Stimulation in Healthy Adults
Transcranial Alternating Current Stimulation (tACS), particularly at gamma frequencies, may enhance fast brain oscillations (especially gamma and possibly beta), while reducing slower rhythms such as theta. These effects are not confined to the stimulation site (e.g., the precuneus) but can extend to structurally and functionally connected regions, including the default mode network (DMN). Notably, 40 Hz gamma tACS applied to the left dorsolateral prefrontal cortex (DLPFC) has been associated with improvements in working memory and motor learning during reaction time tasks. While beta-frequency stimulation often shows no significant effect, gamma-frequency tACS has been shown to reduce response times.
Gamma oscillations are commonly disrupted in neuropsychiatric disorders. These rhythms depend on a balance between excitation and inhibition, possibly linked to interneuron dysfunction. Abnormal gamma activity has been proposed as a biomarker for cognitive impairment. In this context, non-invasive rhythmic stimulation aiming to restore gamma activity is a promising cognitive enhancement strategy, though unlike pharmacological approaches, gamma-tACS has not yet been widely adopted in clinical practice.
A meta-analysis of 56 studies emphasized that tACS outcomes vary with stimulation frequency, brain region, and timing protocols. Research suggests that the susceptibility of gamma oscillations to external modulation may provide insights into cognitive reserve, domain-specific processes, and Alzheimer's disease progression. Oscillatory changes may help predict conversion from MCI to Alzheimer's disease. However, evidence on the neural mechanisms of tACS remains limited and heterogeneous, and outcomes appear to depend on task type, frequency, and intensity.
In this study, we will deliver a single 20-minute tACS session over the bilateral DLPFC using gamma frequencies (40 Hz, 80 Hz, and individualized gamma), and a theta-gamma coupling range (6-80 Hz). A sham group will also be included. The anodal electrode will be placed over F3, and the cathodal electrode over F4 (10-20 system). Cognitive performance will be assessed pre- and post-stimulation using neuropsychological tests, and EEG will measure theta-gamma phase-amplitude coupling and changes in oscillatory activity.
Inclusion Criteria:
Exclusion Criteria:
Having a neurological or psychiatric disorder
Use of medications with sedative or stimulant effects
Presence of metal brain implants or a pacemaker