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