The review, authored by Hou-Ming Kan of Macau University of Science and Technology, Hong-Yan Ni of Suqian First Hospital, and colleagues across institutions in China, surveys a rapidly expanding toolkit of non-invasive neuromodulation techniques and evaluates their promise against one of medicine’s most underappreciated complications. The authors systematically examine nine distinct approaches: transcranial direct current stimulation, repetitive transcranial magnetic stimulation, theta burst stimulation, transcranial alternating current stimulation, transcranial ultrasound stimulation, temporal interference stimulation, transcutaneous auricular vagus nerve stimulation, transcranial photobiomodulation, and 40-hertz gamma entrainment using sensory stimuli. Each technique manipulates neural activity from outside the skull, and each, according to the accumulating evidence reviewed by the team, may offer a route to protecting the aging brain from the assault of anesthesia and surgery.

The appeal of these technologies lies in their physical diversity. Transcranial direct current stimulation passes a weak, constant electrical current through electrodes on the scalp, subtly shifting the excitability of cortical neurons beneath them. Repetitive transcranial magnetic stimulation, by contrast, uses rapidly alternating magnetic fields to induce electrical currents inside the brain, and its condensed cousin, theta burst stimulation, delivers the same influence in bursts that mimic the brain’s natural theta rhythm, cutting session times from nearly an hour to just minutes. Transcranial alternating current stimulation goes further, entraining neural oscillations at specific frequencies, while transcranial ultrasound stimulation uses focused sound waves to excite or suppress neurons with millimeter-scale precision. Temporal interference stimulation represents perhaps the most elegant trick of all: two high-frequency currents that are harmless on their own are steered so that they cross deep inside the brain, where their interference produces a low-frequency beat capable of stimulating structures that scalp electrodes can never reach.

Two of the most intriguing techniques bypass the skull entirely. Transcutaneous auricular vagus nerve stimulation delivers gentle electrical pulses to the ear, activating the vagus nerve’s auricular branch and, through its connections to the nucleus tractus solitarius and the dorsal raphe nucleus, modulating widespread networks that govern inflammation, arousal, and mood. Transcranial photobiomodulation takes an entirely different route, shining near-infrared light through the scalp and skull to be absorbed by cytochrome c oxidase in neuronal mitochondria, boosting adenosine triphosphate production and triggering downstream effects on blood flow, neurotrophic factors, and antioxidant defenses. And in a nod to research that has captivated the Alzheimer’s field, the review also covers gamma entrainment using sensory stimuli, in which flickering lights or clicking sounds tuned to 40 hertz coax the brain’s gamma oscillations back into sync, a rhythm that grows feeble in dementia and delirium alike.

Why would any of this matter for a patient undergoing a hip replacement or cardiac surgery? The review lays out the biology of perioperative neurocognitive disorders in sobering detail. Anesthesia and the surgical stress response trigger a cascade of peripheral inflammation, and inflammatory signals breach the weakened blood-brain barrier, activating microglia and astrocytes. The complement cascade, the NLRP3 inflammasome, and markers such as high-mobility group box 1 and lipocalin 2 all feature in the preclinical literature as drivers of neuronal injury. Cholinergic deficits, oxidative stress marked by molecules like 4-hydroxynonenal and malondialdehyde, disrupted calcium handling through the SERCA pump, and impaired clearance of waste through the aquaporin-4-dependent glymphatic system complete a picture of a brain under siege. Crucially, many of these mechanisms are precisely the targets that neuromodulation can reach: vagus nerve stimulation dampens systemic inflammation, photobiomodulation restores mitochondrial energy metabolism, and gamma entrainment appears to enhance microglial clearance of amyloid and improve synaptic integrity in animal models.

The preclinical evidence reviewed by the authors is encouraging. In rodent models of surgery-induced cognitive impairment, transcranial direct current stimulation and near-infrared light have been shown to preserve long-term potentiation, the cellular substrate of memory, while reducing inflammatory cytokines such as interleukin-1 beta and interleukin-6 in the hippocampus. Photobiomodulation studies report increased expression of brain-derived neurotrophic factor, protection of myelin basic protein, and even promotion of oligodendrocyte precursor cell maturation, suggesting the technique may help repair white matter damaged by the perioperative insult. Vagus nerve stimulation in animal models reduces neuroinflammation through the cholinergic anti-inflammatory pathway, engaging alpha-7 nicotinic acetylcholine receptors on immune cells. Even gut-directed photobiomodulation has entered the picture, with the review noting emerging work on gut microbiota-targeted approaches that modulate the microbiome-gut-brain axis through short-chain fatty acids.

Translating these findings to the clinic, however, is where the story becomes both promising and cautionary. The review compiles preliminary clinical trials in which non-invasive neuromodulation was applied to surgical patients, including studies using transcranial direct current stimulation and transcutaneous auricular vagus nerve stimulation in populations at high risk for postoperative delirium, such as elderly patients undergoing total joint arthroplasty. The early signals suggest reductions in delirium incidence and improvements in cognitive screening scores measured with instruments like the Mini-Mental State Examination and the Montreal Cognitive Assessment, alongside objective monitoring using electroencephalography and functional near-infrared spectroscopy. Yet the authors are explicit that the evidence base remains immature: sample sizes are small, stimulation protocols vary widely between studies, and few trials have been designed with the methodological rigor of large, multicenter randomized controlled trials.

The technical challenges are considerable. The review emphasizes that parameters matter enormously: current intensity, electrode montage, session duration, timing relative to surgery, and frequency selection can each determine whether a protocol helps, does nothing, or theoretically causes harm. The dorsolateral prefrontal cortex, a hub of executive control that frequently falters in delirium, has been the favored target for most stimulation protocols, but the authors argue that future work must move beyond single regions and consider the brain as a network. They call for multimodal monitoring that combines electroencephalography, functional magnetic resonance imaging of the default mode network, and near-infrared spectroscopy to track how stimulation reshapes global connectivity, rather than merely measuring whether a patient passes a bedside confusion assessment. The posterior cingulate cortex, the hippocampal dentate gyrus, and even the nucleus accumbens all appear in the review as nodes whose dysfunction may contribute to the delirium phenotype.

What emerges from this comprehensive synthesis is a field standing at an inflection point. The convergence of an aging surgical population, a complete absence of pharmacological options, and a maturing neuromodulation industry creates a rare window for translational progress. The authors, whose work was supported by the Suqian Sci&Tech Program and the China Postdoctoral Science Foundation, lay out a roadmap that reads like a checklist for the coming decade: strict randomized clinical trials, standardized stimulation protocols, optimization of device parameters, and adoption of network-level brain monitoring. If those steps succeed, the prospect of a patient slipping on a lightweight stimulation cap before surgery, or listening to 40-hertz tones in the recovery room, could shift from science fiction to standard of care. For the millions of patients and families who dread the fog that can follow anesthesia, the idea that the brain might be shielded by nothing more than carefully patterned electricity, magnetism, light, and sound is a vision worth watching closely, and one that the next generation of clinical trials will soon put to the test.

Subject of Research: Non-invasive neuromodulation for preventing perioperative neurocognitive disorders and postoperative delirium

Article Title: Perioperative non-invasive neuromodulation for delirium and cognitive recovery: from preclinical evidence to clinical translation

Article References: Perioperative non-invasive neuromodulation for delirium and cognitive recovery: from preclinical evidence to clinical translation. (n.d.). https://doi.org/10.1186/s12967-026-08979-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08979-1

Keywords: perioperative neurocognitive disorders, postoperative delirium, postoperative cognitive dysfunction, non-invasive neuromodulation, transcranial direct current stimulation, transcranial magnetic stimulation, vagus nerve stimulation, photobiomodulation, gamma entrainment, anesthesia, neuroinflammation, brain stimulation

The review, led by Myeonghae Hyun, Yeseung Park, Seo Yoon Park, and senior author Ki Woong Kim of Seoul National University, followed PRISMA 2020 reporting guidelines and searched four major databases, PubMed, Embase, Scopus, and Web of Science, for English-language articles published between January 2016 and December 2025. From an initial haul of 1,310 records, the team winnowed the literature down to just eight studies that met their strict eligibility criteria: human participants aged 60 or older, noninvasive sensory stimulation delivered at approximately 40 hertz through visual, auditory, or combined audiovisual means, and at least one quantitative outcome related to brain structure, function, electrophysiology, or cognition. The included studies ranged from single-session experiments to six-month daily interventions, with sample sizes between 10 and 38 participants, spanning cognitively normal older adults to patients with mild Alzheimer’s dementia. That small and heterogeneous evidence base, the authors emphasize, fundamentally shapes what can and cannot be concluded.

The biological rationale behind GENUS is worth unpacking. Gamma oscillations arise largely from interactions between excitatory pyramidal neurons and fast-spiking parvalbumin-positive interneurons, the inhibitory cells that act as the brain’s metronome. In transgenic mouse models of amyloid pathology, gamma power is reduced in the hippocampus and entorhinal cortex even before plaques become visible, suggesting that gamma dysfunction may be an early pathophysiological event rather than a mere consequence of neurodegeneration. When researchers delivered 40 Hz flicker or sound to these mice, they observed changes in amyloid and tau pathology, glial and immune signaling, synaptic and myelin integrity, and even behavior. One 2024 study reported that multisensory gamma stimulation promotes glymphatic clearance of amyloid, implicating the brain’s waste-clearance system. These preclinical findings provided the impetus for translating the technique to humans, but translation has focused mainly on feasibility, target engagement, and early signals rather than definitive efficacy.

On the structural front, the review found the most tantalizing, and most fragile, evidence. Two randomized pilot trials reported comparable magnetic resonance imaging outcomes. In a three-month trial of daily 40 Hz light and sound stimulation in mild probable Alzheimer’s dementia, Chan and colleagues found less ventricular enlargement and less hippocampal atrophy in the active group than in controls. Agger and colleagues, using invisible spectral flicker in a placebo-controlled double-blinded pilot study, saw a similar directional pattern that only emerged by week 12, with no meaningful separation at week 6. A third study, by Da and colleagues, reported favorable white matter and myelin-related findings after six months of daily stimulation, with the most prominent effects in the entorhinal region, though that study was rated at high overall risk of bias. The review’s exploratory meta-analysis pooled the hippocampal and ventricular data from the two controlled trials using a random-effects model.

The pooled numbers tell a story about statistical fragility as much as about the brain. For ventricular volume, the conventional DerSimonian–Laird analysis yielded a statistically significant effect favoring active stimulation, with a standardized mean difference of −1.330 and a p-value of 0.004, indicating less ventricular enlargement. But because only two studies contributed to the estimate, the authors applied the more conservative Hartung–Knapp–Sidik–Jonkman adjustment with a lower-bound modification, which is recommended when meta-analyses contain very few studies. Under that stricter approach, the confidence interval ballooned from roughly −2.2 to −0.4 to a sprawling −7.2 to 4.6, and the result was no longer statistically significant. The hippocampal estimate, directionally favorable with a pooled g of 0.687, was never significant under either method, and a sensitivity analysis substituting a different follow-up timepoint attenuated both results further. The authors are blunt: these pooled estimates are hypothesis-generating, not evidence of efficacy.

Functional neuroimaging offered a somewhat more coherent, if still preliminary, picture. In the Chan trial, resting-state functional MRI suggested that active stimulation was associated with relative preservation or enhancement of connectivity in networks relevant to Alzheimer’s dementia, most clearly in the medial visual network and posterior cingulate-related connectivity. A separate delayed-start feasibility study in prodromal Alzheimer’s disease, by He and colleagues, found that functional connectivity between the posterior cingulate cortex and precuneus increased after eight weeks of daily flicker, but not after four weeks of no stimulation or only four weeks of flicker. Because that study lacked a sham control, the finding is best read as evidence of network modulation rather than treatment benefit. Fluid biomarkers added another exploratory thread: core Alzheimer’s markers in cerebrospinal fluid, including amyloid-beta 42, total tau, and phosphorylated tau, showed no significant change, but the immune factor profile shifted after eight weeks, including a decrease in TWEAK, hinting at neuroimmune engagement.

The strongest mechanistic support came from electroencephalography. Five studies examined whether the stimulation actually does what it claims, and the answer is generally yes, with important caveats. Entrainment was stronger at lower stimulation frequencies and higher luminance, showing that success depends on careful parameter optimization rather than the mere presence of 40 Hz stimulation. How far the entrained rhythm spreads through the brain appears to depend on each participant’s individual center frequency and on white matter microstructural integrity, suggesting that structural connectivity moderates downstream network engagement. Individual variability emerged as a recurring theme, with some people proving to be strong entrainers and others not, possibly reflecting differences in baseline neural state. The authors note an important transparency caveat here: three of the five EEG studies were authored by members of the review team itself, and excluding them would substantially narrow the parameter-optimization and propagation findings while preserving the core evidence for target engagement.

Cognitive outcomes, the domain patients and families care most about, remain the least convincing. In the Chan trial, the active group improved on a face-name association delayed recall test and showed better circadian rhythm regularity on actigraphy, but global cognitive measures such as the Mini-Mental State Examination and the Montreal Cognitive Assessment did not differ between groups. The Agger trial found directionally lower, but statistically non-significant, scores on an extended cognitive and functional scale at both six and twelve weeks. With tiny samples and divergent measures, the review concludes that cognitive findings from these small exploratory studies do not establish a consistent benefit. The authors also flag methodological vulnerabilities in the underlying trials, including baseline age imbalances of 6.4 and 8.2 years between groups in two studies, a serious concern for outcomes like brain volume that are strongly age-sensitive, and a retrospectively registered review protocol.

Where does this leave the flickering light? The honest answer is that GENUS stands at the classic juncture of translational science: biologically plausible, mechanistically supported in animals, safe and feasible in humans, and demonstrably capable of engaging its neural target, yet unproven as a therapy. The review’s authors frame their synthesis as a rationale for adequately powered, standardized, sham-controlled trials rather than as evidence of therapeutic benefit, and they call for larger studies that harmonize stimulation parameters, outcome measures, and follow-up durations so that results can finally be pooled meaningfully. Until then, the 40 Hz flicker remains one of the most captivating hypotheses in dementia research, a reminder that sometimes the brain’s own rhythms, nudged by nothing more than light and sound, may hold therapeutic potential that rigorous science is only beginning to test.

Subject of Research: Noninvasive 40 Hz sensory gamma entrainment as an investigational approach for cognitive impairment and Alzheimer's disease in older adults

Article Title: Sensory gamma entrainment in older adults with or without cognitive impairment: a systematic review and exploratory meta-analysis

Article References: Hyun, M., Park, Y., Park, S. Y., & Kim, K. W. (2026). Sensory gamma entrainment in older adults with or without cognitive impairment: a systematic review and exploratory meta-analysis. GeroScience. https://doi.org/10.1007/s11357-026-02564-6

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02564-6

Keywords: gamma entrainment, GENUS, sensory stimulation, Alzheimer's disease, cognitive impairment, systematic review, meta-analysis, EEG, hippocampal atrophy, neuroimaging, GeroScience, brain stimulation