Objectives: The purpose of this study was to test the transcutaneous noninvasive vagus nerve stimulator (nVNS) (gammaCoreV C ) device to determine if it modulates the peripheral immune system, as has been previously published for implanted vagus nerve stimulators. Materials and Methods:A total of 20 healthy males and females were randomized to receive either nVNS or sham stimulation (SST). All subjects underwent an initial blood draw at 8:00 AM, followed by stimulation with nVNS or SST at 8:30 AM. Stimulation was repeated at 12:00 PM and 6:00 PM. Additional blood samples were withdrawn 90 min and 24 hour after the first stimulation session. After samples were cultured using the Myriad RBM TruCulture (Austin, TX) system (WBCx), levels of cytokines and chemokines were measured by the Luminex assay and statistical analyses within and between groups were performed using the Wilcoxon Signed Ranks Test and Mann-Whitney U with the statistical program R.Results: A significant percent decrease in the levels of the cytokine interleukin [IL]-1b, tumor necrosis factor [TNF] levels, and chemokine, interleukin [IL]-8 IL-8, macrophage inflammatory protein [MIP]-1a, and monocyte chemoattractant protein [MCP]-1 levels was observed in the nVNS group non-lipopolysaccharide (LPS)-stimulated whole blood culture (n-WBCx) at the 24-hour time point (p < 0.05). In SST group, there was a significant percent increase in IL-8 at 90 min post-stimulation (p < 0.05). At 90 min, the nVNS group had a greater percent decrease in IL-8 concentration (p < 0.05) compared to SST group. The nVNS group had a greater percent decrease in cytokines (TNF, IL-1b) and chemokines (MCP-1 and IL-8) at 24 hour (p < 0.05) in comparison to SST. LPSstimulated whole blood cultures (L-WBCx) did not show a significant decrease in cytokine levels in either the nVNS or SST group across any time points. The nVNS group showed a significant percent increase in LPS-stimulated IL-10 levels at the 24-hour time point in comparison to SST.Conclusions: nVNS downregulates inflammatory cytokine release suggesting that nVNS may be an effective anti-inflammatory treatment.

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.

We report two occurrences of high-grade tears of the lateral collateral ligament complex (LCLC), consisting of the anterolateral ligament (ALL) and fibular collateral ligament (FCL). One injury occurred in a rock climber and the other in a martial artist. Increasing awareness of isolated injuries of the LCLC will allow for appropriate diagnosis and management. We review and discuss the anatomy of the LCLC, the unique mechanism of isolated injury, as well as physical and imaging examination findings.

a b s t r a c tObjective: Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1␤), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF␣) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). Methods: After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30 min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110 min post capsaicin injection. Inflammatory (IL-1␤, IL-6, IL-8 TNF␣) and antiinflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110 min. Results: Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNF␣, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1␤ significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10 min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70 min post injection. Conclusion: These findings show significant central nervous system (CNS) differences in the inflammatory response to a deep pain stimulus in combat veterans with and without PTSD. They support the concept that abnormally elevated neuroinflammatory response to pain stimuli may be one CNS mechanism accounting for the high co-occurrence of PTSD and pain.Published by Elsevier Ltd.

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 nVNS group (p < .0005) in 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.Adding to preclinical work, multiple translational clinical studies also show similar antinociceptive effects of acute (10,(35)(36)(37)(38) and chronic VNS (39).Recent fMRI studies have revealed that nVNS affects brain areas important in pain processing (e.g. the medial thalamus, dorsal ACC, IC, and PFC; (40-43), thus highlighting a potential supraspinal vagal influence on pain perception. Only a single small pilot study (n = 20) has evaluated the neural effects of transcutaneous VNS using auricular "Arnold's nerve" stimulation on experimental pain (36). The results did not show a difference between groups, but a post-hoc analysis of "responders", i.e. subjects (n = 12) with increased pain threshold post-nVNS, showed decreased activation during the application of pain stimuli in the left dorsoposterior insula, ACC, ventromedial PFC, caudate nucleus, and hypothalamus (36). Notably, this study performed continuous transcutaneous auricular VNS during the noxious thermal challenge, possibly confounding the results as emerging literature shows pronociceptive effects during actual VNS, while the antinociceptive effects occur post-VNS (44,45). Taken together, the evidence accumulated to date suggests that VNS alters clinical pain perception, but that VNS must be carefully timed to produce antinociceptive effects. Study objectivesThe objective of this study was to gain a richer understanding of post-nVNS effects on sensory discriminative neurocircuits, affective pain neurocircuits, and the peripheral autonomic response to noxious thermal stimuli. Our goa...