Delta power during sleep is modulated by EEG-gated auricular vagal afferent nerve stimulation (EAVANS).

Vagus nerve stimulation (VNS) has many clinical applications under development. In particular, there is a large interest in transcutaneous auricular VNS (taVNS) because it is non-invasive and provides easy access to neuromodulation. The present study proposes a novel approach for electroencephalography (EEG)-gated taVNS, with the ultimate goal of enhancing therapeutic outcomes, including for the treatment of delirium. Delirium arises from an altered state of consciousness and is the most common neuropsychiatric disorder observed in hospitalized patients, especially the elderly. Delirium has been linked to specific disturbances in EEG rhythms. Here, we propose an EEG-gated auricular vagal afferent nerve stimulation (EAVANS) approach to deliver stimulation targeting a specific instantaneous phase of the EEG Delta rhythm to modulate arousal and downstream reduction of neuroinflammation, two of the contributing factors to delirium. We hypothesize that treatment with EAVANS will modulate Delta power, which has been linked with delirium. As dominant Delta power is also a typical feature of non-rapid eye movement (NREM) sleep, we applied a prototype of an EAVANS device on healthy volunteers during sleep to establish preliminary validation. We successfully employed our closed-loop approach to target vagal afference during the rising Delta phase in the range [-π/2 0] radians. We found a significant reduction in Delta wave power for stimulation during the rising Delta phase compared to 1) absence of stimulation, 2) active stimulation during the descending Delta phase, and 3) active stimulation targeting non-vagal territory (i.e. greater auricular nerve) during the rising Delta phase. Further validation of our EEG-gated taVNS approach in the peri-operative period will be needed. As there is presently a lack of effective treatments for delirium, our non-pharmacological and non-invasive approach, if validated, could be easily deployed in clinical settings.Clinical Relevance- Given the serious health consequences and costs associated with delirium, and the absence of effective non-pharmacological treatments, the proposed neuromodulatory approach may be a promising option for reducing delirium and other disorders of consciousness. Our EAVANS prototype system has been tested on healthy volunteers during a NREM sleep state and will require further validation in different patient populations to optimize the proposed technology and gather more evidence to support its clinical utility. This novel non-pharmacological and non-invasive closed-loop neuromodulatory device could be used peri-operatively and in inpatient hospital settings to treat patients at risk of developing delirium. For instance, in a pre-operative setting, this technology may provide an effective preventative "pre-habilitation" approach for patients at high risk of developing delirium. Post-operatively, our technology may help manage patients with delirium more effectively.

The neuroinflammatory component of negative affect in patients with chronic pain.

Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18 kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4 ± 13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9 ± 13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET)/magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [11C]PBR28. The relationship between [11C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared with controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region's functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.

Patient-Clinician Brain Response During Clinical Encounter and Pain Treatment.

The patient-clinician relationship is known to significantly affect the pain experience, as empathy, mutual trust and therapeutic alliance can significantly modulate pain perception and influence clinical therapy outcomes. The aim of the present study was to use an EEG hyperscanning setup to identify brain and behavioral mechanisms supporting the patient-clinician relationship while this clinical dyad is engaged in a therapeutic interaction. Our previous study applied fMRI hyperscanning to investigate whether brain concordance is linked with analgesia experienced by a patient while undergoing treatment by the clinician. In this current hyperscanning project we investigated similar outcomes for the patient-clinician dyad exploiting the high temporal resolution of EEG and the possibility to acquire the signals while patients and clinicians were present in the same room and engaged in a face-to-face interaction under an experimentally-controlled therapeutic context. Advanced source localization methods allowed for integration of spatial and spectral information in order to assess brain correlates of therapeutic alliance and pain perception in different clinical interaction contexts. Preliminary results showed that both behavioral and brain responses across the patient-clinician dyad were significantly affected by the interaction style.Clinical Relevance- The context of a clinical intervention can significantly impact the treatment of chronic pain. Effective therapeutic alliance, based on empathy, mutual trust, and warmth can improve treatment adherence and clinical outcomes. A deeper scientific understanding of the brain and behavioral mechanisms underlying an optimal patient-clinician interaction may lead to improved quality of clinical care and physician training, as well as better understanding of the social aspects of the biopsychosocial model mediating analgesia in chronic pain patients.

The central autonomic network at rest: Uncovering functional MRI correlates of time-varying autonomic outflow.

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).

Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: A cross-comparison with migraine and healthy adults.

Cyclic Vomiting Syndrome (CVS) has been linked to episodic migraine, yet little is known about the precise brain-based mechanisms underpinning CVS, and whether these associated conditions share similar pathophysiology. We investigated the functional integrity of salience (SLN) and sensorimotor (SMN) intrinsic connectivity networks in CVS, migraine and healthy controls using brain functional Magnetic Resonance Imaging. CVS, relative to both migraine and controls, showed increased SLN connectivity to middle/posterior insula, a key brain region for nausea and viscerosensory processing. In contrast, this same region showed diminished SMN connectivity in both CVS and migraine. These results highlight both unique and potentially shared pathophysiology between these conditions, and suggest a potential target for therapeutics in future studies.

The imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients.

BACKGROUND: Psychological factors are known to significantly modulate itch in patients suffering from chronic itch. Itch is also highly susceptible to both placebo and nocebo (negative placebo) effects. Brain activity likely supports nocebo-induced itch, but is currently unknown. METHODS: We collected functional MRI (fMRI) data from atopic dermatitis (AD) patients, in a within-subject design, and contrast brain response to nocebo saline understood to be allergen vs open-label saline control. Exploratory analyses compared results to real allergen itch response and placebo responsiveness, evaluated in the same patients. RESULTS: Nocebo saline produced greater itch than open saline control (P < 0.01). Compared to open saline, nocebo saline demonstrated greater fMRI response in caudate, dorsolateral prefrontal cortex (dlPFC), and intraparietal sulcus (iPS) - brain regions important for cognitive executive and motivational processing. Exploratory analyses found that subjects with greater dlPFC and caudate activation to nocebo-induced itch also demonstrated greater dlPFC and caudate activation, respectively, for real allergen itch. Subjects reporting greater nocebo-induced itch also demonstrated greater placebo reduction of allergen-evoked itch, suggesting increased generalized modulation of itch perception. CONCLUSIONS: Our study demonstrates the capacity of nocebo saline to mimic both the sensory and neural effects of real allergens and provides an insight to the brain mechanisms supporting nocebo-induced itch in AD, thus aiding our understanding of the role that expectations and other psychological factors play in modulating itch perception in chronic itch patients.

Complementary integrative approach for treating pruritus.

Complementary and alternative medicine (CAM) is a conservative and increasingly popular approach to treat pruritus for both patients and medical providers. CAM includes natural products, mind-body medicine, and manipulative and body-based practices. In this overview, we summarize current evidence, possible mechanisms and clinical approaches for treating pruritus with CAM techniques. We focus on pruritus associated with atopic dermatitis, herpes zoster, chronic urticaria, burns, and postoperative contexts where the evidence for CAM approaches is promising.

Brain white matter microstructure is associated with susceptibility to motion-induced nausea.

Nausea is associated with significant morbidity, and there is a wide range in the propensity of individuals to experience nausea. The neural basis of the heterogeneity in nausea susceptibility is poorly understood. Our previous functional magnetic resonance imaging (fMRI) study in healthy adults showed that a visual motion stimulus caused activation in the right MT+/V5 area, and that increased sensation of nausea due to this stimulus was associated with increased activation in the right anterior insula. For the current study, we hypothesized that individual differences in visual motion-induced nausea are due to microstructural differences in the inferior fronto-occipital fasciculus (IFOF), the white matter tract connecting the right visual motion processing area (MT+/V5) and right anterior insula. To test this hypothesis, we acquired diffusion tensor imaging data from 30 healthy adults who were subsequently dichotomized into high and low nausea susceptibility groups based on the Motion Sickness Susceptibility Scale. We quantified diffusion along the IFOF for each subject based on axial diffusivity (AD); radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA), and evaluated between-group differences in these diffusion metrics. Subjects with high susceptibility to nausea rated significantly (P < 0.001) higher nausea intensity to visual motion stimuli and had significantly (P < 0.05) lower AD and MD along the right IFOF compared to subjects with low susceptibility to nausea. This result suggests that differences in white matter microstructure within tracts connecting visual motion and nausea-processing brain areas may contribute to nausea susceptibility or may have resulted from an increased history of nausea episodes.

Itch and the brain.

The sensation of itch - defined as unpleasant sensation inducing the urge to scratch - is processed by a network of different brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational patterns. Patients with atopic eczema show different activation patterns and kinetics compared to healthy volunteers. This review summarizes current studies investigating itch in the brain.

Acupuncture compared with oral antihistamine for type I hypersensitivity itch and skin response in adults with atopic dermatitis: a patient- and examiner-blinded, randomized, placebo-controlled, crossover trial.

BACKGROUND: Itch is the major symptom of atopic dermatitis (AD). Acupuncture has been shown to exhibit a significant effect on experimental itch in AD. Our study evaluated acupuncture and antihistamine itch therapy (cetirizine) on type I hypersensitivity itch and skin reaction in AD using a patient and examiner-blinded, randomized, placebo-controlled, crossover trial. METHODS: Allergen-induced itch was evaluated in 20 patients with AD after several interventions in separate sessions: preventive (preceding) and abortive (concurrent) verum acupuncture (VAp and VAa), cetirizine (10 mg, VC), corresponding placebo interventions (preventive, PAp, and abortive, PAa, placebo acupuncture; placebo cetirizine pill, PC) and a no-intervention control (NI). Itch was induced on the forearm and temperature modulated over 20 min, using our validated model. Outcome parameters included itch intensity, wheal and flare size and the D2 attention test. RESULTS: Mean itch intensity (SE: 0.31 each) was significantly lower following VAa (31.9) compared with all other groups (PAa: 36.5; VC: 36.8; VAp: 37.6; PC: 39.8; PAp: 39.9; NI: 45.7; P < 0.05). There was no significant difference between VAp and VC (P > 0.1), although both therapies were significantly superior to their respective placebo interventions (P < 0.05). Flare size following VAp was significantly smaller (P = 0.034) than that following PAp. D2 attention test score was significantly lower following VC compared with all other groups (P < 0.001). CONCLUSIONS: Both VA and cetirizine significantly reduced type I hypersensitivity itch in patients with AD, compared with both placebo and NI. Timing of acupuncture application was important, as VAa had the most significant effect on itch, potentially because of counter-irritation and/or distraction. Itch reduction following cetirizine coincided with reduced attention.

A combined HRV-fMRI approach to assess cortical control of cardiovagal modulation by motion sickness.

Nausea is a commonly occurring symptom typified by epigastric discomfort with the urge to vomit. To date, the brain circuitry underlying the autonomic nervous system response to nausea has not been fully understood. Functional MRI (fMRI), together with a point process adaptive recursive algorithm for computation of the high-frequency (HF) index of heart rate variability (HRV) was combined to evaluate the brain circuitry underlying autonomic nervous system response to nausea. Alone, the point process analysis revealed increasing sympathetic and decreasing parasympathetic response during nausea with significant increased heart rate (HR) and decreased HF. The combined HRV-fMRI analysis demonstrated that the fMRI signal in the medial prefrontal cortex (MPFC) and pregenual anterior cingulate cortex (pgACC), regions of higher cortical functions and emotion showed a negative correlation at the baseline and a positive correlation during nausea. Overall, our findings confirm a sympathovagal shift (toward sympathetic) during nausea, which was related to brain activity in regions associated with emotion and higher cognitive function.

Dynamic Cardiovagal Response to Motion Sickness: A Point-Process Heart Rate Variability Study.

A visual display of stripes was used to examine cardio-vagal response to motion sickness. Heart rate variability (HRV) was investigated using dynamic methods to discern instantaneous fluctuations in reaction to stimulus and perception-based events. A novel point process adaptive recursive algorithm was applied to the R-R series to compute instantaneous heart rate, HRV, and high frequency (HF) power as a marker of vagal activity. Results show interesting dynamic trends in each of the considered subjects. HF power averaged across ten subjects indicates a significant decrease 20s to 60s following the transition from "no nausea" to "mild." Conversely, right before "strong" nausea, the group average shows a transient trending increase in HF power. Findings confirm gradual sympathetic activation with increasing nausea, and further evidence transitory increases in vagal tone before flushes of strong nausea.

Hypothalamus and amygdala response to acupuncture stimuli in Carpal Tunnel Syndrome.

Brain processing of acupuncture stimuli in chronic neuropathic pain patients may underlie its beneficial effects. We used fMRI to evaluate verum and sham acupuncture stimulation at acupoint LI-4 in Carpal Tunnel Syndrome (CTS) patients and healthy controls (HC). CTS patients were retested after 5 weeks of acupuncture therapy. Thus, we investigated both the short-term brain response to acupuncture stimulation, as well as the influence of longer-term acupuncture therapy effects on this short-term response. CTS patients responded to verum acupuncture with greater activation in the hypothalamus and deactivation in the amygdala as compared to HC, controlling for the non-specific effects of sham acupuncture. A similar difference was found between CTS patients at baseline and after acupuncture therapy. For baseline CTS patients responding to verum acupuncture, functional connectivity was found between the hypothalamus and amygdala--the less deactivation in the amygdala, the greater the activation in the hypothalamus, and vice versa. Furthermore, hypothalamic response correlated positively with the degree of maladaptive cortical plasticity in CTS patients (inter-digit separation distance). This is the first evidence suggesting that chronic pain patients respond to acupuncture differently than HC, through a coordinated limbic network including the hypothalamus and amygdala.

Quantitative analysis of three-dimensional-resolved fiber architecture in heterogeneous skeletal muscle tissue using nmr and optical imaging methods.

The determination of principal fiber directions in structurally heterogeneous biological tissue substantially contributes to an understanding of its mechanical function in vivo. In this study we have depicted structural heterogeneity through the model of the mammalian tongue, a tissue comprised of a network of highly interwoven fibers responsible for producing numerous variations of shape and position. In order to characterize the three-dimensional-resolved microscopic myoarchitecture of the intrinsic musculature of the tongue, we viewed its fiber orientation at microscopic and macroscopic length scales using NMR (diffusion tensor MRI) and optical (two-photon microscopy) imaging methods. Diffusion tensor imaging (DTI) of the excised core region of the porcine tongue resulted in an array of 3D diffusion tensors, in which the leading eigenvector corresponded to the principal fiber orientation at each location in the tissue. Excised axially oriented lingual core tissues (fresh or paraffin-embedded) were also imaged with a mode-locked Ti-Sapphire laser, (76 MHz repetition rate, 150 femtosecond pulse width), allowing for the visualization of individual myofibers at in situ orientation. Fiber orientation was assessed by computing the 3D autocorrelation of discrete image volumes, and deriving the minimal eigenvector of the center voxel Hessian matrix. DTI of the fibers, comprising the intrinsic core of the tongue, demonstrated directional heterogeneity, with two distinct populations of fibers oriented orthogonal to each other and in-plane to the axial perspective. Microscopic analysis defined this structural heterogeneity as discrete regions of in-plane parallel fibers, with an angular separation of ~80 degrees, thereby recapitulating the macroscopic angular relationship. This analysis, conceived at two different length scales, demonstrates that the lingual core is a spatially complex tissue, composed of repeating orthogonally oriented and in-plane fiber patches, which are capable of jointly producing hydrostatic elongation and displacement.

Determination of regional pulmonary parenchymal strain during normal respiration using spin inversion tagged magnetization MRI.

In clinical practice, the assessment of lung mechanics is limited to a global physiological evaluation, which measures, in the aggregate, the contributions of the pulmonary parenchyma, pleura, and chest wall. In this study, we used an MR imaging methodology which applies two-dimensional bands of inverted magnetization directly onto the pulmonary parenchyma, thus allowing for the quantification of local pulmonary tissue deformation, or strain, throughout inhalation. Our results showed that the magnitude of strain was maximal at the base and apex of the lung, but was curtailed at the hilum, the anatomical site of the poorly mobile bronchial and vascular insertions. In-plane shear strain mapping showed mostly positive shear strain, predominant at the apex throughout inhalation, and increasing with expanding lung volume. Anisotropy mapping showed that superior-inferior axial strain was greater than medial-lateral axial strain at the apex and base, while the opposite was true for the middle lung field. This study demonstrates that localized pulmonary deformation can be measured in vivo with tagging MRI, and quantified by applying finite strain definitions from continuum mechanics.

Demonstration of primary and secondary muscle fiber architecture of the bovine tongue by diffusion tensor magnetic resonance imaging.

The myoarchitecture of the tongue is comprised of a complex array of muscle fiber bundles, which form the structural basis for lingual deformations during speech and swallowing. We used magnetic resonance imaging of the water diffusion tensor to display the primary and secondary fiber architectural attributes of the excised bovine tongue. Fiber orientation mapping provides a subdivision of the tongue into its principal intrinsic and extrinsic muscular components. The anterior tongue consists of a central region of orthogonally oriented intrinsic fibers surrounded by an axially oriented muscular sheath. The posterior tongue consists principally of a central region of extrinsic fibers, originating at the inferior surface and projecting in a fan-like manner in the superior, lateral, and posterior directions, and lateral populations of extrinsic fibers directed posterior-inferior and posterior-superior. Analysis of cross-fiber anisotropy indicates a basic contrast of design between the extrinsic and the intrinsic fibers. Whereas the extrinsic muscles exhibit a uniaxial architecture typical of skeletal muscle, the intrinsic core muscles, comprised of the verticalis and the transversus muscles, show strong cross-fiber anisotropy. This pattern is consistent with the theory that the tongue's core functions as a muscular hydrostat in that conjoint contraction of the transverse and vertical fibers enable the tissue to expand at right angles to these fibers. These findings suggest that three-dimensional analysis of diffusion tensor magnetic resonance imaging provides a structural basis for understanding the micromechanics of the mammalian tongue.

Ultrafast MR grid-tagging sequence for assessment of local mechanical properties of the lungs.

While MR imaging with tagged magnetization has shown great utility in the study of muscle mechanics, the evaluation of pulmonary mechanics has long been hindered by the technical difficulties in MR imaging of lung parenchyma. In this study, a fast MR grid-tagging technique is described for dynamic assessment of regional pulmonary deformation. The method is based on a fast FLASH sequence with short TR and short TE. Tagging was achieved by using double DANTE pulse train or inversion pulses. Our results show that this technique is able to detect changes of the tagging grid caused by physiological deformation of the lung. Quantitative analysis of the data shows that this method is capable of assessing local pulmonary mechanics. The application of this technique could improve our understanding of ventilatory control, and thus provide a unique metric for assessing pulmonary disorders. Magn Reson Med 45:24-28, 2001.

Biomechanical basis for lingual muscular deformation during swallowing.

Our goal was to quantify intramural mechanics in the tongue through an assessment of local strain during the physiological phases of swallowing. Subjects were imaged with an ultrafast gradient echo magnetic resonance imaging (MRI) pulse sequence after the application of supersaturated magnetized bands in the x and y directions. Local strain was defined through deformation of discrete triangular elements defined by these bands and was depicted graphically either as color-coded two-dimensional strain maps or as three-dimensional octahedra whose axes correspond to the principal strains for each element. During early accommodation, the anterior tongue showed positive strain (expansive) in the anterior-posterior direction (x), whereas the middle tongue showed negative strain (contractile) in the superior-inferior direction (y). During late accommodation, the anterior tongue displayed increased positive x-direction and y-direction strain, whereas the posterior tongue displayed increased negative y-direction strain. These findings were consistent with contraction of the anterior-located intrinsic muscles and the posterior-located genioglossus and hyoglossus muscles. During propulsion, posterior displacement of the tongue was principally associated with positive strain directed in the x and y directions. These findings were consistent with posterior passive stretch in the midline due to contraction of the laterally inserted styloglossus muscle, as well as contraction of the posterior located transversus muscle. We conclude that MRI of lingual deformation during swallowing resolves the synergistic contractions of the intrinsic and extrinsic muscle groups.

Intramural mechanics of the human tongue in association with physiological deformations.

Contraction of the tongue musculature during speech and swallowing is associated with characteristic patterns of tissue deformation. In order to quantify local deformation (strain) in the human tongue, we used a non-invasive NMR tagging technique that represents tissue as discrete deforming elements. Subjects were studied with a fast gradient echo pulse sequence (TR,TE 2.3/0.8 ms, slice thickness 10 mm, and effective spatial resolution 1.3x1.3 mm). Individual elements were defined by selectively supersaturating bands of magnetic spills in resting tongue tissue along the antero-posterior and superior inferior directions of the mid-sagittal plane, resulting in a rectilinear square grid. Axial and shear strains relative to the rest condition were determined for each clement and represented by two-dimensional surface strain maps. During forward protrusion, the anterior tongue underwent positive antero posterior strain (elongation) (maximum 200%) and symmetrical negative medial lateral and superior inferior strain (contraction). During sagittal curl directed to the hard palate, the tongue exhibited positive asymmetrical antero posterior strain (maximum 160%) that increased radially as a function of distance from the center of curvature (r = 0.9216, p<0.0005), and commensurate negative strain in the medial lateral direction. Similarly, the magnitude of anterior posterior strain during left-directed tongue curl was proportional to the distance from the curved inner surface (r = O.8978, p<0.0005). We conclude that the regulation of tongue position for the motions studied was related to regional activation of the intrinsic lingual musculature.