Ectopically expressed rhodopsin is not sensitive to X-rays.

Visual perception of X-radiation is a well-documented, but poorly understood phenomenon. Scotopic rod cells and rhodopsin have been implicated in visual responses to X-rays, however, some evidence suggests that X-rays excite the retina via a different mechanism than visible light. While rhodopsin's role in X-ray perception is unclear, the possibility that it could function as an X-ray receptor has led to speculation that it could act as a transgenically expressed X-ray receptor. If so, it could be used to transduce transcranial X-ray signals and control the activity of genetically targeted populations of neurons in a less invasive version of optogenetics, X-genetics. Here we investigate whether human rhodopsin (hRho) is capable of transducing X-ray signals when expressed outside of the retinal environment. We use a live-cell cAMP GloSensor luminescence assay to measure cAMP decreases in hRho-expressing HEK293 cells in response to visible light and X-ray stimulation. We show that cAMP GloSensor luminescence decreases are not observed in hRho-expressing HEK293 cells in response to X-ray stimulation, despite the presence of robust responses to visible light. Additionally, irradiation had no significant effect on cAMP GloSensor responses to subsequent visible light stimulation. These results suggest that ectopically expressed rhodopsin does not function as an X-ray receptor and is not capable of transducing transcranial X-ray signals into neural activity for X-ray mediated, genetically targeted neuromodulation.

Noninvasive Electromagnetic Neuromodulation of the Central and Peripheral Nervous System for Upper-Limb Motor Strength and Functionality in Individuals with Cervical Spinal Cord Injury: A Systematic Review and Meta-Analysis.

(1) Background: Restoring arm and hand function is one of the priorities of people with cervical spinal cord injury (cSCI). Noninvasive electromagnetic neuromodulation is a current approach that aims to improve upper-limb function in individuals with SCI. The aim of this study is to review updated information on the different applications of noninvasive electromagnetic neuromodulation techniques that focus on restoring upper-limb functionality and motor function in people with cSCI. (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to structure the search protocol. A systematic review of the literature was performed in three databases: the Cochrane Library, PubMed, and Physiotherapy Evidence Database (PEDro). (3) Results: Twenty-five studies were included: four were on transcranial magnetic stimulation (TMS), four on transcranial direct current stimulation (tDCS), two on transcutaneous spinal cord stimulation (tSCS), ten on functional electrical stimulation (FES), four on transcutaneous electrical nerve stimulation (TENS), and one on neuromuscular stimulation (NMS). The meta-analysis could not be completed due to a lack of common motor or functional evaluations. Finally, we realized a narrative review of the results, which reported that noninvasive electromagnetic neuromodulation combined with rehabilitation at the cerebral or spinal cord level significantly improved upper-limb functionality and motor function in cSCI subjects. Results were significant compared with the control group when tSCS, FES, TENS, and NMS was applied. (4) Conclusions: To perform a meta-analysis and contribute to more evidence, randomized controlled trials with standardized outcome measures for the upper extremities in cSCI are needed, even though significant improvement was reported in each non-invasive electromagnetic neuromodulation study.

Frequency-Specific Effects of Noninvasive Median Nerve Stimulation on Gastric Slow Wave Activity in Humans.

OBJECTIVES: The present study explored the effects of different frequencies of noninvasive median nerve stimulation (nMNS) on two autonomic responses: gastric slow waves under water-loading condition and heart rate variability (HRV). To the best of our knowledge, this is the first study to document the effects of different frequencies of nMNS on gastric slow waves (GSW) in humans under 5-minute water-loading condition. MATERIALS AND METHODS: Twenty healthy adult participants were fitted with a noninvasive body-surface gastric mapping, electrocardiogram (ECG), and a transcutaneous electrical nerve stimulation device and administered with four different nMNS frequencies (placebo-0 Hz, 40 Hz, 120 Hz, and 200 Hz) on four separate counterbalanced days. After the baseline and stimulation periods, a 5-minute water-load test was applied, and a post-water-load period also is recorded for ECG and GSW activity. Time-domain HRV parameters are analyzed with repeated-measures one-way analysis of variance (ANOVA) and a post hoc Tukey multiple comparison test. Parameters that failed normality tests underwent a Freidman test with a post hoc Dunn multiple comparison test. GSW data are analyzed with repeated-measures mixed-effects ANOVA. RESULTS: In empty stomach (baseline vs stimulation), only the 40-Hz frequency statistically significantly (p = 0.0129) increased GSW amplitude in comparison with its own baseline. In full (distended) stomach, 40-Hz and 200-Hz stimulations showed a statistically significant difference (post hoc multiple comparison adjusted, p = 0.0016 and p = 0.0183, respectively) in the Gastric Rhythm Index in comparison with the change obtained by placebo stimulation (baseline vs poststimulation periods); 120-Hz nMNS showed a statistically significant difference (p = 0.0300) in the stress index in comparison with the decrease observed in the placebo group. However, 120-Hz nMNS did not induce a statistically significant change in gastric electrical activity compared to placebo stimulation. The nMNS did not follow the linear "dose-response" relationship between nMNS frequency and gastric/HRV parameters. CONCLUSIONS: The 40-Hz and 200-Hz nMNS frequencies showed the most promising results in response to gastric distension, in addition to 40 Hz for an empty stomach. Further research is essential to explore the potential therapeutic effects of these frequencies on gastric diseases such as gastroparesis, gastroesophageal reflux disease, and functional dyspepsia that can be used in wrist wearables.

Transcranial direct current stimulation for focal status epilepticus or lateralized periodic discharges in four patients in a critical care setting.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4-mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting. METHODS: Patients in the intensive care unit were referred for tDCS treatment when focal status epilepticus or clinically relevant lateralized periodic discharges did not resolve with conventional antiseizure medications and anesthetics. Battery-powered direct cathodal current at 2 mA was delivered by an ActivaDose (Caputron) tDCS device via a saline-soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 min, repeated twice in a day, then again 1-4 times more over the next few days. RESULTS: Three females and one male, aged 34-68 years, were treated. Etiologies of status epilepticus were posterior reversible encephalopathy syndrome in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke, and central nervous system lupus. tDCS led to significant reduction of interictal spikes (.78 to .38/s, p < .0001) in three cases and electrographic seizures (3.83/h to 0/h, p < .001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home, and one became fully responsive as seizures were controlled with tDCS. SIGNIFICANCE: Spikes and electrographic seizure frequency significantly improved within 1 day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.

A new synthesis method for complex electric field patterning using a multichannel dense array system with applications in low-intensity noninvasive neuromodulation.

Multichannel coil array systems offer precise spatiotemporal electronic steering and patterning of electric and magnetic fields without the physical movement of coils or magnets. This capability could potentially benefit a wide range of biomagnetic applications such as low-intensity noninvasive neuromodulation or magnetic drug delivery. In this regard, the objective of this work is to develop a unique synthesis method, that enabled by a multichannel dense array system, generates complex current pattern distributions not previously reported in the literature. Simulations and experimental results verify that highly curved or irregular (e.g., zig-zag) patterns at singular and multiple sites can be efficiently formed using this method. The synthesis method is composed of three primary components; a pixel cell (basic unit of pattern formation), a template array ("virtual array": code that disseminates the coil current weights to the "physical" dense array), and a hexagonal coordinate system. Low-intensity or low-field magnetic stimulation is identified as a potential application that could benefit from this work in the future and as such is used as an example to frame the research.

Transspinal Focused Ultrasound Suppresses Spinal Reflexes in Healthy Rats.

OBJECTIVES: Low-intensity, focused ultrasound (FUS) is an emerging noninvasive neuromodulation approach, with improved spatial and temporal resolution and penetration depth compared to other noninvasive electrical stimulation strategies. FUS has been used to modulate circuits in the brain and the peripheral nervous system, however, its potential to modulate spinal circuits is unclear. In this study, we assessed the effect of trans-spinal FUS (tsFUS) on spinal reflexes in healthy rats. MATERIALS AND METHODS: tsFUS targeting different spinal segments was delivered for 1 minute, under anesthesia. Monosynaptic H-reflex of the sciatic nerve, polysynaptic flexor reflex of the sural nerve, and withdrawal reflex tested with a hot plate were measured before, during, and after tsFUS. RESULTS: tsFUS reversibly suppresses the H-reflex in a spinal segment-, acoustic pressure- and pulse-repetition frequency (PRF)-dependent manner. tsFUS with high PRF augments the degree of homosynaptic depression of the H-reflex observed with paired stimuli. It suppresses the windup of components of the flexor reflex associated with slower, C-afferent, but not faster, A- afferent fibers. Finally, it increases the latency of the withdrawal reflex. tsFUS does not elicit neuronal loss in the spinal cord. CONCLUSIONS: Our study provides evidence that tsFUS reversibly suppresses spinal reflexes and suggests that tsFUS could be a safe and effective strategy for spinal cord neuromodulation in disorders associated with hyperreflexia, including spasticity after spinal cord injury and painful syndromes.

A pilot randomized controlled clinical trial of Transcranial Alternating Current Stimulation in patients with multifocal pharmaco-resistant epilepsy.

Transcranial Alternating Current Stimulation (tACS) is a promising noninvasive electrical stimulation therapy for neuropsychiatric diseases. Invasive neuromodulation using alternating current has been efficacious for drug-resistant epilepsy, but it is associated with surgical and medical complications. We aimed to explore the safeness and effectivity on seizure frequency reduction of two tACS protocols against placebo in patients with multifocal refractory epilepsy. This was a randomized, double-blinded, placebo-controlled clinical trial with 3-arm parallel-group (placebo, 30 min/2 mA daily sessions for 3 days [tACS-30], and 60 min/2 mA weekday sessions [tACS-60]). The main outcome was considered a change in reducing seizure frequency at 2 months after the intervention. Secondary outcomes were the apparition of any adverse effects during follow-up. At the second month, we observed a nonsignificant reduction in the seizure frequency in the placebo (7.3 ±â€¯40.4%, p > 0.05) and the tACS-60 (26 ±â€¯37.7%, p > 0.05). While the tACS-30 group showed a nonsignificant increase in seizure frequency (63.6 ±â€¯155.3%, p > 0.05). No changes were statistically different from the placebo group. Otherwise, participants experienced only minor adverse events - the most common being an initial local transient tingling sensation (21%). This pilot study of tACS raises no severe safety issues, but provides negligible evidence for efficacy using this brief treatment protocol. Therefore, more studies are warranted testing different parameters to further verify the safety and effectivity of tACS in multifocal epilepsy.

Noninvasive neuromodulation for unilateral neglect after stroke: a systematic review and network meta-analysis.

OBJECTIVE: To systematically evaluate the effect of noninvasive neuromodulation (NINM) on unilateral neglect (UN) after stroke and compare the effects of different NINMs. METHODS: Randomized controlled trials (RCTs) on the effect of NINM on UN after stroke were retrieved from the PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and CBM databases from inception to January 2022. The risk of bias and quality of the trials were assessed following the Cochrane Handbook of Systematic Reviews and the physiotherapy evidence database PEDro Scale. Statistical analysis was conducted with Stata 16.0 and R 4.0.2. This study was registered on PROSPERO (No. CRD42021295336). RESULTS: A total of 12 RCTs involving 291 patients were included. Meta-analysis showed that NINM could reduce the line bisection test (LBT) score (SMD = - 1.56, 95% CI - 2.10 ~ - 1.03, P < 0.05), the line cancellation test score (SMD = - 1.83, 95% CI - 2.39 ~ - 1.27, P < 0.05), and the star cancellation test score (SMD = - 2.85, 95% CI - 4.93 ~ - 0.76, P < 0.05). Network meta-analysis showed that the best probabilistic ranking of the effects of different NINMs on the LBT score was theta-burst stimulation (TBS) (P = 0.915) > repetitive transcranial magnetic stimulation (P = 0.068) > transcranial direct current stimulation (P = 0.018). CONCLUSION: Existing evidence showed that NINM could improve UN after stroke and that TBS was best. Due to the number of included studies and sample size, more large-sample, multicenter, double-blinded, high-quality clinical RCTs are still needed in the future to further confirm the results of this research.

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. METHODS AND RESULTS: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 µs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. CONCLUSIONS: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Feasibility of Interferential and Pulsed Transcranial Electrical Stimulation for Neuromodulation at the Human Scale.

OBJECTIVES: Transcranial electrical stimulation (tES) is a promising tool for modulating neural activity, but tES has poor penetrability and spatiotemporal resolution compared to invasive techniques like deep brain stimulation (DBS). Interferential strategies for alternating-current stimulation (IF-tACS) and pulsed/intersectional strategies for transcranial direct-current stimulation (IS-tDCS) address some of the limitations of tES, but the comparative advantages and disadvantages of these new techniques is not well understood. This study's objective was to evaluate the suprathreshold and subthreshold membrane dynamics of neurons in response to IF-tACS and IS-tDCS. MATERIALS AND METHODS: We analyzed the biophysics of IF-tACS and IS-tDCS using a bioelectric field model of tES. Neural responses were quantified for suprathreshold generation of action potentials in axons and for subthreshold modulation of membrane dynamics in spiking pyramidal neurons. RESULTS: IF-tACS and IS-tDCS could not directly activate axons at or below 10 mA, but within this current range, these fields were able to modulate, albeit indirectly, spiking activity in the neuron model. IF-tACS facilitated phase synchronization similar to tACS, and IS-tDCS enhanced and suppressed spiking activity similar to tDCS; however, in either case, the modulatory effects of these fields were less potent than their standard counterparts at a matched field intensity. Moreover, neither IF-tACS nor IS-tDCS improved the spatial selectivity of their parent strategies. CONCLUSIONS: Enhancing the spatiotemporal precision and penetrability of tES with interferential and intersectional strategies is possible at the human scale. However, IF-tACS or IS-tDCS will likely require spatial multiplexing with multiple simultaneous sources to counteract their reduced potency, compared to standard techniques, to maintain stimulation currents at tolerable levels.

Preventing Episodic Migraine With Caloric Vestibular Stimulation: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. BACKGROUND: Migraine causes significant disability in ∼12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. METHODS: In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNM™ device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance. RESULTS: Per-protocol, active-arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3 months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.9 ± 0.6 from a baseline burden of 7.7 ± 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1 ± 0.6 from a baseline burden = 6.9 ± 0.7 migraine days) and represented a therapeutic gain of -2.8 migraine days, CI = -0.9 to -4.7, P = .012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. CONCLUSION: The TNM™ device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine.

Technical Report: Efficacy and Safety of Low-Intensity Transcranial Magnetic Stimulation in the Remission of Depressive Symptoms in Patients With Treatment-Resistant Depression in Mexico.

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that induces action potentials in the stimulated cortical area and has been approved by the Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The prevalence of MDD in Mexico almost tripled after the COVID-19 pandemic. In this study, we evaluated the safety and therapeutic effects of low-intensity TMS (Li-TMS) - characterized by inducing electric currents below the action potential threshold on the cerebral cortex - in 41 subjects diagnosed with treatment-resistant depression (TRD). A Li-TMS device dispensed repetitive magnetic pulses at 30 mT for 60 minutes during 20 sessions (once daily from Monday to Saturday) with the theta burst pattern. Our results suggest that Li-TMS is a safe therapy with antidepressant effects, demonstrated by the decrease in Beck Depression Inventory (BDI) scores and lessening of depressive symptoms.

Efficacy of Radio Electric Asymmetric Conveyer Neuro Psycho Physical Optimization - Brain Wave Optimization-Gamma (REAC NPPO BWO-G) Treatment in Neurovegetative Dysfunction: A Case Report of Enhanced Cognitive Processing and Stress Resilience.

Neurovegetative dysfunction from chronic stress impairs cognition, emotional regulation, and quality of life, with limited relief from conventional therapies. The Radio Electric Asymmetric Conveyer (REAC) Neuro Psycho Physical Optimization - Brain Wave Optimization-Gamma (NPPO BWO-G) offers a novel non-invasive approach to restore autonomic balance through brain modulation. This case involves a 63-year-old businessman with atrial fibrillation, fatigue, cognitive decline, and sleep issues. Pre-treatment quantitative electroencephalogram (qEEG) showed low brain activity and excess delta rhythms. After REAC NPPO BWO-G sessions, the patient experienced improved brainwave patterns, cognitive clarity, stress management, and reduced fatigue. These results highlight its potential as a promising treatment for stress-related neurovegetative dysfunction, warranting further study.

The Role of Continuous Theta Burst Stimulation on Primary Motor Cortex in Improving Bladder Function in Post-stroke Patients: A Case Report.

Neurogenic bladder (NB) is a frequently encountered post-stroke complication, characterized by symptoms, such as urinary incontinence, dysuria, increased frequency, and urgency. Here, we present a case of a 75-year-old male with urgent urination, frequent urination, urinary incontinence, conspicuous discomfort during urination, and an unpleasant smell in the urine following a stroke. By reviewing the patient's previous medical records of stroke and ruling out other potential causes for bladder dysfunction, a diagnosis of NB could be established. We implemented conventional physical therapy, pelvic floor muscle training with the electromyography biofeedback device, and continuous theta burst stimulation (cTBS) on the contralesional primary motor cortex area to manage bladder function. To the best of our knowledge, this is the first case report on cTBS applied to manage NB after stroke. Our treatment has demonstrated remarkable efficacy in enhancing bladder and kidney function, improving the overall quality of life, and alleviating anxiety and depression symptoms in this patient. This case study concludes that the noninvasive neuromodulation approach exhibits significant potential in the clinical field when addressing this specific patient population.

LITE-1 mediates behavioral responses to X-rays in Caenorhabditis elegans.

Rapid sensory detection of X-ray stimulation has been documented across a wide variety of species, but few studies have explored the underlying molecular mechanisms. Here we report the discovery of an acute behavioral avoidance response in wild type Caenorhabditis elegans to X-ray stimulation. The endogenous C. elegans UV-photoreceptor protein LITE-1 was found to mediate the locomotory avoidance response. Transgenic expression of LITE-1 in C. elegans muscle cells resulted in paralysis and egg ejection responses to X-ray stimulation, demonstrating that ectopic expression of LITE-1 can confer X-ray sensitivity to otherwise X-ray insensitive cells. This work represents the first demonstration of rapid X-ray based genetically targeted (X-genetic) manipulation of cellular electrical activity in intact behaving animals. Our findings suggest that LITE-1 has strong potential for use in this minimally invasive form of neuromodulation to transduce transcranial X-ray signals for precise manipulation of neural activity in mammals, bypassing the need for invasive surgical implants to deliver stimulation.

Noninvasive electrical neuromodulation for gastrointestinal motility disorders.

INTRODUCTION: Gastrointestinal motility disorders are highly prevalent without satisfactory treatment. noninvasive electrical neuromodulation is an emerging therapy for treating various gastrointestinal motility disorders. AREAS COVERED: In this review, several emerging noninvasive neuromodulation methods are introduced, including transcutaneous auricular vagal nerve stimulation, percutaneous auricular vagal nerve stimulation, transcutaneous cervical vagal nerve stimulation, transcutaneous electrical acustimulation, transabdominal interference stimulation, tibial nerve stimulation, and translumbosacral neuromodulation therapy. Their clinical applications in the most common gastrointestinal motility are discussed, including gastroesophageal reflux disease, functional dyspepsia, gastroparesis, functional constipation, irritable bowel syndrome, and fecal incontinence. PubMed database was searched from 1995 to June 2023 for relevant articles in English. EXPERT OPINION: Noninvasive neuromodulation is effective and safe in improving both gastrointestinal symptoms and dysmotility; it can be used when pharmacotherapy is ineffective. Future directions include refining the methodology, improving device development and understanding mechanisms of action.

Noninvasive Neuromodulation in Parkinson's Disease: Insights from Animal Models.

The mainstay treatments for Parkinson's Disease (PD) have been limited to pharmacotherapy and deep brain stimulation. While these interventions are helpful, a new wave of research is investigating noninvasive neuromodulation methods as potential treatments. Some promising avenues have included transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electroconvulsive therapy (ECT), and focused ultrasound (FUS). While these methods are being tested in PD patients, investigations in animal models of PD have sought to elucidate their therapeutic mechanisms. In this rapid review, we assess the available animal literature on these noninvasive techniques and discuss the possible mechanisms mediating their therapeutic effects based on these findings.

Non-invasive neuromodulation: an emerging intervention for visceral pain in gastrointestinal disorders.

Gastrointestinal (GI) disorders, which extend from the esophagus to the anus, are the most common diseases of the GI tract. Among these disorders, pain, encompassing both abdominal and visceral pain, is a predominant feature, affecting the patients' quality of life and imposing a substantial financial burden on society. Pain signals originating from the gut intricately shape brain dynamics. In response, the brain sends appropriate descending signals to respond to pain through neuronal inhibition. However, due to the heterogeneous nature of the disease and its limited pathophysiological understanding, treatment options are minimal and often controversial. Consequently, many patients with GI disorders use complementary and alternative therapies such as neuromodulation to treat visceral pain. Neuromodulation intervenes in the central, peripheral, or autonomic nervous system by alternating or modulating nerve activity using electrical, electromagnetic, chemical, or optogenetic methodologies. Here, we review a few emerging noninvasive neuromodulation approaches with promising potential for alleviating pain associated with functional dyspepsia, gastroparesis, irritable bowel syndrome, inflammatory bowel disease, and non-cardiac chest pain. Moreover, we address critical aspects, including the efficacy, safety, and feasibility of these noninvasive neuromodulation methods, elucidate their mechanisms of action, and outline future research directions. In conclusion, the emerging field of noninvasive neuromodulation appears as a viable alternative therapeutic avenue for effectively managing visceral pain in GI disorders.

A Review of Chronic Pain and Device Interventions: Benefits and Future Directions.

Chronic pain is a debilitating condition with a growing prevalence both in the USA and globally. The complex nature of this condition necessitates a multimodal approach to pain management that extends beyond the established pharmaceutical interventions currently employed. A variety of devices comprising both invasive and noninvasive approaches are available to patients, serving as adjuvants to existing regimens. The benefits of these interventions are notable for their lack of addiction potential, potential for patient autonomy regarding self-administration, minimal to no drug interaction, and overall relative safety. However, there remains a need for further research and more robust clinical trials to assess the true efficacy of these interventions and elucidate if there is an underlying physiological mechanism to their benefit in treating chronic pain or if their effect is predominantly placebo in nature. Regardless, the field of device-based intervention and treatment remains an evolving field with much promise for the future chronic pain management.