Causal influence of brainstem response to transcutaneous vagus nerve stimulation on cardiovagal outflow.

BACKGROUND: The autonomic response to transcutaneous auricular vagus nerve stimulation (taVNS) has been linked to the engagement of brainstem circuitry modulating autonomic outflow. However, the physiological mechanisms supporting such efferent vagal responses are not well understood, particularly in humans. HYPOTHESIS: We present a paradigm for estimating directional brain-heart interactions in response to taVNS. We propose that our approach is able to identify causal links between the activity of brainstem nuclei involved in autonomic control and cardiovagal outflow. METHODS: We adopt an approach based on a recent reformulation of Granger causality that includes permutation-based, nonparametric statistics. The method is applied to ultrahigh field (7T) functional magnetic resonance imaging (fMRI) data collected on healthy subjects during taVNS. RESULTS: Our framework identified taVNS-evoked functional brainstem responses with superior sensitivity compared to prior conventional approaches, confirming causal links between taVNS stimulation and fMRI response in the nucleus tractus solitarii (NTS). Furthermore, our causal approach elucidated potential mechanisms by which information is relayed between brainstem nuclei and cardiovagal, i.e., high-frequency heart rate variability, in response to taVNS. Our findings revealed that key brainstem nuclei, known from animal models to be involved in cardiovascular control, exert a causal influence on taVNS-induced cardiovagal outflow in humans. CONCLUSION: Our causal approach allowed us to noninvasively evaluate directional interactions between fMRI BOLD signals from brainstem nuclei and cardiovagal outflow.

Sonographic measures and sensory threshold of the normal sciatic nerve and hamstring muscles.

PURPOSE: The sciatic nerve innervates the hamstring muscles. Occasionally, the sciatic nerve is injured along with a hamstring muscle. Detailed biomechanical and sensory thresholds of these structures are not well-characterized. Therefore, we designed a prospective study that explored high-resolution ultrasound (US) at multiple sites to evaluate properties of the sciatic nerve, including cross-sectional area (CSA) and shear-wave elastography (SWE). We also assessed SWE of each hamstring muscle at multiple sites. Mechanical algometry was obtained from the sciatic nerve and hamstring muscles to assess multi-site pressure pain threshold (PPT). METHODS: Seventy-nine asymptomatic sciatic nerves and 147 hamstring muscles (25 males, 24 females) aged 18-50 years were evaluated. One chiropractic radiologist with 4.5 years of US experience performed the evaluations. Sciatic nerves were sampled along the posterior thigh at four sites obtaining CSA, SWE, and algometry. All three hamstring muscles were sampled at two sites utilizing SWE and algometry. Descriptive statistics, two-way ANOVA, and rater reliability were assessed for data analysis with p ≤ 0.05. RESULTS: A significant decrease in sciatic CSA from proximal to distal was correlated with increasing BMI (p < 0.001). Intra-rater and inter-rater reliability for CSA was moderate and poor, respectively. Elastographic values significantly increased from proximal to distal with significant differences in gender and BMI (p = 0.002). Sciatic PPT significantly decreased between sites 1 and 2, 1 and 3, and 1 and 4. Significant correlation between gender and PPT was noted as well as BMI (p < 0.001). Hamstring muscle elastographic values significantly differed between biceps femoris and semitendinosus (p < 0.001) and biceps femoris and semimembranosus (p < 0.001). All three hamstring muscles demonstrated increased PPT in males compared to females (p < 0.001). In addition, PPT of the biceps femoris correlated with BMI (p = 0.02). CONCLUSION: High-resolution US provided useful metrics of sciatic nerve size and biomechanical properties. PPT for the normal sciatic nerve and hamstring muscles was obtained for future clinical application.

S1 Brain Connectivity in Carpal Tunnel Syndrome Underlies Median Nerve and Functional Improvement Following Electro-Acupuncture.

Carpal Tunnel Syndrome (CTS) is a median nerve entrapment neuropathy that alters primary somatosensory cortex (S1) organization. While electro-acupuncture (EA), a form of peripheral neuromodulation, has been shown to improve clinical and neurophysiological CTS outcomes, the role of EA-evoked brain response during therapy (within and beyond S1) for improved outcomes is unknown. We investigated S1-associated whole brain fMRI connectivity during both a resting and sustained EA stimulation state in age-matched healthy controls (N = 28) and CTS patients (N = 64), at baseline and after 8 weeks of acupuncture therapy (local, distal, or sham EA). Compared to healthy controls, CTS patients at baseline showed decreased resting state functional connectivity between S1 and thalamic pulvinar nucleus. Increases in S1/pulvinar connectivity strength following verum EA therapy (combined local and distal) were correlated with improvements in median nerve velocity (r = 0.38, p = 0.035). During sustained local EA, compared to healthy controls, CTS patients demonstrated increased functional connectivity between S1 and anterior hippocampus (aHipp). Following 8 weeks of local EA therapy, S1/aHipp connectivity significantly decreased and greater decrease was associated with improvement in patients' functional status (r = 0.64, p = 0.01) and increased median nerve velocity (r = -0.62, p = 0.013). Thus, connectivity between S1 and other brain areas is also disrupted in CTS patients and may be improved following EA therapy. Furthermore, stimulus-evoked fMRI connectivity adds therapy-specific, mechanistic insight to more common resting state connectivity approaches. Specifically, local EA modulates S1 connectivity to sensory and affective processing regions, linked to patient function and median nerve health.

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation.

BACKGROUND: The therapeutic potential of transcutaneous auricular VNS (taVNS) is currently being explored for numerous clinical applications. However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize this promising approach. HYPOTHESIS: We proposed that stimulation frequency would have a significant effect on nucleus tractus solitarii (NTS) functional MRI (fMRI) response to respiratory-gated taVNS (RAVANS). METHODS: Brainstem fMRI response to auricular RAVANS (cymba conchae) was assessed for four different stimulation frequencies (2, 10, 25, 100 Hz). Sham (no current) stimulation was used to control for respiration effects on fMRI signal. RESULTS: Our findings demonstrated that RAVANS delivered at 100 Hz evoked the strongest brainstem response, localized to a cluster in the left (ipsilateral) medulla and consistent with purported NTS. A co-localized, although weaker, response was found for 2 Hz RAVANS. Furthermore, RAVANS delivered at 100 Hz also evoked stronger fMRI responses for important monoamine neurotransmitter source nuclei (LC, noradrenergic; MR, DR, serotonergic) and pain/homeostatic regulation nuclei (i.e. PAG). CONCLUSION: Our fMRI results support previous localization of taVNS afference to pontomedullary aspect of NTS in the human brainstem, and demonstrate the significant influence of the stimulation frequency on brainstem fMRI response.

The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study.

BACKGROUND: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. HYPOTHESIS: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. METHODS: Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded during fMRI. RESULTS: Our findings demonstrated that eRAVANS evoked fMRI signal increase in ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem response to GANctrl localized a partially-overlapping cluster, more ventrolateral, consistent with spinal trigeminal nucleus. A region-of-interest analysis also found eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic) and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei. Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming enhanced eRAVANS response on both central and peripheral neurophysiological levels. CONCLUSION: 7T fMRI localized brainstem response to taVNS, linked such response with autonomic outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients.

Migraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous vagus nerve stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62 × 2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared with sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior midcingulate cortex, compared with both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Poststimulation effects were also noted immediately after eRAVANS, as we found increased activation in putative pontine serotonergic (ie, nucleus raphe centralis) and noradrenergic (ie, locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.