BACKGROUND:Migraine is a major cause of disability and efficacious interventions are needed. In this mechanistic study, we investigate the combined, and potentially synergistic, effects of a multimodal intervention combining Mindfulness-Based Stress Reduction (MBSR) and transcutaneous auricular Vagal Nerve Stimulation (taVNS) for migraine. METHODS:We utilize a modified double-blinded, placebo-controlled, 2 × 2 factorial randomized longitudinal design to assess the effects of an 8-week MBSR intervention with concomitant Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) taVNS on migraine pathophysiology primary outcomes. We will enroll 150 patients with migraine (4-20 headache days/month). After a run-in month of daily diaries, we expect to randomly assign N = 96 participants to one of four treatment groups: (1) MBSR+RAVANS taVNS, (2) MBSR+Sham taVNS, (3) Nature Education Control (NEC) + RAVANS taVNS, or (4) NEC + Sham taVNS. Before and after intervention, participants have three in-person assessments (a 7 T MRI scan, an autonomic/sensory testing (AST) visit, and a 3 T PET-MRI scan). The primary outcomes for this study assess (1) central sensitization (brainstem/cortical response to trigeminal sensory afference), (2) autonomic dysfunction (High Frequency-Heart Rate Variability (HF-HRV) response to stressors), and (3) neuroinflammation (PET[11C]PBR28 signal). RESULTS:Funded by NIH (P01AT009965), registered (NCT03592329). Final longitudinal outcomes will be collected by May 2025. CONCLUSION:This mechanistic study is designed to investigate both independent and synergistic neurobiological effects of MBSR and RAVANS taVNS interventions on three distinct pathophysiological mechanisms of migraine. This research will elucidate the mechanistic and potentially synergistic effects of behavioral interventions (e.g., mindfulness) and device-based treatments (e.g., taVNS) for migraine.

Although the pathophysiology of migraine involves a complex ensemble of peripheral and CNS changes that remain incompletely understood, the activation and sensitization of the trigeminovascular system are believed to play a major role. However, non-invasive, in vivo neuroimaging studies investigating the underlying neural mechanisms of trigeminal system abnormalities in human migraine patients are limited. Here, we studied 60 patients with migraine (55 females, mean ± standard deviation age: 36.28 ± 11.95 years) and 20 age- and sex-matched healthy controls (19 females, age: 35.45 ± 13.30 years) using ultra-high field 7 T diffusion tensor imaging and functional MRI, in addition to PET with the translocator protein ligand 11C-PBR28. We evaluated MRI diffusivity measures and the PET signal at the trigeminal nerve root, in addition to the brainstem functional MRI response to innocuous ophthalmic trigeminal nerve territory stimulation. Patients with migraine demonstrated altered white matter microstructure at the trigeminal nerve root (n = 53), including reduced fractional anisotropy, in comparison to healthy controls (n = 18). Furthermore, in patients, lower fractional anisotropy was accompanied by higher neuroinflammation (i.e. elevated 11C-PBR28 PET signal) at the nerve root (n = 36) and by lower functional MRI activation in an ipsilateral pontine cluster consistent with the spinal trigeminal nucleus (n = 51). These findings were more robust on the right side, which was consistent with the observation that right headache-dominant patients demonstrated higher migraine severity in comparison to left headache-dominant patients in our cohort. Multimodal imaging of the integrated neural mechanisms that characterize migraine underscores the importance of trigeminal system remodelling as both a key aspect of the dynamics underlying migraine pathophysiology and a target for therapeutic interventions.

Behavior change often requires overcoming discomfort or difficult emotions. Emotional dysregulation associated with anxiety or depression may prevent behavior change initiation among people managing chronic illness. Mindfulness training may catalyze chronic disease self-management by reducing experiential avoidance of aversive experiences that act as barriers to change initiation. Using a fMRI evoked pain task, we examined the effects of 8 weeks of Mindfulness Training for Primary Care (MTPC) on brain response to the anticipation of a noxious event (i.e., pain) among patients with anxiety and/or depression. We modeled the association between post-MTPC changes in brain response to pain anticipation and post-MTPC Action Plan Initiation (API), a measure of successful initiation of health behavior change. Greater post-MTPC increase in response to pain anticipation in the dorsal medial prefrontal cortex (dmPFC) was associated with higher levels of API (r=0.77, p<0.001). This increase in dmPFC response correlated with post-MTPC self-reported increase in emotion regulation skills related to goal-directed behaviors (r=-0.52, p=0.002). This suggests that mindfulness training increases the capacity to maintain goal-directed behavior in the face of aversive experiences by strengthening neural mechanisms of emotion- and self-regulation supporting successful health behavior change initiation in patients struggling with anxiety and/or depression.

Self-judgment is a trans-diagnostic symptom among various psychological disorders, therefore can be a therapeutic target for many common psychiatric conditions. Self-judgment often arises among those who experienced childhood maltreatment, which increases the risk for developing comorbid psychiatric disorders that are resistant to traditional pharmacological and psychological interventions. Understanding the neural correlates of the therapeutic effect of behavioral interventions for reducing self-judgment is key for developing and refining evidence-based intervention programs. This single arm pilot study (N=24) explored the neural correlates of reduction in self-judgment after an eight-week mindful self-compassion (MSC) intervention program for a sample of adult patients with either anxiety or depressive disorders, with 83% having more than one diagnoses. The results demonstrated significant reduction of self-judgment after the intervention (p < 0.001, d = -1.04) along with increased self-compassion (p < 0.001, d =1.20); in particular, participants with above median score on the Childhood Trauma Questionnaire had significantly more improvement than those with below median scores (p<0.05). Resting state fMRI was used to study neural correlates and showed that reduced self-judgment was associated with increased posterior cingulate cortex functional connectivity with dorsal lateral prefrontal cortex, inferior frontal gyrus, and dorsal medial prefrontal cortex, accompanied by reduced posterior cingulate cortex functional connectivity with the amygdala-hippocampal complex. These findings suggest reduced self-judgment after MSC training was substantiated by reduced fear circuitry influences on self-referential processes along with enhanced frontal regulation from the executive network and language network.

Language and social symptoms improve with age in some autistic toddlers, but not in others, and such outcome differences are not clearly predictable from clinical scores alone. Here we aim to identify early-age brain alterations in autism that are prognostic of future language ability. Leveraging 372 longitudinal structural MRI scans from 166 autistic toddlers and 109 typical toddlers and controlling for brain size, we find that, compared to typical toddlers, autistic toddlers show differentially larger or thicker temporal and fusiform regions; smaller or thinner inferior frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most differences are replicated in an independent cohort of 75 toddlers. These brain alterations improve accuracy for predicting language outcome at 6-month follow-up beyond intake clinical and demographic variables. Temporal, fusiform, and inferior frontal alterations are related to autism symptom severity and cognitive impairments at early intake ages. Among autistic toddlers, brain alterations in social, language and face processing areas enhance the prediction of the child’s future language ability.

Elevated risk for schizophrenia is associated with a variation in the DTNBP1 gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with Dtnbp1 mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the Dtnbp1 mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. Dntbp1 mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in Dtnbp1 mutants (MUT), whereas mice heterozygous for the Dtnbp1 mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that Dtnbp1 mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content.

We sought to determine which brain regions may be responsible for alpha power (AP) decreases during the experience of pain.We hypothesized BOLD activity in the ACC, S1, and insula would be associated with AP decreases.We collected EEG-fMRI from 20 healthy participants during a thermal paradigm with three pain intensities (intense, moderate, and slight) and a control warm stimulus applied to the lower left leg.Initial analysis showed channels identified FC2 and C2 as responsive to thermal stimuli.AP values for each stimulus intensity were calculated using a linear mixed effects model for C2 and FC2.AP decreased as stimulation intensity increased for intense, slight, and warm stimuli.The moderate stimuli did not follow this pattern and was removed from further analysis.Clusters representing brain regions displaying increased activity during intense relative to slight, intense relative to warm, and slight relative to warm stimuli were extracted from the fMRI data and used in a temporal modulation analysis.Slight versus warm resulted in only one cluster and was omitted.Connectivity between L dorsal M2 and the L mid insula negatively correlated with C2 AP during intense versus slight.(T = -2.84,p = 0.01) There were no significant findings for FC2 AP for intense versus slight.For intense versus warm, right supramarginal gyrus and right lateral PMC (T = 3.33, p = 0.003) displayed connectivity covarying with AP power changes at C2. FC2 power changes corelated with right thalamus and left lateral S1 (T = 3.27, p = 0.004) connectivity.R01 NS112356-01 to DAS.T a g g e d E n d

Identifying prognostic early brain alterations is crucial for autism spectrum disorder (ASD). Leveraging structural MRI data from 166 ASD and 109 typical developing (TD) toddlers and controlling for brain size, we found that, compared to TD, ASD toddlers showed larger or thicker lateral temporal regions; smaller or thinner frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most of these differences were replicated in an independent cohort of 38 ASD and 37 TD toddlers. Moreover, the identified brain alterations were related to ASD symptom severity and cognitive impairments at intake, and, remarkably, they improved the accuracy for predicting later language outcome beyond intake clinical and demographic variables. In summary, brain regions involved in language, social, and face processing were altered in ASD toddlers. These early-age brain alterations may be the result of dysregulation in multiple neural processes and stages and are promising prognostic biomarkers for future language ability.

ABSTRACTAutism spectrum disorder is a heterogeneous neurodevelopmental disorder. Early brain overgrowth yet reduced cerebellar size is well recognized for autism, but cortical regions involved show inconsistent patterns of alteration. No complete and replicable map of early regional brain size alterations has been charted. It is also not clear whether individual differences in brain size relate to autism symptom severity and cognitive deficits and predict later language outcomes. We leveraged structural MRI data from 166 autistic and 109 typical developing toddlers to comprehensively and systematically investigate regional gray matter volume alterations and cortical surface area and thickness perturbations in autism compared to typical developing toddlers using linear mixed-effect models. We then examined their replicability in an independent cohort of 38 autistic and 37 typical developing toddlers. We further investigated associations between regional brain size and symptom severity, Mullen and Vineland cognitive performance using linear regression models. Lastly, we investigated whether early brain size (at intake mean age of 2.5 years) can improve support vector machine prediction of language outcome at 3-4 years of age when added to a model containing intake clinical and behavioral measures. Compared to typical developing toddlers, autistic toddlers presented larger or thicker lateral temporal regions, smaller or thinner frontal lobe and midline structures, larger callosal subregion volume, and smaller cerebellum. Most of these differences were replicated in an independent toddler cohort. Moreover, the identified gray matter alterations were related to autism symptom severity and cognitive impairments at intake, and, remarkably, they improved the accuracy for predicting later language outcome beyond intake clinical and demographic variables. Gray matter volume, thickness, and surface area in regions involved in language, social, and face processing were altered in autistic toddlers. Alterations in these regions are major early-age developmental attributes of autism. The early-age alterations in these cortical attributes in different regions may be the result of dysregulation in multiple neural processes and stages, consistent with prenatal multi-process, multi-stage models of autism. Here we also show these gray matter alterations are promising prognostic biomarkers for language outcome prediction.

Interoceptive dysfunction is often present in anxiety and depression. We investigated the effects of an 8-week intervention, Mindfulness Training for Primary Care (MTPC), on brain mechanisms of interoceptive attention among patients with anxiety and/or depression. We hypothesized that fMRI brain response to interoception in the insula, a region known for interoceptive processing, would increase following the MTPC intervention, and that such increases would be associated with post-intervention changes in self-reported measures of interoceptive awareness. Adults (n = 28) with anxiety and/or depression completed baseline and post-intervention fMRI visits, including a task in which they alternated between focusing on their heartbeat (interoception (INT)) and a control visual attention task (exteroception (EXT)). Following MTPC, we observed increased evoked fMRI response (relative to baseline) in left anterior insula during the INT-EXT task contrast (z > 3.1, p < 0.001 corrected). In patients with moderate-to-severe depression as defined by the Patient Reported Outcomes Measurement Infor-mation System (PROMIS), increased post-intervention insula response was associated with increased Body Trusting, a subscale of the Multidimensional Assessment of Interoceptive Awareness (z > 3.1, p = 0.007 cor-rected). This study demonstrates that patients with mood disorders may respond differentially to mindfulness -based treatment depending on depression severity, and that among those who are more depressed, increased trusting in one's own body sensations and experiencing the body as a safe place to attend to may be necessary components of positive responses to mindfulness-based interventions.

Objectives Various active control interventions for Mindfulness-Based Stress Reduction (MBSR) have been developed, though many can fall short in controlling for non-specific or placebo effects. We developed a Nature-Based Stress Reduction (NBSR) program based on previously reported positive results from virtual natural environment exposure on mental health. Methods In the present study, we present the NBSR program with its components that were matched with MBSR to ensure equality in structure, duration, contacts, and intensity, but not in specific active components (i.e., mindfulness meditation). Furthermore, we characterized the nature video component of NBSR (videos consisting of scenes of nature) as an attention-matched activity equivalent to the formal meditation practice components of MBSR. Videos were edited with creator permissions and freely online available content to include ten 3-min clips for scenes of nature from 8 different biomes. All clips were viewed by 3 different staff members and rated based on hedonic valence (pleasant to unpleasant). Each 30-min video set was designed to have a ratio of 4 pleasant, 3 unpleasant, and 3 neutral valence clips consistent with the documented heterogeneity of affective experiences during mindfulness meditation. Amazon Mechanical Turk Workers (n = 127) rated hedonic valence and self-reported arousal for individual video clips. We conducted ANOVA and t-tests to establish how hedonic valence differed by proposed valence category. Results Mean valence ratings significantly differed between the three categories of nature video clips using an ANOVA test (p < .001). Follow-up pairwise t-tests revealed significant differences between valence ratings for pleasant vs. unpleasant (p < .001), neutral vs. unpleasant (p < .001), and pleasant vs. neutral (p < .01). Conclusions The subjective experience of NBSR nature videos was reported as pleasant, with higher variability reported for unpleasant clips. This pattern generally parallels the variability and heterogeneity of subjective experiences during mindfulness meditation. These findings demonstrate that the nature video component of NBSR provides promising attention- and valence-matched placebo activity unrelated to mindfulness meditation. A comparison of NBSR versus MBSR in a randomized controlled trial is needed to validate NBSR; however, the freely available nature videos may be a useful component to match mindfulness meditation practice in studies.

While the neural correlates of migraine have been widely studied, it remains unclear whether glial cells contribute to neuroinflammation in migraine. One marker of glial activation is the presence of elevated levels of 18 kDa translocator protein (TSPO), and earlier studies have shown that individuals suffering from migraine with aura (MWA) exhibit increased brain TSPO PET signal in a widespread set of regions, compared to healthy controls (Albrecht et al., Neurology 2019, Hadjikhani et al., 2020). The purpose of the present study was to apply [11C]PBR28 PET neuroimaging to extend our initial observations from patients suffering from MWA to include patients with migraine without aura. A total of 24 migraine patients and 17 healthy controls were scanned in a Siemens 3T with PET insert and injected with [11C]PBR28 radioactive tracer. For all subjects, 30-minute static SUV images were acquired ∼60-90 minutes after injection of the tracer. SUV maps were registered to MNI space and smoothed with an 8mm Gaussian filter. SUV ratio (SUVR) images were obtained via intensity-normalization using the cerebellum as pseudo-reference region (showing no statistical difference between the two groups; p>0.5). A non-parametric voxel-wise analysis of the whole brain was performed to evaluate the presence of group differences in the [11C]PBR28 signal. Results show that [11C]PBR28 elevations were observed in the thalamus, insula, hippocampus, pallidum, putamen, SCC and frontal orbital cortex. These cortical and subcortical regions uptake increases were similar to those observed in our previous study in patients with MWA. This work provides in vivo evidence that migraine, with or without aura, may be accompanied by neuroinflammation in humans, paving the way to therapeutic strategies targeting glial activation. Grant support from Boosting mind-body mechanisms and outcomes for chronic pain P01 AT009965-01. While the neural correlates of migraine have been widely studied, it remains unclear whether glial cells contribute to neuroinflammation in migraine. One marker of glial activation is the presence of elevated levels of 18 kDa translocator protein (TSPO), and earlier studies have shown that individuals suffering from migraine with aura (MWA) exhibit increased brain TSPO PET signal in a widespread set of regions, compared to healthy controls (Albrecht et al., Neurology 2019, Hadjikhani et al., 2020). The purpose of the present study was to apply [11C]PBR28 PET neuroimaging to extend our initial observations from patients suffering from MWA to include patients with migraine without aura. A total of 24 migraine patients and 17 healthy controls were scanned in a Siemens 3T with PET insert and injected with [11C]PBR28 radioactive tracer. For all subjects, 30-minute static SUV images were acquired ∼60-90 minutes after injection of the tracer. SUV maps were registered to MNI space and smoothed with an 8mm Gaussian filter. SUV ratio (SUVR) images were obtained via intensity-normalization using the cerebellum as pseudo-reference region (showing no statistical difference between the two groups; p>0.5). A non-parametric voxel-wise analysis of the whole brain was performed to evaluate the presence of group differences in the [11C]PBR28 signal. Results show that [11C]PBR28 elevations were observed in the thalamus, insula, hippocampus, pallidum, putamen, SCC and frontal orbital cortex. These cortical and subcortical regions uptake increases were similar to those observed in our previous study in patients with MWA. This work provides in vivo evidence that migraine, with or without aura, may be accompanied by neuroinflammation in humans, paving the way to therapeutic strategies targeting glial activation. Grant support from Boosting mind-body mechanisms and outcomes for chronic pain P01 AT009965-01.

Migraine is a highly prevalent chronic pain disorder that is characterized by sensitization and dysregulation of the central autonomic nervous system. Interoception is the sensing of signals originating from within the body, and is altered in chronic pain conditions including episodic migraine. The relationship between brain mechanisms of interoceptive awareness and clinical measures of migraine severity has not been fully explored. We used functional MRI to investigate whether insula response to interoceptive awareness is associated with clinical and behavioral measures in patients with episodic migraine. In this study, 18 patients with episodic migraine (17 F, 1 M, mean age ± SD: 41.3 ± 13.1 years). All patients underwent a 3-Tesla fMRI scan and completed a novel interoceptive awareness task (TR=2s,). During the task, patients were asked to focus on and rate the intensity of sensation for two interoceptive conditions (heart and lungs), as well as two exteroceptive conditions (sight and sound). Participants completed survey measures related to interoception, mindfulness, self-compassion, and migraine frequency. Bold response to the interoception - exteroception task contrast (z > 3.1, p = 0.05 corrected) included two clusters overlapping with bilateral mid-insula (left center: x=-46,y=-1.5,z=7.4, 2615 voxels, 33% overlap with anatomical insula, right center: x=44,y=7.1,z=3.9, 1332 voxels, 46% overlap with anatomical insula). Significant inverse associations were observed between insula response to interoception and SCS (r = -0.65, p = 0.003), Freiburg Mindfulness (r = -0.68, p = 0.002), and the number of migraine days reported within 30 days prior to the MRI scan (r = -0.64, p = 0.004) (all significant after Bonferroni correction). Patients with episodic migraine showed insula response during a novel interoceptive awareness task, and this response was inversely correlated with recent migraine frequency, and measures of both trait mindfulness and self-compassion. Grant support from NIH NCCIH P01AT009965. Migraine is a highly prevalent chronic pain disorder that is characterized by sensitization and dysregulation of the central autonomic nervous system. Interoception is the sensing of signals originating from within the body, and is altered in chronic pain conditions including episodic migraine. The relationship between brain mechanisms of interoceptive awareness and clinical measures of migraine severity has not been fully explored. We used functional MRI to investigate whether insula response to interoceptive awareness is associated with clinical and behavioral measures in patients with episodic migraine. In this study, 18 patients with episodic migraine (17 F, 1 M, mean age ± SD: 41.3 ± 13.1 years). All patients underwent a 3-Tesla fMRI scan and completed a novel interoceptive awareness task (TR=2s,). During the task, patients were asked to focus on and rate the intensity of sensation for two interoceptive conditions (heart and lungs), as well as two exteroceptive conditions (sight and sound). Participants completed survey measures related to interoception, mindfulness, self-compassion, and migraine frequency. Bold response to the interoception - exteroception task contrast (z > 3.1, p = 0.05 corrected) included two clusters overlapping with bilateral mid-insula (left center: x=-46,y=-1.5,z=7.4, 2615 voxels, 33% overlap with anatomical insula, right center: x=44,y=7.1,z=3.9, 1332 voxels, 46% overlap with anatomical insula). Significant inverse associations were observed between insula response to interoception and SCS (r = -0.65, p = 0.003), Freiburg Mindfulness (r = -0.68, p = 0.002), and the number of migraine days reported within 30 days prior to the MRI scan (r = -0.64, p = 0.004) (all significant after Bonferroni correction). Patients with episodic migraine showed insula response during a novel interoceptive awareness task, and this response was inversely correlated with recent migraine frequency, and measures of both trait mindfulness and self-compassion. Grant support from NIH NCCIH P01AT009965.

OBJECTIVE Respiratory-gated Auricular Vagal Afferent Nerve stimulation (RAVANS) is a safe nonpharmacological approach to managing chronic pain. The purpose of the current study was to examine (1) the feasibility and acceptability of RAVANS, combined with mindful meditation (MM) for chronic low back pain (CLBP), (2) the potential synergy of MM+RAVANS on improving pain, and (3) possible moderators of the influence of MM+RAVANS on pain. DESIGN Pilot feasibility and acceptability study. SETTING Pain management center at large academic medical center. SUBJECTS Nineteen adults with CLBP and previous MM training. METHODS Participants attended two sessions during which they completed quantitative sensory testing (QST), rated pain severity, and completed a MM+stimulation session. Participants received RAVANS during one visit and sham stimulation during the other, randomized in order. Following intervention, participants repeated QST. RESULTS MM+RAVANS was well tolerated, acceptable, and feasible to provide relief for CLBP. Both MM+stimulation sessions resulted in improved back pain severity, punctate pain ratings, and pressure pain threshold. Individuals with greater negative affect showed greater back pain improvement from MM+RAVANS while those with greater mindfulness showed greater back pain improvement from MM+sham. CONCLUSIONS Results suggest that for CLBP patients with prior MM training, the analgesic effects of MM may have overshadowed effects of RAVANS given the brief single session MM+RAVANS intervention. However, those with greater negative affect may benefit from combined MM+RAVANS.

Chronic low back pain (CLBP) is the leading cause of disability in the United States. There is considerable interest in the development of safe, effective, nonpharmacological approaches to managing CLBP. Respiratory-gated electrical stimulation of the somatosensory vagal afferent receptors in the ear (RAVANS), has been shown to reduce chronic pelvic pain and migraine headache pain. Further, there is evidence to suggest that the benefits of RAVANS are enhanced when paired with mindful meditation. The purpose of the current study was to examine the effects of RAVANS on pain sensitivity and back pain severity among patients with CLBP. Nineteen adults (mean age =54) with CLBP who had previous mindfulness meditation training participated. Participants attended two laboratory sessions. During each session, they completed brief quantitative sensory testing (QST) including punctate pain ratings (PPR) and pressure pain thresholds (PPT) and rated their back pain severity. Participants then completed a 28-minute stimulation session paired with a mindfulness of breath meditation. During one visit, participants received RAVANS stimulation and during the other, they received sham stimulation. Session order was randomized. Following stimulation, participants repeated QST and provided pain ratings. Results of 2 (treatment: RAVANS vs Sham) X 2 (time: pre- vs. post-stimulation) RMANOVAS indicated that, regardless of treatment condition, PPT increased while PPR and back pain severity decreased post-stimulation. Greater negative affect (e.g., depression and anxiety) was associated with greater improvement in backpain in the RAVANS condition and less improvement in the sham condition. Greater mindfulness was associated with greater improvement in back pain in the sham condition, ut not the RAVANS condition. This suggests that the analgesic effects of mindfulness meditation may have overshadowed any effect of RAVANS stimulation, especially given the brief duration and single session design. Moreover, patients with more negative affect may be more likely to benefit from RAVANS. Chronic low back pain (CLBP) is the leading cause of disability in the United States. There is considerable interest in the development of safe, effective, nonpharmacological approaches to managing CLBP. Respiratory-gated electrical stimulation of the somatosensory vagal afferent receptors in the ear (RAVANS), has been shown to reduce chronic pelvic pain and migraine headache pain. Further, there is evidence to suggest that the benefits of RAVANS are enhanced when paired with mindful meditation. The purpose of the current study was to examine the effects of RAVANS on pain sensitivity and back pain severity among patients with CLBP. Nineteen adults (mean age =54) with CLBP who had previous mindfulness meditation training participated. Participants attended two laboratory sessions. During each session, they completed brief quantitative sensory testing (QST) including punctate pain ratings (PPR) and pressure pain thresholds (PPT) and rated their back pain severity. Participants then completed a 28-minute stimulation session paired with a mindfulness of breath meditation. During one visit, participants received RAVANS stimulation and during the other, they received sham stimulation. Session order was randomized. Following stimulation, participants repeated QST and provided pain ratings. Results of 2 (treatment: RAVANS vs Sham) X 2 (time: pre- vs. post-stimulation) RMANOVAS indicated that, regardless of treatment condition, PPT increased while PPR and back pain severity decreased post-stimulation. Greater negative affect (e.g., depression and anxiety) was associated with greater improvement in backpain in the RAVANS condition and less improvement in the sham condition. Greater mindfulness was associated with greater improvement in back pain in the sham condition, ut not the RAVANS condition. This suggests that the analgesic effects of mindfulness meditation may have overshadowed any effect of RAVANS stimulation, especially given the brief duration and single session design. Moreover, patients with more negative affect may be more likely to benefit from RAVANS.

Current treatments for smoking yield suboptimal outcomes, partly because of an inability to reduce cue-induced smoking. Mindfulness training (MT) has shown preliminary efficacy for smoking cessation, yet its neurobiological target remains unknown. Our prior work with nonsmokers indicates that MT reduces posterior cingulate cortex (PCC) activity. In individuals who smoke, the PCC, consistently a main hub of the "default mode network," activates in response to smoking cues. In this randomized controlled trial, we tested the effects of app-delivered MT on PCC reactivity to smoking cues and whether individual differences in MT-mediated PCC changes predicted smoking outcomes. Smoking cue-induced PCC reactivity was measured using functional magnetic resonance imaging at baseline and 1 month after receiving smartphone app-based MT (n = 33) vs. an active control (National Cancer Institute's QuitGuide, n = 34). Whether individual differences in treatment-related changes in PCC activity predicted smoking behavior was assessed. The MT group demonstrated a significant correlation between a reduction in PCC reactivity to smoking cues and a decline in cigarette consumption (r = 0.39, p = 0.02). No association was found in the control group (r = 0.08, p = 0.65). No effects of group alone were found in PCC or cigarette reduction. Post hoc analysis revealed this association is sex specific (women, r = 0.49, p = 0.03; men: r = −0.08, p = 0.79). This initial report indicates that MT specifically reduces smoking cue-induced PCC activity in a subject-specific manner, and the reduction in PCC activity predicts a concurrent decline in smoking. These findings link the hypothesized behavioral effects of MT for smoking to neural mechanisms particularly in women. This lays the groundwork for identifying individuals who may benefit from targeted digital therapeutic treatments such as smartphone-based MT, yielding improved clinical outcomes.

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between ‘social brain’ circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals.

Objective: To accurately deliver a source-estimated neurofeedback (NF) signal developed on a 128-sensors EEG system on a reduced 32-sensors EEG system. Methods: A linearly constrained minimum variance beamformer algorithm was used to select the 64 sensors which contributed most highly to the source signal. Monte Carlo-based sampling was then used to randomly generate a large set of reduced 32-sensors montages from the 64 beamformer-selected sensors. The reduced montages were then tested for their ability to reproduce the 128-sensors NF. The high-performing montages were then pooled and analyzed by a k-means clustering machine learning algorithm to produce an optimized reduced 32-sensors montage. Results: Nearly 4500 high-performing montages were discovered from the Monte Carlo sampling. After statistically analyzing this pool of high performing montages, a set of refined 32-sensors montages was generated that could reproduce the 128-sensors NF with greater than 80% accuracy for 72% of the test population. Conclusion: Our Monte Carlo reduction method was used to create reliable reduced-sensors montages which could be used to deliver accurate NF in clinical settings. Significance: A translational pathway is now available by which high-density EEG-based NF measures can be delivered using clinically accessible low-density EEG systems. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.