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Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n = 15 sham and n = 15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in the nVNS group (p < .0005) bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

This study introduces a flexible, adhesive-integrated electrode array that was developed to enable non-invasive monitoring of cervical nerve activity. The device uses silver-silver chloride as the electrode material of choice and combines it with an electrode array consisting of a customized biopotential data acquisition unit and integrated graphical user interface (GUI) for visualization of real-time monitoring. Preliminary testing demonstrated this electrode design can achieve a high signal to noise ratio during cervical neural recordings. To demonstrate the capability of the surface electrodes to detect changes in cervical neuronal activity, the cold-pressor test (CPT) and a timed respiratory challenge were employed as stressors to the autonomic nervous system. This sensor system recording, a new technique, was termed Cervical Electroneurography (CEN). By applying a custom spike sorting algorithm to the electrode measurements, neural activity was classified in two ways: (1) pre-to-post CPT, and (2) during a timed respiratory challenge. Unique to this work: (1) rostral to caudal channel position-specific (cephalad to caudal) firing patterns and (2) cross challenge biotype-specific change in average CEN firing, were observed with both CPT and the timed respiratory challenge. Future work is planned to develop an ambulatory CEN recording device that could provide immediate notification of autonomic nervous system activity changes that might indicate autonomic dysregulation in healthy subjects and clinical disease states.

The field of bioelectronic medicine has advanced rapidly from rudimentary electrical therapies to cutting-edge closed-loop systems that integrate real-time physiological monitoring with adaptive neuromodulation. Early innovations, such as cardiac pacemakers and deep brain stimulation, paved the way for these sophisticated technologies. This review traces the historical and technological progression of bioelectronic medicine, culminating in the emerging potential of closed-loop devices for multiple disorders of the brain and body. We emphasize both invasive techniques, such as implantable devices for brain, spinal cord and autonomic regulation, while we introduce new prospects for non-invasive neuromodulation, including focused ultrasound and newly developed autonomic neurography enabling precise detection and titration of inflammatory immune responses. The case for closed-loop non-invasive autonomic neuromodulation (incorporating autonomic neurography and splenic focused ultrasound stimulation) is presented through its applications in conditions such as sepsis and chronic inflammation, illustrating its capacity to revolutionize personalized healthcare. Today, invasive or non-invasive closed-loop systems have yet to be developed that dynamically modulate autonomic nervous system function by responding to real-time physiological and molecular signals; it represents a transformative approach to therapeutic interventions and major opportunity by which the bioelectronic field may advance. Knowledge gaps remain and likely contribute to the lack of available closed loop autonomic neuromodulation systems, namely, (1) significant exogenous and endogenous noise that must be filtered out, (2) potential drift in the signal due to temporal change in disease severity and/or therapy induced neuroplasticity, and (3) confounding effects of exogenous therapies (e.g., concurrent medications that dysregulate autonomic nervous system functions). Leveraging continuous feedback and real-time adjustments may overcome many of these barriers, and these next generation systems have the potential to stand at the forefront of precision medicine, offering new avenues for individualized and adaptive treatment.

BackgroundThis technical report describes a durable, low-cost, anatomically accurate, and easy-to-prepare combined ultrasound (US) and fluoroscopic phantom of the cervical spine. This phantom is meant to augment training in US- and fluoroscopic-guided pain medicine procedures.MethodsThe combined US and fluoroscopic phantom (CUF-P) is prepared from commercially available liquid plastic that is ordinarily used to prepare synthetic fishing lures. The liquid plastic is heated and then poured into a metal canister that houses an anatomical cervical spine model. Drops of dark purple dye are added to make the phantom opaque. After cooling, tubing is attached to the CUF-P to simulate blood vessels.ResultsThe CUF-P accurately simulates human tissue by imitating both the tactile texture of skin and the haptic resistance of human tissue as the needle is advanced. This phantom contains simulated fluid-filled vertebral arteries that exhibit pulsed flow under color Doppler US. Under fluoroscopic examination, the CUF-P–simulated vertebral arteries also exhibit uptake of contrast dye if mistakenly injected.ConclusionsThe creation of a training phantom allows the pain physician to practice needle positioning technique while simultaneously visualizing both targeted and avoidable vascular structures under US and fluoroscopic guidance. This low-cost CUF-P is easy to prepare and is reusable, making it an attractive alternative to current homemade and commercially available phantom simulators.

Introduction Spinal cord stimulation (SCS), an FDA-approved therapy for chronic pain, uses paresthesia (low frequency SCS (LF-SCS)) or paresthesia-free (such as high-frequency SCS (HF-SCS)) systems, providing analgesia through partially-elucidated mechanisms, with recent studies indicating a sexual dimorphism in pain pathogenesis (Bretherton et al., Neuromodulation, 2021; Paller et al., Pain Med 10:289–299, 2009; Slyer et al., Neuromodulation, 2019; Van Buyten et al., Neuromodulation 20:642–649, 2017; Mekhail et al., Pain Pract, 2021). We aim to evaluate SCS therapy sex effects based on paradigm, utilizing visual analog scores (VAS), perceived pain reduction (PPR), and opioid use. Methods A retrospective cohort study of SCS patients implanted between 2004 and 2020 ( n  = 237) was conducted. Descriptive statistics and linear mixed methods analyses were used. Results HF-SCS (10 kHz) was implanted in 94 patients (40 females, 54 males), and LF-SCS in 143 (70 females, 73 males). At 3 months and 6 months, HF-SCS ( p  < 0.001) and LF-SCS ( p  < 0.005) had lower VAS scores compared to baseline ( p  < 0.005), with no differences across groups. PPR improved in both post-implantation ( p  < 0.006) and at 3 months ( p  < 0.004 respectively), compared to baseline persisting to 6 ( p  < 0.003) and 12 months ( p  < 0.01) for HF-SCS, with significantly better PPR for HF-SCS at 3 ( p  < 0.008) and 6 ( p  < 0.001) months compared to LF-SCS. There were no differences in opioid use from baseline for either modality; however LF-SCS patients used more opioids at every time point ( p  < 0.05) compared to HF-SCS. VAS was improved for all modalities in both sexes at 3 months ( p  = 0.001), which persisted to 6 months ( p  < 0.05) for HF-SCS males and females, and LF-SCS females. Female HF-SCS had improved PPR at 3 ( p  = 0.016) and 6 ( p  = 0.022) months compared to baseline, and at 6 ( p  = 0.004) months compared to LF-SCS. Male HF-SCS and LF-SCS had improved PPR post-implantation ( p  < 0.05) and at 3 months ( p  < 0.05), with HF-SCS having greater benefit at 3 ( p  < 0.05) and 6 ( p  < 0.05) months. LF-SCS males but not females used less opioids at 6 months ( p  = 0.017) compared to baseline; however this effect did not persist. On linear mixed model analyses, including age, sex and stimulator type, VAS decreased with age, at each timepoint, and had a trend towards increasing with female sex, while PPR increased at 3 and 6 months and lastly HF-SCS was associated with decreased opioid use. Discussion PPR at 3 and 6 months improved to a greater extent in HF-SCS. HF-SCS females had improved PPR at 3 and 6 months, and only LF-SCS males used less opioids at 6 months, potentially indicating sex-based pathway. Future studies should further elucidate differences in sex-based pathways and identify optimal SCS opioid-sparing paradigms for chronic pain patients.

Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individual’s distinct endophenotype. Ventral cervical magnetoneurography responses after LPS administration temporally aligned with the changes in TNF-α levels, making it a potential sensitive bioindicator of the neuroimmune axis for clinical use.

Background Chronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vulnerability to cognitive decline, particularly in those at elevated risk for Alzheimer’s disease. We examined how multisite chronic pain relates to cognitive decline in older adults, the possible moderating role of APOE‐e4 allele status, and—in a postmortem subsample—associations with amyloid and tau. Method We examined 751 participants without dementia at baseline from the Religious Orders Study/Rush Memory and Aging Project (ROSMAP; Mean age = 79.47, SD = 6.93, Mean education = 6.42, SD = 3.63; 64% women) followed for up to 30 years with repeated cognitive testing measuring episodic memory, working memory, perceptual orientation, and processing speed (Mean years followed = 7.32, SD = 4.51). Individuals with multisite chronic pain, defined as joint pain in >2 body regions over the first 2 study waves, were compared to those without pain. Amyloid‐beta and tau were measured in a postmortem subsample assessed around 10 months after their last clinical evaluation using computer‐assisted immunoreactivity assays across 8 regions associated with Alzheimer’s disease (hippocampus; entorhinal cortex; midfrontal cortex; inferior temporal; angular gyrus; calcarine cortex; anterior cingulate cortex; superior frontal cortex Result Multisite chronic pain (n = 105) was associated with accelerated decline in episodic memory (b = ‐.03, p = .016) and processing speed (b = ‐.06, p<.001), particularly in APOE‐e4‐positive individuals (bs = ‐.05 and ‐.04, respectively, ps<.01). Only APOE‐e4‐positive individuals with multisite chronic pain showed significant decline in perceptual orientation (b = ‐.08, p = .015). Only APOE‐e4‐positive individuals with multisite chronic pain had higher levels of amyloid‐beta load compared to those without chronic pain (b = .51, p<.001). No differences in tau burden were detected. People with single‐site chronic pain showed no significant differences from people without chronic pain. Conclusion The results suggest that multisite chronic pain exacerbates cognitive decline, particularly in those at genetic risk for Alzheimer’s disease. In addition, the postmortem analyses suggest that early treatment of multisite chronic pain—a modifiable risk factor—might help to reduce amyloid accumulation.

Background Chronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vulnerability to cognitive decline, particularly in those at elevated risk for Alzheimer’s disease. We examined how multisite chronic pain relates to cognitive decline in older adults, the possible moderating role of APOE‐ε4 allele status, and—in a postmortem subsample—associations with amyloid and tau. Method We examined 751 participants without dementia at baseline from the Religious Orders Study/Rush Memory and Aging Project (ROSMAP; Mean age = 79.47, SD = 6.93, Mean education = 6.42, SD = 3.63; 64% women) followed for up to 30 years with repeated cognitive testing measuring episodic memory, working memory, perceptual orientation, and processing speed (Mean years followed = 7.32, SD = 4.51). Individuals with multisite chronic pain, defined as joint pain in >2 body regions over the first 2 study waves, were compared to those without pain. Amyloid‐beta and tau were measured in a postmortem subsample assessed around 10 months after their last clinical evaluation using computer‐assisted immunoreactivity assays across 8 regions associated with Alzheimer’s disease (hippocampus; entorhinal cortex; midfrontal cortex; inferior temporal; angular gyrus; calcarine cortex; anterior cingulate cortex; superior frontal cortex Result Multisite chronic pain (n = 105) was associated with accelerated decline in episodic memory (b = ‐.03, p = .016) and processing speed (b = ‐.06, p<.001), particularly in APOE‐ε4‐positive individuals (bs = ‐.05 and ‐.04, respectively, ps<.01). Only APOE‐ε4‐positive individuals with multisite chronic pain showed significant decline in perceptual orientation (b = ‐.08, p = .015). Only APOE‐ε4‐positive individuals with multisite chronic pain had higher levels of amyloid‐beta load compared to those without chronic pain (b = .51, p<.001). No differences in tau burden were detected. People with single‐site chronic pain showed no significant differences from people without chronic pain. Conclusion The results suggest that multisite chronic pain exacerbates cognitive decline, particularly in those at genetic risk for Alzheimer’s disease. In addition, the postmortem analyses suggest that early treatment of multisite chronic pain—a modifiable risk factor—might help to reduce amyloid accumulation.

Chronic pain affects one in five older adults and is linked to increased risk for Alzheimer's disease (AD) dementia. Few studies have investigated associations between chronic pain and AD biomarkers, especially chronic pain at moderate-to-severe levels considered clinically significant. We included 2487 participants without baseline dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At baseline, participants were categorized by absence/presence of moderate-to-severe chronic pain, defined as persistent/recurring pain with onset >3 months prior. For sensitivity analyses, we categorized people based on the absence/presence of chronic pain at mild levels. Cognitive outcomes included the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), episodic memory, and executive function (minimal n = 1328, mean follow-up-years=1.49, SD=2.78). AD biomarkers included cerebrospinal fluid levels of Aβ42, total tau, and phosphorylated tau (minimal n = 1057, mean follow-up-years=.53, SD=1.24); and structural MRI (AD structural brain signature, hippocampal volume, entorhinal cortical thickness, and whole brain volume, minimal n = 2136, mean follow-up-years=1.11, SD=2.28). Mixed-effects models assessed differences in baseline levels and change in each outcome between pain groups, and mediation analyses explored Aβ and neurodegeneration pathways. Covariates included baseline age, sex, APOE ε4 status, depressive symptoms, and opioid use (intracranial volume for structural MRI outcomes). Moderate-to-severe chronic pain relative to mild or none was associated with accelerated decline in global cognition (increase in CDR-SB: b=.05), memory, executive function (b=-.04), and whole brain volume (b=-.02), and faster accumulation of Aβ pathology (CSF Aβ42 decline: b=-.07, all p's < .05). It was not associated with neurodegeneration in AD brain signature regions, hippocampal volume, or entorhinal cortex (all ps>.05). Accumulation of Aβ pathology (absolute b's range=.03 to .05) and whole brain volume loss (absolute b's range=.001-.002) mediated associations of moderate-to-severe chronic pain with cognitive decline, with Aβ also mediating moderate-to-severe chronic pain's association with brain volume loss (b=-.01, all ps<.05). Mild chronic pain relative to none did not significantly relate to cognitive or biomarker outcomes (all ps>.05). Moderate-to-severe chronic pain contributes to accelerated cognitive decline and general neurodegeneration, primarily via Aβ. These findings highlight the need to consider moderate-to-severe chronic pain, rather than just presence/absence of chronic pain in AD risk assessments and interventions.