Galvanizing Neuroimmunity: Implication for Perioperative Neurocognitive Disorders

The nervous system connects to virtually every cell in the body, and regulates remote organ function via rapid and fine-tuned circuits. The vagus nerve, a major component of the bidirectional communication between the brain and peripheral organs, is one of the best-studied circuits for central/peripheral neuro/immune interactions¹. Tracey and colleagues were the first to describe the so-called “inflammatory reflex”, a vagally-mediated neuronal circuit that can provide information about the body’s inflammatory status to the brain in real time². The cellular machinery underlying this inflammatory reflex is complex, with several intermediate players including the celiac ganglion, splenic nerve axons, acetylcholine-releasing subset of T cells, and monocyte-derived macrophages³. More specifically, acetylcholine released after vagus nerve stimulation (VNS) significantly inhibits pro-inflammatory cytokine release via mechanism(s) that require expression of the α7 subtype of nicotinic acetylcholine receptor (α7 nAChR)⁴, and cytoprotective effects of VNS or cholinergic agonists have been demonstrated in a variety of acute and chronic inflammatory conditions including rheumatoid arthritis⁵.

VNS is providing a selective and targeted approach to modulating inflammation including central nervous system (CNS) inflammation, or neuroinflammation, which contributes to many neurologic conditions⁶. Mounting evidence implicates neuroinflammation in the pathophysiology of perioperative neurocognitive disorders (PND), which now encompass postoperative delirium and long-term postoperative cognitive dysfunction, especially as they relate to the acute-phase response to surgical trauma⁷. PND has become a quintessential geriatric complication that affects up to 40% of older adults, and is associated with significant mortality and morbidity, reduced quality of life, and substantial healthcare costs⁸. Patients with delirium and cognitive decline following anesthesia and surgery have high levels of inflammatory and neuronal damage biomarkers in different bodily fluids as well as increased neuroinflammation based on imaging of microglial reactivity (recently reviewed in⁹). Mouse models of PND have recapitulated similar changes in the (neuro)inflammatory response to peripheral surgery. Notably, using prophylactic agonists of α7 nAChR to harness cholinergic signaling prior to orthopedic surgery prevents trauma-induced neuroinflammation, endothelial dysfunction, and subsequent cognitive decline by inhibiting pro-inflammatory cytokine release and nuclear factor (NF)-kB activation in monocyte-derived peripheral macrophages^10-13. Currently, minimally invasive approaches to VNS, such as ultrasound-guided needle electrode placement on the vagus nerve, are also providing significant anti-inflammatory effects by modulating microglial morphology and delirium-like behavior in mice¹⁴.

This is an exciting time for biomedical research when molecular medicine, bioengineering, neuroscience, immunology, and physiology are connecting to develop and implement technologies that can monitor and treat neuroinflammatory disorders. Bioelectronic medicine is rapidly establishing its footprint across different fields including anesthesiology and perioperative medicine¹⁵. Mechanistically-driven studies to fully elucidate the translational potential for this growing discipline are needed, especially to better characterize neuro-immune interactions. For example, in addition to the well-defined actions of cholinergic signaling in regulating inflammation as part of the splenic anti-inflammatory reflex, acetylcholine is an important neurotransmitter that modulates synaptic plasticity processes involved in both hippocampal plasticity and memory. Neurons expressing choline acetyltransferase, an important enzyme in acetylcholine biosynthesis, play a role in controlling adult neurogenesis¹⁶. Indeed, surgery can impair neurogenesis in different PND preclinical models. After orthopedic surgery in rodents, we found changes in synaptic plasticity and hippocampal long-term potentiation, with pain signaling being critically implicated in this response^17,18. Recent evidence suggests that neurogenesis is also impaired in humans with Alzheimer’s disease; thus, its modulation in disease states may offer solutions to neurodegenerative conditions that do not yet have effective therapy¹⁹. Since there are parallels between the pathologic features of neurodegeneration and delayed neurocognitive recovery, it is plausible for acute synaptic dysfunction, and perhaps loss of neurogenesis soon after surgery-induced neuroinflammation, to contribute to prolonged memory decline. Further studies are warranted to address these questions, and to determine whether bioelectronic approaches may be used to modulate these endpoints in PND. Recent data from elective surgical patients suggest that acetylcholinesterase activity is higher in patients with delirium, supporting the potential of altered cholinergic regulation in treating or preventing postoperative delirium²². Further, patients in perioperative or critical care are, to varying degrees, unable to maintain homeostasis including body temperature, heart rate, blood pressure, and a wide range of other organ functions that regulate their internal physiology, due to combinations of therapeutic interventions (eg, surgery and anesthesia) and disease. Decreased vagus nerve activity is also evident in patients with acute inflammatory conditions^24,25 as well as in older patients^26,27. Thus, boosting cholinergic signaling within the vagal reflex pathway has the potential to provide a novel strategy for reducing inflammatory conditions, including PND.

The possibility of regulating a predictable injury, such as aseptic trauma, is providing new frontiers for applying bioelectronic strategies to curtail excessive inflammation. The ability to tightly control the dose, intensity, and duration of electrical impulses via VNS holds promise for delivering better therapeutic anti-inflammatory outcomes that may be personalized to individual patient needs. The atmosphere is electric, and neuromodulation may soon provide more targeted treatments that are urgently needed for common perioperative complications.

Disclosures

Part of this work in the Terrando laboratory is funded by the National Institute of Aging. NT is Associate Editor for Bioelectronic Medicine, Springer-Nature publishing.

References

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Author

Niccolò Terrando, B.Sc. (hons), D.I.C., Ph.D.

Associate Professor of Anesthesiology

Duke University Medical Center

Department of Anesthesiology, Center for Translational Pain Medicine

Durham, North Carolina