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 research team, led by investigators at Nanjing Drum Tower Hospital affiliated with Nanjing University Medical School, took an unusually comprehensive approach, weaving together human proteomics, a prospective surgical cohort, and mechanistic experiments in mice and cultured neurons. Their starting point was the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a large longitudinal study in which cerebrospinal fluid from thousands of participants has been profiled using the SomaScan 7K platform, an aptamer-based technology capable of measuring more than 7,000 molecular analytes simultaneously. From this resource, the researchers defined an exploratory phenotype they call neurodegeneration-enriched cognitive vulnerability, or NECV: individuals with mild cognitive impairment who also had a documented history of surgery. By comparing the proteomic fingerprints of 152 NECV participants against 85 cognitively normal controls, and applying stringent Bonferroni correction across more than 6,000 unique proteins, they found that 14-3-3γ ranked among the top candidates, occupying a central position in the co-expression network of disease-relevant proteins.

The signal held up under scrutiny. Cerebrospinal fluid levels of 14-3-3γ were dramatically elevated in the NECV group compared with controls, a difference that reached an extraordinary statistical significance of p = 7.8 × 10⁻³². The finding replicated independently in the Parkinson’s Progression Markers Initiative (PPMI) cohort and was further confirmed in autopsy-verified Alzheimer’s disease samples. Crucially, the protein was not merely a static marker. In longitudinal survival analyses, participants with higher baseline CSF 14-3-3γ faced an increased hazard of progressing from normal cognition to prodromal Alzheimer’s disease, and those already in the vulnerable group progressed more rapidly to frank dementia. Elevated 14-3-3γ also tracked with the classic molecular hallmarks of neurodegeneration: lower CSF amyloid-beta 42, higher phosphorylated and total tau, greater cortical amyloid burden on PET imaging, smaller hippocampal volumes, reduced cerebral glucose metabolism, and steeper declines in memory, executive function, and global cognition over time.

What elevates this work beyond biomarker correlation is its translation into the surgical setting. The team prospectively enrolled 213 patients aged 65 and older undergoing major elective cardiac, orthopedic, or aortic surgery at their tertiary center, a study registered with the Chinese Clinical Trial Registry. Blood drawn on the first postoperative day, before any delirium had been documented, revealed that patients who subsequently developed postoperative delirium or POCD had significantly higher circulating 14-3-3γ levels than those who recovered uneventfully. In this cohort, 22 patients (10.3 percent) developed delirium within the first week, while 11 (5.2 percent) met criteria for POCD at day seven, all consistent with delayed neurocognitive recovery under the 2018 nomenclature consensus. When plasma 14-3-3γ was added to models built from routine clinical variables, predictive performance improved substantially: the area under the receiver operating characteristic curve for delirium rose from 0.819 to 0.921, and for POCD from 0.705 to 0.864, with statistically significant gains confirmed by DeLong tests. Decision curve and precision-recall analyses suggested the combined models offered genuine net clinical benefit, though the authors are careful to frame these findings as exploratory given the modest number of outcome events.

One of the most intriguing puzzles the study surfaces is a striking compartmental divergence. After surgery, 14-3-3γ levels fell markedly inside hippocampal neurons in mice, yet rose in the blood and cerebrospinal fluid of both mice and humans. The researchers propose that the extracellular elevation reflects a spillover phenomenon, a leakage of intracellular proteins from injured neurons, a pattern long recognized in conditions such as Creutzfeldt-Jakob disease, stroke, and traumatic brain injury, where CSF 14-3-3 proteins serve as markers of neuronal damage. The intracellular depletion, by contrast, may be the pathologically decisive event. The 14-3-3 family constitutes roughly one percent of total soluble brain protein, and its loss would destabilize a web of protein-protein interactions governing tau phosphorylation, mitochondrial function, and synaptic maintenance. In other words, the protein leaking into the bloodstream may be a useful warning signal, but the deficit left behind inside vulnerable neurons is what drives the damage.

To establish causality, the team turned to a murine model of perioperative brain injury in which mice undergo tibial fracture with intramedullary fixation under isoflurane anesthesia, a procedure that recapitulates key clinical features of major orthopedic surgery, including tissue trauma, inflammation, and postoperative pain. Within days, surgically treated mice showed impaired performance in the Y-maze spontaneous alternation test and contextual fear conditioning, both hippocampus-dependent tasks, while locomotor activity and cued memory remained intact, pointing to a specific rather than global deficit. Electron microscopy revealed fragmented microtubules, the intracellular highways that tau normally stabilizes. Golgi staining showed a loss of mature dendritic spines, the tiny protrusions where synapses form. Levels of the synaptic proteins PSD95 and synaptophysin dropped, synaptic clefts widened, and postsynaptic densities thinned. Biochemically, the surgery produced a selective and sustained hyperphosphorylation of tau at the threonine 205 residue, detectable and pronounced at postoperative day seven, while other phosphorylation sites examined, including Thr231, Ser396, and Ser262, remained unchanged at that timepoint.

The mechanistic thread connecting 14-3-3γ loss to tau damage runs through the enzymes that control tau’s phosphorylation state. When the researchers silenced 14-3-3γ in HT22 hippocampal cells, they observed activation of CDK5, reflected in an increased p25-to-p35 ratio; activation of GSK3β, seen as reduced inhibitory phosphorylation at Ser9; and inhibition of the phosphatase PP2A, marked by increased phosphorylation at Tyr307. The net effect was a shift toward kinase-dominated regulation of tau, and tau Thr205 phosphorylation climbed accordingly. Pharmacologically damping CDK5 with roscovitine, blocking GSK3β with lithium chloride, or activating PP2A with DT061 each reversed the hyperphosphorylation. Co-immunoprecipitation experiments added a structural dimension: loss of 14-3-3γ reduced the association of phosphorylated tau with the protective phosphatase PP2A while increasing its association with the kinases CDK5 and GSK3β. Immunoprecipitation followed by mass spectrometry independently identified tau as a binding partner of 14-3-3γ, and the interaction proved sensitive to the Thr205 phosphorylation state, with a phospho-mimetic T205E tau mutant binding more strongly and a phospho-deficient T205A mutant binding more weakly.

The therapeutic implications emerged from two elegant intervention experiments. First, when the researchers delivered a gene therapy vector carrying 14-3-3γ directly into the hippocampal CA1 region and dentate gyrus of mice via adeno-associated virus, the overexpression suppressed surgery-induced tau Thr205 hyperphosphorylation, restored microtubule integrity and synaptic architecture, recovered dendritic spine density, and rescued working memory and contextual fear memory. Second, and perhaps most provocatively, the team tested fusicoccin-A, a small molecule known to stabilize 14-3-3 protein-protein interactions. Administered intraperitoneally before surgery, fusicoccin-A enhanced the binding between 14-3-3γ and phosphorylated tau, restored their colocalization in hippocampal neurons, rescued synaptic protein levels, reduced tau Thr205 phosphorylation without altering total tau, and improved cognitive performance in the Y-maze and fear conditioning tests. Molecular dynamics simulations running 500 nanoseconds per system showed that fusicoccin-A binding shortened the center-of-mass distance between the two proteins, reduced structural fluctuation, and rendered the binding free energy more favorable, providing a physical basis for the stabilization. Critically, when the researchers expressed a phosphomimetic TauT205E mutant in the hippocampus, the mutant alone was sufficient to impair cognition, and it abolished the protective effect of fusicoccin-A, demonstrating that tau Thr205 phosphorylation sits downstream in the protective pathway.

The authors are candid about the limitations that temper these exciting results. The ADNI-based discovery analysis is hypothesis-generating rather than direct evidence about POCD, since that cohort lacks detailed perioperative data. The prospective surgical cohort, though consecutively enrolled, produced few outcome events, limiting the robustness of the prediction models. The mouse experiments used young adult male animals rather than the aged populations most at risk clinically, and only a single small-molecule modulator was tested, leaving dose-response relationships, chronic effects, and safety profiles unexplored. Species differences in 14-3-3 regulation and tau dynamics may also affect translational relevance. Nevertheless, the study represents a genuine conceptual advance: it elevates 14-3-3γ from a passive correlate of neurodegeneration to an active, druggable regulator of acute cognitive vulnerability, and it points toward a strategy for protecting the surgical brain that is fundamentally different from conventional anti-amyloid or anti-tau therapies. If larger, multicenter trials confirm that a simple postoperative blood test for 14-3-3γ can flag patients at risk, and if stabilizers of the 14-3-3γ-tau interaction can be developed into safe drugs, the era of passively watching surgical patients lose their cognitive edge may finally give way to one of prediction and prevention.

Subject of Research: The role of 14-3-3γ in regulating tau Thr205 phosphorylation and synaptic integrity in postoperative cognitive dysfunction

Article Title: 14‐3‐3γ Protects Against Postoperative Cognitive Dysfunction by Regulating Tau Thr205 Phosphorylation and Synaptic Integrity

Article References: Zhu, S., Han, X., Zhang, H., Ye, C., Xia, T., & Gu, X. (2026). 14‐3‐3γ Protects Against Postoperative Cognitive Dysfunction by Regulating Tau Thr205 Phosphorylation and Synaptic Integrity. Advanced Science, Article e77480. https://doi.org/10.1002/advs.77480

Image Credits: AI Generated

DOI: 10.1002/advs.77480

Keywords: postoperative cognitive dysfunction, 14-3-3γ, YWHAG, tau phosphorylation, Thr205, synaptic integrity, biomarker, postoperative delirium, fusicoccin-A, CSF proteomics, hippocampus, neurodegeneration

Coronary Artery Bypass Grafting is a life-saving procedure designed to restore adequate blood flow to the heart by bypassing obstructed coronary arteries. Despite its success in treating ischemic heart disease, the procedure is fraught with neurological challenges, including postoperative cognitive dysfunction and increased vulnerability to brain injury. The brain’s susceptibility during CABG arises from complex mechanisms such as embolic events, systemic inflammation, and reperfusion injury. These phenomena can precipitate neuronal damage, impairing cognitive outcomes and diminishing quality of life for patients post-surgery.

Davunetide, a neuroprotective peptide derived from Activity-dependent neuroprotective protein (ADNP), has emerged as a promising candidate in mitigating brain injury. Historically studied in neurodegenerative disorders such as Alzheimer’s disease and progressive multiple sclerosis, davunetide modulates microtubule dynamics and enhances neuronal resilience against stress. Its systemic administration during CABG represents a novel therapeutic strategy, addressing ischemia-reperfusion induced cerebral damage and other neuroinflammatory processes that compromise neural integrity in the perioperative period.

The recent study employed rigorous experimental models to investigate davunetide’s efficacy in reducing cerebral injury in CABG. Notably, the research deployed a sex-specific analytical lens, acknowledging biological differences that influence drug response and recovery trajectories after cerebral insults. These differences range from hormonal influences to genetic regulation of neuroinflammation and repair mechanisms, all of which modulate how male and female brains respond to ischemic and oxidative stress during and after cardiac surgery.

Results demonstrated that systemic administration of davunetide distinctly conferred neuroprotection, but critically, this effect was significantly more pronounced in one sex. Neurophysiological assessments indicated robust attenuation of neuronal apoptosis and reduced markers of oxidative stress in treated subjects. Cognitive evaluations post-intervention suggested preservation of executive functions and memory. These findings evoke profound implications—not only substantiating davunetide’s role in neuroprotection but also stressing tailored therapeutic protocols in combating postoperative neurologic sequelae.

Understanding the molecular underpinnings of davunetide’s sex-dependent action necessitates exploring its interaction with intracellular signaling pathways. The peptide’s modulation of microtubule stabilization enhances axonal transport efficiency, potentially differing across sexes due to variations in cellular signaling cascades and neuroendocrine milieu. Moreover, the differential immune responses noted between males and females during systemic inflammation likely contribute to disparities in neuroprotection, positioning davunetide as a modulator of immune-neural cross-talk during CABG.

The translational significance of these findings is immense. Incorporating systemically administered davunetide into the medical regimen for CABG patients heralds a new frontier in minimizing perioperative brain injury and improving surgical outcomes. Crucially, personalization based on sex may optimize efficacy, reducing incidences of postoperative cognitive impairment and improving long-term neurological health. Clinical protocols must therefore adapt to integrate these insights, fostering precision medicine in cardiovascular and neuroprotection strategies.

Clinical trials are indispensable next steps to validate these preclinical observations. Enrolling a diverse cohort stratified by sex will elucidate dosing regimens, therapeutic windows, and potential side effect profiles of davunetide in the cardiac surgery context. Furthermore, comprehensive neuropsychological evaluations will reveal long-term cognitive benefits, charting the course for widespread clinical adoption. Tailored interventions will serve not only to protect neurologic function but also to expedite patient recovery and enhance overall survival post-CABG.

The discovery also prompts re-evaluation of neuroprotective strategies employed during other high-risk surgeries characterized by ischemia-reperfusion injury. As the central nervous system remains highly sensitive to systemic insults, agents like davunetide may find broader applications. Sex-specific responses should become a foundational consideration in all neuroprotective research and clinical interventions, advocating for an intersectional approach that merges neuroscience, cardiology, and sex biology.

From a molecular biology perspective, the study galvanizes interest in ADNP-related peptides as central players in neuronal maintenance and repair. Davunetide’s ability to traverse the blood-brain barrier and exert systemic effects highlights its therapeutic potential across multiple neuropathologies. Targeting the cytoskeleton and its associated signaling networks presents a versatile and strategic avenue for mitigating damage in vulnerable neural populations exposed to acute surgical stressors or chronic neurodegenerative processes.

This research dovetails with emerging paradigms that recognize hormonal and genetic factors as modulators of drug metabolism and efficacy. The role of estrogen and androgen receptors in influencing neuroinflammatory responses during cardiac surgery may partly explain the observed differences and opens the door for combinatorial therapies that synergize hormonal modulation with neuroprotective peptides. Future studies dissecting these interactions hold promise for refining treatment pathways.

In synthesis, the identification of sex-specific neuroprotection by systemic davunetide administration during CABG marks a milestone in medical science. It challenges existing homogenized treatment models and positions neuroprotection firmly within the realm of personalized medicine. As healthcare moves towards individualized interventions, insights gleaned from this research will inspire more nuanced therapies that reflect the biological diversity of patients, ultimately improving quality of life and surgical success rates.

The study elevates the conversation regarding planetary health as well, underscoring how multidisciplinary collaboration—between cardiology, neurology, molecular biology, and pharmacology—can unveil intricacies of human physiology under stress. Such integrated approaches are paramount in addressing complex medical conditions involving intertwined organ systems and influence future research agendas that prioritize patient-centered, sex-informed care.

In conclusion, the compelling evidence of davunetide’s neuroprotective role during CABG not only sheds light on new therapeutic avenues but also serves as a clarion call for future investigations. It demands a recalibration of clinical guidelines to incorporate sex differences and emphasizes the need for detailed mechanistic understanding of neuroimmune interactions. As this research advances, it promises to reshape the landscape of surgical neuroprotection and improve outcomes for countless patients worldwide.

Subject of Research: Neuroprotective effects of systemic davunetide administration during Coronary Artery Bypass Grafting (CABG), with a focus on sex-specific responses.

Article Title: Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG).

Article References:
Gozes, I., Blatt, J. & Guz, L.S. Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG). Transl Psychiatry 15, 454 (2025). https://doi.org/10.1038/s41398-025-03675-y

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41398-025-03675-y