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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.

Patient–clinician concordance in behavior and brain activity has been proposed as a potential key mediator of mutual empathy and clinical rapport in the therapeutic encounter. However, the specific elements of patient–clinician communication that may support brain-to-brain concordance and therapeutic alliance are unknown. Here, we investigated how pain-related, directional facial communication between patients and clinicians is associated with brain-to-brain concordance. Patient–clinician dyads interacted in a pain-treatment context, during synchronous assessment of brain activity (fMRI hyperscanning) and online video transfer, enabling face-to-face social interaction. In-scanner videos were used for automated individual facial action unit (AU) time-series extraction. First, an interpretable machine-learning classifier of patients’ facial expressions, from an independent fMRI experiment, significantly distinguished moderately painful leg pressure from innocuous pressure stimuli. Next, we estimated neural-network causality of patient-to-clinician directional information flow of facial expressions during clinician-initiated treatment of patients’ evoked pain. We identified a leader–follower relationship in which patients predominantly led the facial communication while clinicians responded to patients’ expressions. Finally, analyses of dynamic brain-to-brain concordance showed that patients’ mid/posterior insular concordance with the clinicians’ anterior insula cortex, a region identified in previously published data from this study1, was associated with therapeutic alliance, and self-reported and objective (patient-to-clinician-directed causal influence) markers of negative-affect expressivity. These results suggest a role of patient-clinician concordance of the insula, a social-mirroring and salience-processing brain node, in mediating directional dynamics of pain-directed facial communication during therapeutic encounters.

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.

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.

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

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.

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.

The brain networks supporting nausea not yet understood. We previously found that while visual stimulation activated primary (V1) and extrastriate visual cortices (MT+/V5, coding for visual motion), increasing nausea was associated with increasing sustained activation in several brain areas, with significant co-activation for anterior insula (aIns) and mid-cingulate (MCC) cortices. Here, we hypothesized that motion sickness also alters functional connectivity between visual motion and previously identified nausea-processing brain regions. Subjects prone to motion sickness and controls completed a motion sickness provocation task during fMRI/ECG acquisition. We studied changes in connectivity between visual processing areas activated by the stimulus (MT+/V5, V1), right aIns and MCC when comparing rest (BASELINE) to peak nausea state (NAUSEA). Compared to BASELINE, NAUSEA reduced connectivity between right and left V1 and increased connectivity between right MT+/V5 and aIns and between left MT+/V5 and MCC. Additionally, the change in MT+/V5 to insula connectivity was significantly associated with a change in sympathovagal balance, assessed by heart rate variability analysis. No state-related connectivity changes were noted for the control group. Increased connectivity between a visual motion processing region and nausea/salience brain regions may reflect increased transfer of visual/vestibular mismatch information to brain regions supporting nausea perception and autonomic processing. We conclude that vection-induced nausea increases connectivity between nausea-processing regions and those activated by the nauseogenic stimulus. This enhanced low-frequency coupling may support continual, slowly evolving nausea perception and shifts toward sympathetic dominance. Disengaging this coupling may be a target for biobehavioral interventions aimed at reducing motion sickness severity.

The human brainstem plays a central role in connecting the cerebrum, the cerebellum and the spinal cord to one another, hosting relay nuclei for afferent and efferent signaling, and providing source nuclei for several neuromodulatory systems that impact central nervous system function. While the investigation of the brainstem with functional or structural magnetic resonance imaging has been hampered for years due to this brain structure's physiological and anatomical characteristics, the field has seen significant advances in recent years thanks to the broader adoption of ultrahigh-field (UHF) MRI scanning. In the present review, we focus on the advantages offered by UHF in the context of brainstem imaging, as well as the challenges posed by the investigation of this complex brain structure in terms of data acquisition and analysis. We also illustrate how UHF MRI can shed new light on the neuroanatomy and neurophysiology underlying different brainstem-based circuitries, such as the central autonomic network and neurotransmitter/neuromodulator systems, discuss existing and foreseeable clinical applications to better understand diseases such as chronic pain and Parkinson's disease, and explore promising future directions for further improvements in brainstem imaging using UHF MRI techniques.

13 p., While autonomic outflow is an important co-factor of nausea physiology, central control of this outflow is poorly understood. We evaluated sympathetic (skin conductance level) and cardiovagal (high-frequency heart rate variability) modulation, collected synchronously with functional MRI (fMRI) data during nauseogenic visual stimulation aimed to induce vection in susceptible individuals. Autonomic data guided analysis of neuroimaging data, using a stimulus-based (analysis windows set by visual stimulation protocol) and percept-based (windows set by subjects’ ratings) approach. Increased sympathetic and decreased parasympathetic modulation was associated with robust and anti-correlated brain activity in response to nausea. Specifically, greater autonomic response was associated with reduced fMRI signal in brain regions such as the insula, suggesting an inhibitory relationship with premotor brainstem nuclei. Interestingly, some sympathetic/parasympathetic specificity was noted. Activity in default mode network and visual motion areas was anti-correlated with parasympathetic outflow at peak nausea. In contrast, lateral prefrontal cortical activity was anticorrelated with sympathetic outflow during recovery, soon after cessation of nauseogenic stimulation. These results suggest divergent central autonomic control for sympathetic and parasympathetic response to nausea. Autonomic outflow and the central autonomic network underlying ANS response to nausea may be an important determinant of overall nausea intensity and, ultimately, a potential therapeutic target.

Investigation of causal interactions within brain networks using Granger causality analysis (GCA) is a key challenge in studying neural activity on the basis of functional magnetic resonance imaging (fMRI). The article describes an open-source software toolbox GMAC (Granger multivariate autoregressive connectivity) implementing multivariate spectral GCA. Available features are: fMRI data importing/exporting, network nodes definition, time series preprocessing, multivariate autoregressive modeling, spectral Granger causality indexes estimation, statistical significance assessment using surrogate data, network analysis and visualization of connectivity results. All functions have been integrated into a user-friendly graphical interface developed in the Matlab environment, easily accessible to both technical and clinical users.

The skin conductance (SC) signal is one of the most important non-invasive indirect measures of autonomic outflow. Several mathematical models have been proposed in the literature to characterize specific SC features. In this work, we present a method for the estimation of central control of sudomotor nerve impulse (SMI) function using SC. The method is based on a differential formulation decomposed into two first order differential equations. We validate our estimation framework by applying it on an experimental protocol where eleven motion sickness-prone subjects were exposed to a nauseogenic visual stimulus while SC and fMRI signals were recorded. Our results show an expected significant increase in the mean amplitude of SMI peaks during the highest reported nausea, as well as a decreasing trend during recovery, which was not evident for skin conductance level. Importantly, SMI/fMRI analysis found a negative association between SMI and fMRI signal in orbitofrontal, dorsolateral prefrontal, and posterior insula cortices, consistent with previous studies correlating brain fMRI and microneurographic signals.

This paper investigates the relation between mental engagement level and sustained attention in 9 healthy adults performing a Conners' "not-X" continuous performance test (CPT), while their electroencephalographic (EEG) activity was simultaneously acquired. Spectral powers were estimated and extracted in the classical EEG frequency bands. The engagement index (β/α) was calculated employing four different cortical montages suggested by the literature. Results show the efficacy of the estimated measures in detecting changes in mental state and its correlation with subject reaction times throughout the test. Moreover, the influence of the recording sites was proved underling the role of frontal cortex in maintaining a constant sustained attention level.

In the last decade, an increasing interest has arisen in investigating the relationship between the electrophysiological and hemodynamic measurements of brain activity, such as EEG and (BOLD) fMRI. In particular, changes in BOLD have been shown to be associated with changes in the spectral profile of neuronal activity, rather than with absolute neural power. On the other hand, though, recent findings showed that different EEG rhythms are independently related to changes in the BOLD signal: therefore, it would be important to distinguish between the contributions of the different EEG rhythms to BOLD fluctuations when modeling the relationship between EEG and BOLD. Here we proposed a novel method to perform EEG-informed fMRI analysis, so that the EEG regressors take into account both the changes in the spectral profile and the rhythms distinction. We applied it to EEG-fMRI data during a bimanual motor task in healthy subjects, and compared the results with those obtained by regressing fMRI data onto a single regressor covering the entire range of frequencies, ignoring the distinction between different EEG rhythms. Our results showed that the proposed method better captures the correlations between BOLD signal and EEG rhythms modulations, identifying task-related well localized activated volumes.

The aim of this work is to improve fMRI Granger Causality Analysis (GCA) by proposing and comparing two strategies for defining the topology of the networks among which cerebral connectivity is measured and to apply fMRI GCA for studying epileptic seizure propagation. The first proposed method is based on information derived from anatomical atlas only; the other one is based on functional information and employs an algorithm of hierarchical clustering applied to fMRI data directly. Both methods were applied to signals recorded during seizures on a group of epileptic subjects and two connectivity matrices were obtained for each patient. The performances of the different parcellation strategies were evaluated in terms of their capability to recover information about the source and the sink of the network (i.e., the starting and the ending point of the seizure propagation). The first method allows to clearly identify the seizure onset in all patients, whereas the network sources are not so immediately recognizable when the second method was used. Nevertheless, results obtained using functional clustering do not contradict those obtained with the anatomical atlas and are able to individuate the main pattern of propagation. In conclusion, the way nodes are defined can influence the easiness of identification of the epileptogenic focus but does not produce contradictory results showing the effectiveness of proposed approach to formulate hypothesis about seizure propagation at least in the early phase of investigation.