Effects of 40 Hz Brain Stimulation Across Modalities: A Comparative Narrative Review

Audio‒Visual Gamma Stimulation for Alzheimer's Disease: Current Evidence and Future Directions.

INTRODUCTION/OBJECTIVE Alzheimer's Disease (AD) is characterized by progressive cognitive decline and disrupted neural oscillations. Recently, 40 Hz gamma stimulation has emerged as a potential non-invasive therapy. This review evaluates the safety, tolerability, and clinical outcomes of this intervention based on evidence from the past decade. METHODS A literature search was conducted across PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published during the last ten years. Registered and ongoing studies were also identified through ClinicalTrials.gov. Extracted data included stimulation modality, stimulation parameters, safety and tolerability outcomes, and reported effects on functional connectivity, brain atrophy, cognitive performance, and sleep-related measures. RESULTS Thirty studies were identified, comprising eight sensory-based 40-Hz gamma stimulation approaches, 12 40-Hz transcranial Alternating Current Stimulation (tACS) protocols, and 10 ongoing clinical trials. Among the 20 completed studies, 40-Hz gamma stimulation was reported to be safe and well-tolerated. The synthesized evidence from these completed trials suggests potential beneficial effects on functional connectivity, brain atrophy progression, cognitive outcomes, and sleep-related measures. DISCUSSION Gamma stimulation may represent a promising approach for modulating neural network activity and cognitive function in AD. Nevertheless, current evidence remains limited by small sample sizes, methodological heterogeneity, differences in stimulation protocols, and short follow-up periods. These factors limit the ability to draw definitive conclusions regarding therapeutic efficacy. CONCLUSION 40-Hz gamma stimulation is a feasible and generally well-tolerated non-invasive intervention with potential relevance for AD treatment. Further large-scale, randomized, and controlled studies are required to establish standardized stimulation protocols, determine long-term efficacy, and clarify its clinical utility.

Electrophysiological signatures of visual cortical dysfunction in Parkinson's disease: An integrative EEG-based review.

Overall, PD is characterized by multilevel visual-pathway dysfunction rather than a single cortex-specific biomarker, which means electrophysiological measures should be controlled before electrophysiological measures are used for localization, stratification, or prognosis.

Neurobiological mechanisms of 40-Hz stimulation in Alzheimer's disease: evidence, heterogeneity, and constraints.

Dose-dependent power and connectivity modulation of low frequency oscillations through transcranial magnetic stimulation in non-human primates.

OBJECTIVE Transcranial magnetic stimulation (TMS) is a powerful non-invasive tool for safely modulating neural activity in humans. In particular, the left dorsolateral prefrontal cortex (DLPFC) is a common target site for clinical interventions in disorders such as treatment-resistant depression. Yet, clinical trials investigating the efficacy of TMS often lack neural markers of target engagement of the DLPFC. Local field potentials (LFPs), such as prefrontal theta oscillations, have been implicated in the clinical symptoms of these disorders. However, non-invasive electroencephalography (EEG) recordings in humans are limited by their spatial resolution and challenges of interpreting EEG signals. APPROACH In this study, we investigate the effects of single-pulse TMS applied to the left prefrontal cortex in non-human primates on LFPs recorded from intracranial stereo EEG electrodes. MAIN RESULTS Compared to sham TMS, the intensity of active TMS pulses scaled with LFP power changes in a 1-13 Hz range at contacts close to the stimulation site in the prefrontal cortex (e.g., caudate nucleus, anterior cingulate cortex, insular cortex) as well as contacts that were more distal (e.g., posterior cingulate cortex, temporal lobe). To test how TMS modulates connectivity between these regions, we conducted a phase-based connectivity analysis. TMS pulses initially enhanced and then disrupted connectivity at 1-13 Hz between the stimulation site and other contacts. Connectivity rebounded approximately 1500 ms post-stimulation. Only the initial enhancement in connectivity scaled with TMS intensity. SIGNIFICANCE Our results demonstrate a dose-dependent power modulation of low frequency LFPs across prefrontal, parietal and temporal cortical regions by single pulses. Furthermore, they show that TMS applied over the left prefrontal cortex can enhance and interrupt short- and long-range connectivity. By establishing neurophysiological responses that scale with stimulation intensity, this study identifies target and network engagement measures for evaluation of neuromodulation interventions in the left DLPFC.

Temporal interference stimulation: A new paradigm for non-invasive deep brain stimulation-mechanistic insights, clinical advances, and future directions.

This review provides a comprehensive synthesis of TI's mechanistic foundations, safety profiles, and therapeutic trajectory, while critically discussing the integration of closed-loop systems, multi-target paradigms, and patient-specific optimization as the next frontiers in non-invasive deep brain stimulation.

Potential modulation of cortical oscillations by temporal interference stimulation in the primary somatosensory cortex

Temporal interference stimulation (TIS) is a promising non-invasive technique for reaching deep brain regions that are difficult to modulate with conventional transcranial electrical stimulation. A critical question is whether TIS can reliably induce neural modulation at its envelope frequency in humans. As an initial step toward applications targeting deeper structures, we investigated whether TIS can modulate cortical oscillations at the envelope frequency within the primary somatosensory cortex (S1). We also examined how electric fields in off-target regions contribute to interindividual variability in stimulation efficacy using individualized simulations based on each participant’s magnetic resonance imaging (MRI). Forty-nine healthy participants were enrolled (24 TIS, 25 active sham without envelope modulation). TIS was applied over the left S1 hand area using a stimulation protocol designed to generate a 10 Hz envelope frequency. Brain activity was recorded with magnetoencephalography (MEG) before and after stimulation. Electric field simulations were conducted using individualized head models reconstructed from each participant’s structural MRI. The primary mixed two-way ANOVA revealed no significant group-by-time interaction for alpha-band power, with a sensitivity analysis indicating that the study was slightly underpowered to detect this interaction effect. Subsequent exploratory within-group analyses showed a post-stimulation increase in alpha band power around 10 Hz in the targeted S1 in the TIS group (Cohen’s d  = 0.570), whereas no significant change was observed in the active sham group. No clear changes were observed in the beta or gamma bands, and the increase was descriptively largest in the alpha band, although a direct statistical comparison across frequency bands did not reach significance. Furthermore, exploratory analyses based on individualized electric field simulations suggested that off-target electric fields may attenuate the relationship between local field strength in S1 and changes in alpha-band oscillations. These findings provide preliminary evidence suggesting that TIS may modulate cortical oscillations in humans in accordance with the envelope frequency, although the evidence remains limited. Furthermore, its effectiveness may be influenced by off-target electric fields.