Inflammatory Reflex Research Articles (Page 1)

Solid organ transplantation is a life-saving intervention for tens of thousands of patients each year in the United States. A major underlying pathophysiologic process limiting the success of transplantation is inflammation. Since the first transplant >70 y ago, advancements in the fields of surgery and immunosuppression have improved both organ and patient survival. However, inflammation and its damaging effects remain the principal clinical problem limiting enduring organ transplant survival. The discovery of the vagus nerve-mediated inflammatory reflex, an endogenous mechanism attenuating inflammatory processes, has provided novel treatment approaches for patients with autoimmune, neurologic, gastrointestinal, and other immune-mediated disorders. Despite these successes, evaluation of whether the inflammatory reflex can improve graft and patient survival in transplantation has yet to be undertaken. Here, we review the fundamentals of transplant rejection and how the inflammatory reflex may provide potential preemptive therapy in deceased donors before organ recovery, as well as attenuate detrimental inflammatory processes in transplant recipients. With this background, we propose that vagus nerve stimulation could be used to improve organ viability and augment current immunosuppressive medication regimens, thereby improving transplantation outcomes.

Traumatic brain injury (TBI) is a major life-threatening event. In addition to neurological deficits, it can lead to long-term impairments of cognitive function. The vagus nerve(VN) provides a direct communication conduit between the central nervous system and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the vagus nerve (VNS) shows efficacy in ameliorating pathology in neurodegenerative diseases. Our objective was to investigate the impact and underlying mechanism of VNS for cognitive impairment in a rat model of TBI. Male rats were implanted with VNS electrodes on the left VN 1week prior to controlled cortical impact. Mitochondrial permeability transition pore blocker cyclosporin A (CsA) and stimulator of interferon genes (STING) agonist 2'3'-cGAMP were delivered by intranasal administration or intraventricular injection. Post-VNS assessments included Morris water maze, Nissl staining, hematoxylin and eosin staining, Western blotting, quantitative polymerase chain reaction, mitochondrial membrane potential, and enzyme-linked immunosorbent assay. We found that VNS treatment significantly improved cognitive impairment, increased mitochondrial membrane potential, reduced accumulation of cytosolic mitochondrial DNA, attenuated cyclic GMP-AMP synthase (cGAS)-STING pathway, suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation, and partially reversed hippocampus neuronal damage and loss caused by TBI. However, 2'3'-cGAMP delivery significantly abrogated these effects of VNS. In addition, CsA also showed neuroprotective effects, including improved cognitive impairment, decreased levels of cGAS, phosphorylated STING, and suppressed the expressions of NLRP3 inflammasome and pyroptosis-pertinent components containing cleaved Caspase-1, ASC, and N-terminal Gasdermin D. CsA also inhibited interleukin-1β and interleukin-18 proinflammatory cytokine concentration. Stimulation of the VN attenuates the pyroptosis and neuroinflammatory cascades in the rat of the TBI model by regulating the mitochondrial DNA/cGAS/STING /NLRP3 pathway.

How the diffuse neuroendocrine system shapes health, homeostasis, and cancer.

The nervous and immune systems engage in critical bidirectional communication that influences both physiologic regulation and disease progression. This review discusses the neuroimmune axis and its role in controlling inflammation in AKI and multiorgan dysfunction. Central to this regulation is the inflammatory reflex pathway, which consists of sensory afferent and motor efferent arcs. The cholinergic anti-inflammatory pathway (CAP) suppresses inflammation through vagus nerve activation, norepinephrine release, and α 7 nicotinic acetylcholine receptor signaling in macrophages. Inflammatory mediators activate the afferent vagus nerve, transmitting signals to the brain initiating an anti-inflammatory response. Vagus nerve stimulation and pulsed ultrasound activate the CAP and attenuate inflammation and protect against AKI. Specifically, pulsed ultrasound before kidney ischemia-reperfusion injury reduces inflammation and preserves kidney function in a CAP-dependent manner. Beyond the CAP, other organ systems receive direct vagal innervation, and stimulation of these pathways leads to an anti-inflammatory effect and organ protection. Multiorgan neuroimmune communications, including lung-kidney interactions are discussed, emphasizing their relevance in systemic inflammatory conditions. The role of the inflammatory reflex pathway in sepsis is addressed, emphasizing its potential to modulate the dysregulated immune response contributing to multiorgan failure. Finally, the discussion covers the role of the sympathetic nervous system, particularly renal sympathetic nerve activity, in modulating kidney function and inflammation in AKI. Understanding and targeting these neural circuits may offer novel therapeutic strategies for AKI and related conditions.

Dysregulated neural coding in the vagus nerve during long sepsis

Inflammation is vital for defence against injury and infection, but excessive inflammation can lead to tissue damage and disease. The central nervous system (CNS) helps regulate immune responses through neuroendocrine pathways, such as the hypothalamic-pituitary-adrenal axis and the anti-inflammatory reflex, which limit systemic inflammation. Immune responses require significant metabolic energy and the liver adapts by increasing glucose production and mobilizing fatty acids. This immune-metabolic coordination is mediated by cytokines and metabolic regulators. This review explores how the anti-inflammatory reflex modulates the interplay between inflammation and metabolism during endotoxaemia, with a focus on the haem oxygenase 1/carbon monoxide (HO1/CO) pathway. Carbon monoxide, a byproduct of HO1 activity, acts as a key signalling molecule that reduces inflammation, supports mitochondrial function and protects tissues. Understanding this pathway provides new insights into potential therapeutic strategies for treating inflammatory and metabolic disorders by targeting neuroimmune-metabolic communication networks.

Study objective: To investigate whether baroreceptor afferents in rats subjected to systemic inflammation express receptors and mediators of the inflammatory response. Hypothesis: Baroreceptor afferents, traditionally known for regulating blood pressure, may also express receptors and mediators of inflammation, contributing to the communication between the immune system and the central nervous system during endotoxemia. Methods: Systemic inflammation was induced in male Sprague-Dawley rats (7–8 weeks old) using lipopolysaccharide (LPS; 1.5 milligrams/kilogram, intravenously). The aortic depressor nerve (ADN), aortic arch (AA), and nodose ganglion (NG) were collected at different time points: before (basal) and after saline (30 minutes) or LPS administration (30, 60, 90, and 120 minutes). Gene expression and total protein content of immune mediators were analyzed using RT-qPCR and Western blot. Data and results:Gene and protein expression analyses revealed that the ADN, AA, and NG express multiple immune mediators, including toll-like receptor 4 (TLR-4), nuclear factor kappa B (NF-κB), myeloid differentiation factor 88 (MyD88), mitogen-activated protein kinases (MAPK), interleukin (IL)-1β, IL-1β receptor (IL-1β-R), tumor necrosis factor (TNF)-α, TNF receptors (TNF-R1 and TNF-R2) in both control and LPS-treated animals. Notably, in the ADN, gene expression of NF-κB (2.84 ± 0.8 fold-change; n = 6; p = 0.04), IL-1β-R (5.01 ± 1.2 fold-change; n = 5; p = 0.005), and TNF-R2 (3.07 ± 1 fold-change; n = 6; p = 0.03) was upregulated 120 minutes post-LPS, suggesting activation of these pathways in baroreceptor afferents during systemic inflammation.Conclusions: These findings suggest a novel role for the ADN, previously recognized primarily for its role in blood pressure regulation, by showing that it may also participate in the sensing of inflammatory mediators and triggering reflex responses. Our research indicates that aortic baroreceptor afferents contribute to the modulation of inflammation, expanding the understanding of their function beyond cardiovascular regulation. FAPESP (2021/03764-8; 2021/05554-0; 2022/13361-0; 2020/06043-7), CAPES (88881.823812/2023-01) and CRID (2013/08216-2). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Neural signaling regulates various reactions in our body including immune responses. Neuromodulation of this signaling using artificial neural activation and/or suppression is a potential treatment for diseases and disorders. We here review neural signaling regulating the immune system, with a special focus on the gateway reflex. The gateway reflex is a novel neuro-immune crosstalk mechanism that regulates tissue-specific inflammatory diseases. We have discovered six gateway reflexes so far; all are induced by environmental or artificial stimulations including gravity, electrical stimulation, pain sensation, stress, light, and inflammation in joints. In the presence of increased autoreactive T cells in the blood, such stimulation activates specific neural signaling to release noradrenaline (NA) from the nerve endings at specific blood vessels in the central nervous system. NA activates the interleukin-6 (IL-6) amplifier, which leads to the hyper-activation of nuclear factor-kappa B (NF-κB) in non-immune cells, resulting in the formation of a gateway. This gateway allows autoreactive T cells and other immune cells to accumulate in the target tissue to induce inflammatory diseases. In gateway reflexes induced by stress or remote inflammation, adenosine triphosphate (ATP) secreted from inflammation sites activates specific neural pathways, resulting in organ dysfunction and inflammation in other tissues, suggesting that the gateway reflex regulates tissue-specific inflammatory diseases by bidirectional crosstalk between the neural and immune systems. We also discuss other cases of neural signaling including the inflammatory reflex.

Next-generation medical devices in bioelectronic medicine integrate neurotechnology with precision therapy to modulate physiological functions in real time. Bioelectronic medicine is an emerging interdisciplinary field that combines biology, electronics, and medicine to provide novel therapeutic solutions for various chronic and acute diseases. With advancements in neurotechnology and biomedical engineering, bioelectronic devices are increasingly being considered alternatives or adjuncts to traditional pharmacological therapies. This paper explores the urgent need for bioelectronic medicine, emphasizing its potential to revolutionize modern health care by reducing drug dependency, minimizing side effects, and addressing economic challenges. Key research goals include the development of a visceral nerve atlas, early validation of therapeutic possibilities, and advancements in neural interfacing technologies. Technical milestones such as the discovery of the inflammatory reflex, innovations in electric implants, and modulation of the vagus nerve have further enhanced therapeutic applications. The clinical relevance of a wide range of bioelectronic devices—including artificial pacemakers, bioelectronic noses, biosensors, and visual prostheses—is discussed. The integration of bioelectronics in health care has shown promising results in treating conditions such as hypertension, diabetes mellitus, central nervous system disorders, rheumatoid arthritis, blindness, and spinal cord injuries. Technological advancements continue to refine signal decoding and device miniaturization, broadening the scope of bioelectronic interventions. However, challenges such as biocompatibility, long-term safety, accessibility, and ethical concerns must be addressed for successful widespread adoption. The article concludes with future directives focused on personalized bioelectronic therapies, regulatory frameworks, and collaborative research, highlighting the potential of bioelectronic medicine to become a cornerstone of precision medicine along with its ethical implications.

ObjectivesGiven the potential role of vagus nerve stimulation in treating rheumatoid arthritis (RA), we examined the incidence of RA and osteoarthritis (OA) in patients who underwent different forms of vagotomy that disparately affect the inflammatory reflex.MethodsUsing nationwide health registries, we constructed cohorts of patients in Denmark who underwent truncal or superselective vagotomy between 1977 and 1995 and comparison members from the general population matched 10:1 on birth year, sex, and calendar year. We identified incident RA or OA and used Cox proportional hazards models to compute adjusted hazard ratios (aHRs) and corresponding 95% CI.ResultsOur cohorts consisted of 2,260 truncal vagotomy patients matched with 22,610 comparators, and 3,810 superselective vagotomy patients matched with 38,090 comparators. The incidence rate (IR) of RA per 1,000 person-years (95% CI) in the truncal vagotomy cohort was 10.2 (6.5–15.3) versus 7.2 (6.1–8.4) in the matched comparison cohort. The aHR (95% CI) for RA development was 2.62 (1.47–4.67) in the truncal vagotomy cohort and 1.05 (0.51–2.17) in the superselective vagotomy cohort, with respect to comparison cohorts. The risk of developing OA was not significantly different for either vagotomy cohort compared with comparison cohorts.ConclusionTruncal vagotomy was associated with an increased incidence of RA; this association was not observed with superselective vagotomy. No association with either form of vagotomy was seen with OA. These findings support the hypothesis that disruption of vagus nerve signaling impacts the inflammatory reflex and contributes to the development of RA.

Cannabidiol exerts antipyretic effects by downmodulating inflammatory mediators in LPS-induced fever

The therapeutic usage of physical stimuli is framed in a highly heterogeneous research area, with variable levels of maturity and of translatability into clinical application. In particular, electrostimulation is deeply studied for its application on the autonomous nervous system, but less is known about the anti- inflammatory effects of such stimuli beyond the inflammatory reflex. Further, reproducibility and meta-analyses are extremely challenging, owing to the limited rationale on dosage and experimental standardization. It is specifically to address the fundamental question on the anti-inflammatory effects of electricity on biological systems, that we propose a series of controlled experiments on the effects of direct and alternate current delivered on a standardized 3D bioconstruct constituted by fibroblasts and keratinocytes in a collagen matrix, in the presence or absence of TNF-α as conventional inflammation inducer. This selected but systematic exploration, with transcriptomics backed by metabolomics at specific time points allows to obtain the first systemic overview of the biological functions at stake, highlighting the differential anti-inflammatory potential of such approaches, with promising results for 5 V direct current stimuli, correlating with the wound healing process. With our results, we wish to set the base for a rigorous systematic approach to the problem, fundamental towards future elucidations of the detailed mechanisms at stake, highlighting both the healing and damaging potential of such approaches.

Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination).

The nervous system has an important role in the regulation of cytokines and inflammation ( Nature, 2002). The celiac-superior mesenteric ganglion complex (CSMGC) is an important component of the vagus nerve based inflammatory reflex, which controls inflammation ( Nat Neuroscience 2017). In addition to receiving cholinergic innervations from the efferent vagus nerve, the CSMGC is innervated by preganglionic sympathetic splanchnic nerves, which also are involved in the inflammatory regulation. Both neuronal types - vagal and preganglionic sympathetic - interact with catecholaminergic neurons, which reside in this ganglionic complex and innervate the liver, spleen, and other abdominal organs. Despite being a prominent locus of neuronal interactions, the possibilities of directly targeting the CSMGC to regulate cytokine responses and inflammation remains unexplored. To provide insight, we subjected the CSMGC in mice to focused ultrasound stimulation (FUS) - a non-invasive approach, which has been increasingly utilized in neuromodulation. We used ultrasound imaging and doppler to localise the complex in anesthetized 10–14-week-old male C57BL/6J mice. To perform stimulation, the FUS transducer was placed on the abdominal surface over the CSMGC and FUS (1.1MHz and 200mV per pulse, 150 burst cycles, 500μs burst period) or sham stimulation was delivered for 2 mins or 5 mins. Five mins post FUS, mice were injected with lipopolysaccharide (endotoxin, 0.25mg/kg, i.p.) and euthanized after 90 mins. Blood and liver were collected and processed for cytokine analysis. Compared to sham stimulation, FUS of the CSMGC for 5mins (n=11,12/group) significantly decreased serum TNF levels (1,875 ± 750 pg/ml vs 672.9 ± 335 pg/ml, P< 0.0001) and hepatic TNF levels (27.8 ± 8.6 pg/mg vs 16.0 ± 7.1 pg/mg, P= 0.0018) in endotoxemic mice. In contrast, FUS of CSMGC for 2 mins (n=15/group) did not significantly alter serum TNF levels (1,458 ± 599.9 pg/ml vs 1,120 ± 332.5 pg/ml, P=0.1607). These results demonstrate the anti-inflammatory effcacy of noninvasive FUS of the CSMGC. Our findings also identify the CSMGC as an easily targetable new therapeutic site for controlling systemic and hepatic inflammation with a potential for clinical translation. This work was partially supported by NIGMS. R01GM128008. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

INTRODUCTION: Vagus nerve stimulation (VNS) is a form of neuromodulation being explored to treat chronic inflammatory conditions by activating the inflammatory reflex, an arc reducing proinflammatory cytokine release through efferent cholinergic signaling. Current VNS approaches are primarily invasive and use electricity, but alternatives may improve vagal fiber specificity and eliminate surgical risks. Red-light optogenetics, a biological tool utilizing red light-activatable channelrhodopsins (ReaChR), can selectively activate genetically-modified neurons transdermally with light. Here, we show that ReaChR activation of cholinergic vagal fibers reduces cytokine production in a model of acute inflammation. METHODS: Vagus nerve cholinergic fibers were selectively activated using ReaChR expressed on choline acetyltransferase-expressing (ChAT) fibers in transgenic ChAT-ReaChR mice. Sensory afferent vagal fibers were activated in a separate cohort of transient receptor potential vanilloid subfamily member 1 (TRPV1)-ReaChR mice. Lipopolysaccharide (LPS) was injected intraperitoneally under anesthesia to induce acute endotoxemia, as measured by elevated tumor necrosis factor-alpha (TNFa). A 635nm fiber optic was targeted onto an isolated, cervical vagus for optogenetic VNS post-LPS administration. RESULTS: Selective ReaChR activation of cholinergic fibers in the cervical vagus nerve stimulates the inflammatory reflex to inhibit splenic TNFa production to bacterial LPS (ChAT-ReaChR: 1.27 ± 1.44 pg/ug; control: 4.26 ± 0.97 pg/ug, p < 0.001), but no significant differences were observed in serum (ChAT-ReaChR: 538 ± 216 pg/ml; littermate: 447 ± 206 pg/ml, p = 0.81). In contrast to efferent activation, ReaChR stimulation of afferent subsets (TRPV1+) failed to show cytokine regulation in splenic nor in serum .Approximate 20% baseline heart rate drop was seen during both ChAT+ and TRPV1+ fiber excitation, but only cholinergic activation sustained bradycardia throughout the stimulation period. CONCLUSIONS: Red-light optogenetic activation of cholinergic vagal fibers reduces splenic inflammatory cytokine production in murine endotoxemia and holds potential as a non-invasive, light-mediated VNS approach.

INTRODUCTION: Electrical stimulation of the vagus nerve activates the inflammatory reflex to inhibit cytokines and decrease clinical signs and symptoms of chronic inflammatory disease such as rheumatoid arthritis (RA) (Genovese et al. Lancet Rheum 2020). METHODS: The device system consists of two implanted components: a miniature integrated pulse generator and a silicon sleeve positioning device that holds the generator in apposition to the nerve. There are two external components: a wireless charger and an iPad application for programming the pulse generator. Subjects were randomly assigned (1:1) after device implantation on the left vagus nerve to receive active or sham stimulation. The risks of the surgical procedure, device, and stimulation were blindly assessed after 12 weeks of stimulation therapy in the first 60 subjects enrolled in the study. RESULTS: All implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events (AEs) were reported during the perioperative period and at the end of 12 weeks of follow-up. No serious AEs related to the device, stimulation, or explant procedures were reported. Vocal cord paresis and prolonged hoarseness were reported in two subjects. The former resolved following vocal cord augmentation with injectable filler; the latter is ongoing and improving with speech therapy. CONCLUSIONS: Initial results demonstrated that implantation and programming of the novel neuroimmune modulation device were safe, and the surgical procedure and device were well tolerated.

Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3’s immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3’s potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.Graphical abstract

Diminazene aceturate attenuates systemic inflammation via microbiota gut-5-HT brain-spleen sympathetic axis in male mice

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. NCT04539964; August 31, 2020.

Technology is tightly interwoven with our surroundings, becoming a crucial aspect of our existence. The iPhone, emblematic of technological progress, continually evolves, introducing enhancements in mobile apps, GPS, and cashless payment systems like Ola Cab and Uber. These advancements address challenges like locating reliable taxis swiftly. Bioelectronic medicine, a recent breakthrough, relies on electrical pulses instead of traditional drugs. Implanting small electronic devices generates digital doses, treating conditions like epilepsy and Parkinsons disease. This approach, synonymous with electroceuticals and neuromodulation, leverages the inflammatory reflex theory to map neural circuits. Despite its potential, challenges exist, including maintaining glycemic control and prosthetic eye usage.