Search

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct ‘neuroinflammatory signatures’. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. ‘radicular’ versus ‘axial’ back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of ‘fibromyalgianess’ (i.e. the degree of pain centralization, or ‘nociplastic pain’). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex–thalamus connectivity across groups. Our findings support the existence of ‘neuroinflammatory signatures’ that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.

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.

Peripheral measures of autonomic nervous system (ANS) activity at rest have been extensively employed as putative biomarkers of autonomic cardiac control. However, a comprehensive characterization of the brain-based central autonomic network (CAN) sustaining cardiovascular oscillations at rest is missing, limiting the interpretability of these ANS measures as biomarkers of cardiac control. We evaluated combined cardiac and fMRI data from 34 healthy subjects from the Human Connectome Project to detect brain areas functionally linked to cardiovagal modulation at rest. Specifically, we combined voxel-wise fMRI analysis with instantaneous heartbeat and spectral estimates obtained from inhomogeneous linear point-process models. We found exclusively negative associations between cardiac parasympathetic activity at rest and a widespread network including bilateral anterior insulae, right dorsal middle and left posterior insula, right parietal operculum, bilateral medial dorsal and ventrolateral posterior thalamic nuclei, anterior and posterior mid-cingulate cortex, medial frontal gyrus/pre-supplementary motor area. Conversely, we found only positive associations between instantaneous heart rate and brain activity in areas including frontopolar cortex, dorsomedial prefrontal cortex, anterior, middle and posterior cingulate cortices, superior frontal gyrus, and precuneus. Taken together, our data suggests a much wider involvement of diverse brain areas in the CAN at rest than previously thought, which could reflect a differential (both spatially and directionally) CAN activation according to the underlying task. Our insight into CAN activity at rest also allows the investigation of its impairment in clinical populations in which task-based fMRI is difficult to obtain (e.g., comatose patients or infants).

PURPOSE: Ulnar nerve instability (UNI) in the cubital tunnel is defined as ulnar nerve subluxation or dislocation. It is a common disorder that may be noted in patients with neuropathy or in the asymptomatic. Our prospective, single-site study utilized high-resolution ultrasonography (US) to evaluate the ulnar nerve for cross-sectional area (CSA) and measures of shear-wave elastography (SWE). Mechanical algometry was obtained from the ulnar nerve in the cubital tunnel to assess pressure pain threshold (PPT). METHODS: Forty-two asymptomatic subjects (n = 84 elbows) (25 males, 17 females) aged 22–40 were evaluated. Two chiropractic radiologists, both with 4 years of ultrasound experience performed the evaluation. Ulnar nerves in the cubital tunnel were sampled bilaterally in three different elbow positions utilizing US, SWE, and algometry. Descriptive statistics, two-way ANOVA, and rater reliability were utilized for data analysis with p ≤ 0.05. RESULTS: Fifty-six percent of our subjects demonstrated UNI. There was a significant increase in CSA in subjects with UNI (subluxation: 0.066 mm(2) ± 0.024, p = 0.027; dislocation: 0.067 mm(2) ± 0.024, p = 0.003) compared to controls (0.057 mm(2) ± 0.017) in all three elbow positions. There were no significant group differences in SWE or algometry. Inter- and intra-observer agreements for CSA of the ulnar nerves within the cubital tunnel were assessed using intraclass correlation coefficient (ICC) and demonstrated moderate (ICC 0.54) and excellent (ICC 0.94) reliability. CONCLUSIONS: Most of the asymptomatic volunteers demonstrated UNI. There was a significant increase in CSA associated with UNI implicating it as a risk factor for ulnar neuropathy in the cubital tunnel. There were no significant changes in ulnar nerve SWE and PPT. Intra-rater agreement was excellent for the CSA assessment of the ulnar nerve in the cubital tunnel. High-resolution US could be utilized to assess UNI and monitor for progression to ulnar neuropathy.

Background Assessment of gastric function in humans has relied on modalities with varying degrees of invasiveness, which are usually limited to the evaluation of single aspects of gastric function, thus requiring patients to undergo a number of often invasive tests for a full clinical understanding. Therefore, the development of a non-invasive tool able to concurrently assess multiple aspects of gastric function is highly desirable for both research and clinical assessments of gastrointestinal (GI) function. Recently, technological advances in magnetic resonance imaging (MRI) have provided new tools for dynamic (or "cine") body imaging. Such approaches can be extended to GI applications. Methods In the present work, we propose a non-invasive assessment of gastric function using a four-dimensional (4D, volumetric cine imaging), free-breathing MRI sequence with gadolinium-free contrast enhancement achieved through a food-based meal. In healthy subjects, we successfully estimated multiple parameters describing gastric emptying, motility, and peristalsis propagation patterns. Key results Our data demonstrated non-uniform kinematics of the gastric wall during peristaltic contraction, highlighting the importance of using volumetric data to derive motility measures. Conclusions & inferences MRI has the potential of becoming an important clinical and gastric physiology research tool, providing objective parameters for the evaluation of impaired gastric function.

Carpal Tunnel Syndrome (CTS) is an entrapment neuropathy of the median nerve that alters the organization of the brain's primary somatosensory cortex (S1), both structurally and functionally. Our prior research also demonstrated that electro-acupuncture (EA), both local and remote/distal to the wrist, but not sham acupuncture, improved S1 somatotopy and peripheral (median) nerve conduction. However, the mechanisms linking EA-evoked brain response during therapy with improved clinical outcomes are unknown. We investigated functional connectivity during both rest and sustained electro-acupuncture at baseline in healthy controls and CTS patients and after 8 weeks of acupuncture therapy (local, distal, or sham EA) in CTS patients. Six minutes of 3T BOLD fMRI data were collected at rest and during EA. Data were processed with FMRIPREP and FSL to generate maps of connectivity between the S1 hand region and the rest of the brain (z > 2.3, pFWE

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

The objective of this study was to determine potential effects of Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) on cardiac autonomic activity in hypertensive patients.20 hypertensive subjects (57.3±6.2 years; 11 females, 9 males) were randomized to receive either active RAVANS at 25 Hz or sham stimulation for 5 consecutive days and were assessed 5 and 10 days later. Continuous electrocardiogram, pulse rate, and blood pressure signals were collected during 10-minute baseline, 30-minute stimulation, and 10-minute recovery periods for each session. LabChart was used to acquire and process heart rate variability and blood pressure indices. Percent changes of mean values during the recovery period were calculated comparing the final stimulation session and follow-up sessions to the first stimulation session. General linear models were applied to assess the effects of RAVANS on the variables evaluated, considering baseline values and sex as covariates in the models.We found that RAVANS increased high frequency (HF-HRV) power during recovery of the final stimulation session and both follow-up sessions in comparison to sham. RAVANS also lowered heart rate and increased average RR and root mean square of successive RR interval differences (RMSSD) during recovery on the final day of stimulation. No significant effects on blood pressure values were observed during these periods.These results suggest that RAVANS effectively stimulates cardiovagal activity in hypertension, with effects lasting up to 10 days. Future research incorporating larger sample sizes is needed to replicate the effects of RAVANS.Clinical Relevance- This research has implications for potential therapeutic effects of respiratory-gated tVNS on cardiovagal modulation in hypertensive patients.

Several studies have proposed transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN) as a non-invasive alternative to vagus nerve stimulation (VNS). In this study we present preliminary results of the effect of respiratory-gated, auricular vagal afferent nerve stimulation (RAVANS) associated with a Handgrip (HG) experiment. Twelve hypertensive subjects underwent three experimental sessions on non-consecutive days. In each session subjects performed HG before and after receiving one of three types of RAVANS stimulation in a counterbalanced order: low-intensity, medium-intensity or sham stimulation. Electrocardiogram recordings were collected and analyzed by point process linear analysis of heartbeat dynamics, and instantaneous time- and frequency-domain features of heart rate variability were estimated. Results provide a preliminary characterization of HG elicited autonomic responses before and after different RAVANS stimulation intensities.

Digital, 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 colocalized, 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., Ciencias Médicas y de la Salud

The objective of this study was to determine potential effects of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) on cardiovagal activity in hypertensive patients. Twenty hypertensive subjects $(54.55\pm 6.23$ years; 12 females) underwent five randomized sessions of RAVANS at frequencies of 0, 2, 10, 25, and 100 Hz. Continuous electrocardiogram (ECG) and pulse rate signals were collected during 10-minute baseline, 30-minute stimulation, and 10-minute recovery periods using a Grass LP511 AC amplifier and piezo device. LabChart was used to acquire ECG and pulse signals and to process heart rate variability (HRV) indices. A significant increase in high frequency (HF) power (%) was observed during the RAVANS-100 Hz session from baseline to recovery $l\mathrm{n}=0.039$ ) when compared to sham, adjusting for sex and baseline values. HRV evaluation for other frequencies did not yield significant results. These results suggest that RAVANS has a frequency-dependent effect on the modulation of cardiovagal activity (HF-HRV) in hypertension.

This is the 7T MRI protocol for a study of the subject to Respiratory-gated Auricular Vagal Afferent Nerve Stimulation in the area of the auricular concha. Scan types include: multi-echo MPRAGE and 6 GRE BOLD scans for the stimulation conditions.

Functional dyspepsia (FD) is a common gastrointestinal (GI) disorder of the upper GI tract associated with a variety of symptoms, such as abdominal pain and bloating, but lacking identifiable organic abnormalities. Altered motility patterns in FD occur in the stomach, pylorus and small intestine during digestive or interdigestive periods, and up to 30% of symptoms are associated with migrating motor complexes-like activity, thus suggesting a link between gastric motility and sensory disturbances. However, gastric functional impairments have proven to be challenging to assess using conventional abdominal imaging, which typically evaluated anatomy at a single time point and relied on a variety of modalities with varying degrees of invasiveness. Magnetic Resonance Imaging (MRI) represents a promising tool for non-invasive assessment of multiple aspects of gastric function, which can be linked with pain intensity. We applied a novel 4D (volume + time), free-breathing MRI sequence at 3T with contrast enhancement achieved through a food-based meal in order to assess human gastric function. Twelve (12) FD patients were asked to consume a high-caloric meal (470 ml semi-solid pudding) containing pineapple as contrast agent. 4D cine-MRI gastric scans were collected continuously for 5 minutes (temporal resolution: 7s) at 3 post-meal times (+15, +45, +75 minutes). Ratings of abdominal pain were collected prior to each scan using a numerical rating scale ranging from 0 (“unnoticeable”) to 100 (“unbearable”). MRI gastric volumes were segmented and a gastric motility index was extracted by dividing gastric wall deformation by gastric volume. This index showed a significant positive correlation with abdominal pain ratings (r=0.39, p-value=0.018). No significant correlations were found between abdominal pain and gastric volume or ingested meal volume, supporting the importance of dynamic gastric measurements. Our results support 4D cine-MRI as a clinically relevant tool for the identification of gastric abnormalities associated with FD symptomatology. NIH NIDDK R21-DK116029, NIH Office Of The Director OT2-OD023867.

While patient/clinician relationships significantly impact pain outcomes, the behavioral and neural mechanisms supporting this phenomenon are unknown. Specifically, the precise role of facial expressions in contributing to analgesia and brain-to-brain communication has not been investigated. In this Hyperscan fMRI study, we explored how pain-related, directional facial communication between patient and clinician engaging in interactive pain treatment is associated with brain concordance. Dyads comprising 20 patients with fibromyalgia and 19 acupuncturists completed two synchronous fMRI scans (two different partners per participant). During fMRI, dyad members saw each other's face through closed-circuit video while interacting. The fMRI scan included a series of moderately painful and minimally/non-painful leg cuff pressure stimuli to the patient while the clinician observed. A separate fMRI scan included clinician-applied and remotely-activated electroacupuncture treatment to the patient while they received moderate cuff pressure pain. In-scanner videos were used for automated individual facial muscle unit (FMU) timeseries extraction. FMU data from pain/observation scans was fed into an interpretable machine learning classifier to determine which FMU's dynamics was most associated with pain. FMUs from the pain/treatment scans were used in conjunction with neural-network causality estimation to investigate directional non-verbal communication and their association with brain-to-brain dynamic fMRI concordance (as reported in Ellingsen et al., 2020). Causality analysis indicated a strong asymmetry in which the patients’ facial expressions elicited a range of facial expressions in clinicians, but not vice-versa. Patient lip movement FMUs were most associated with pain. Interestingly, patient-to-clinician causal influence of these FMUs on similar clinicians’ FMUs was associated with dynamic insula cortex brain-to-brain concordance, demonstrating the key role of this social mirroring and salience processing brain region with respect to facial expression mirroring between patients and clinicians. Supported by the National Institutes of Health, National Center for Complementary and Integrative Health (R61-AT009306), Norwegian Research Council /Marie Sklodowska-Curie Actions (FRICON/COFUND-240553/F20), Neuroimaging Pilot Funding Initiative at the Martinos Center for Biomedical imaging, MGH (R90DA023427), Korea Institute of Oriental Medicine (KIOM), Foundation for the Science of the Therapeutic Encounter, National Center for Research Resources (P41RR14075; CRC 1 UL1 RR025758), Harvard Clinical and Translational Science Center, Martinos Computing facilities, and National Institutes of Health (Grant Nos. S10RR023401, S10RR019307, S10RR019254, and S10RR023043).

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 to 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 mid-cingulate cortex, compared to 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. Post-stimulation effects were also noted immediately following eRAVANS, as we found increased activation in putative pontine serotonergic (i.e. nucleus raphe centralis) and noradrenergic (i.e. 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.

The brainstem is known to be an important brain area for nociception and pain processing, and both relaying and coordinating signaling between the cerebrum, cerebellum, and spinal cord. Although preclinical models of pain have characterized the many roles that brainstem nuclei play in nociceptive processing, the degree to which these circuitries extend to humans is not as well known. Unfortunately, the brainstem is also a very challenging region to evaluate in humans with neuroimaging. The challenges for human brainstem imaging arise from the location of this elongated brain structure, proximity to cardiorespiratory noise sources, and the size of its constituent nuclei. These challenges can require dedicated approaches to brainstem imaging, which should be adopted when study hypotheses are focused on brainstem processing of nociception or modulation of pain perception. In fact, our review will highlight many pain neuroimaging studies that have reported some brainstem involvement in nociceptive processing and chronic pain pathology. However, we note that with recent advances in neuroimaging leading to improved spatial and temporal resolution, more studies are needed that take advantage of data collection and analysis methods focused on the challenges of brainstem neuroimaging.

In this study, we evaluate the acute effects of a novel, non-invasive, respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique on arterial blood pressure levels in hypertensive patients. We consider data from 18 hypertensive subjects (53.6±6.3 years, 9 males) during three stimulation sessions where they received either sham, low-intensity, or medium-intensity stimulation in randomized order. Blood pressure was continuously collected during 15-minute baseline, stimulation, and recovery windows. Our statistical analysis shows that the percent decrease of median systolic blood pressure from baseline was significantly higher during RAVANS (medium-intensity) when compared to sham. Furthermore, a two-way ANOVA reveals a significant interaction between Intervention and Phase for changes in median systolic blood pressure. Post hoc testing reveals that this effect was driven by the Recovery Phase following RAVANS where median Systolic blood pressure significantly decreased in the last 5 minutes compared to sham. Our results indicate that exhalatory-gated RAVANS has acute modulatory effects on systolic blood pressure levels of hypertensive patients. Further longitudinal studies will be required to evaluate the therapeutic potential of the RAVANS electroceutical device.

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.

Introduction: Despite the benefits of existing blood pressure lowering drugs, approximately 50% of hypertensive patients are inadequately controlled while taking medications. Autonomic nervous system dysfunction is associated with the development and progression of hypertension, and neurostimulation devices that target sympathetic or vagal modulation have been suggested as potential novel treatments for this disorder. Hypothesis: In this study, we assessed the hypothesis that respiratory gated transcutaneous vagus nerve stimulation (RAVANS tVNS) reduces blood pressure in hypertensive patients. Methods: Twelve hypertensive subjects (53.2 ± 5.8 years, 7 males) with persistent high blood pressure levels despite current antihypertensive treatment were enrolled in the study. Participants underwent two experimental sessions on non-consecutive days. In each session subjects were evaluated during an initial rest period followed by RAVANS or sham tVNS stimulation. Electrodes were placed over vagal innervated regions in the ear (cymba concha). RAVANS tVNS was delivered for 15 minutes at 25 Hz (pulse width: 15 ms), and gated in real time to exhalation. Sham stimulation was delivered with the current generator shut off, without the subjects’ knowledge. Measurement of blood pressure levels by continuous beat-to-beat recordings were performed with a Finometer device (Finapress Medical System, the Netherlands). Mean arterial pressure (MAP) levels were computed over the rest and stimulation periods and were compared between groups. Results: No significant baseline differences in MAP levels were found between groups (104.9 ± 7.6 mmHg vs 103.6 ± 6.1 mmHg, p=0.6). Administration of exhalatory-gated RAVANS tVNS resulted in a significant reduction of MAP values compared to Sham tVNS (-4.1 ± 7.0 mmHG vs 2.6 ± 5.6 mmHg, p=0.02), whereas no significant effects in heart rate or respiratory frequency were observed. Conclusions: Our findings reveal that exhalatory-gated RAVANS tVNS has a significant effect in the acute reduction of blood pressure levels in hypertensive patients. These promising results support a potential role of this intervention in the treatment of hypertension, however further longitudinal studies will be required to test this hypothesis.

Digital, Transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN) has been proposed as a non-invasive alternative to vagus nerve stimulation (VNS). However, its cardiovagal effects are inconsistent across studies, likely due to inhomogeneity in the stimulation parameters. Here, we evaluate respiratory-gated ABVN stimulation (Respiratory-gated Auricular Vagal Afferent Nerve Stimulation, RAVANS), where the stimuli are delivered in 1 s bursts during the exhalation phase of respiration, thus mimicking the breathing-induced modulation of cardiac vagal activity. In this study, we present preliminary results from an ongoing single-arm, open label trial investigating the effects of different intensities of RAVANS in hypertensive subjects. We found that a mid-intensity RAVANS stimulation (rated as a 5 on a 0-10 scale) increases the cardiovagal tone and reduces the sympathetic tone during a paced breathing task. The present results could contribute to optimize RAVANS as a non-invasive, low-cost therapeutic intervention for hypertension.