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Background About 69% of the 299,000 Americans living with spinal cord injury (SCI) experience long-term debilitating neuropathic pain. New treatments are needed because current treatments do not provide enough pain relief. We have found that insular-opercular brain network alterations may contribute to neuropathic pain and that restoring this network could reduce neuropathic pain. Here, we outline a study protocol using a physical therapy approach, cognitive multisensory rehabilitation (CMR), which has been shown to restore OP1/OP4 connections in adults post stroke, to test our hypothesis that CMR can normalize pain perception through restoring OP1/OP4 connectivity in adults with SCI and relieve neuropathic pain. Objectives To compare baseline brain function via resting-state and task-based functional magnetic resonance imaging in adults with SCI versus uninjured controls, and to identify changes in brain function and behavioral pain outcomes after CMR in adults with SCI. Methods In this phase I randomized controlled trial, adults with SCI will be randomized into two groups: Group A will receive 6 weeks of CMR followed by 6 weeks of standard of care (no therapy) at home. Group B will start with 6 weeks of standard of care (no therapy) at home and then receive 6 weeks of CMR. Neuroimaging and behavioral measures are collected at baseline, after the first 6 weeks (A: post therapy, B: post waitlist), and after the second 6 weeks (A: post-therapy follow-up, B: post therapy), with follow-up of both groups up to 12 months. Conclusion The successful outcome of our study will be a critical next step toward implementing CMR in clinical care to improve health in adults with SCI.

SUMMARYBackgroundNeuropathic pain after spinal cord injury (SCI) is notoriously hard to treat. Mechanisms of neuropathic pain are unclear, which makes finding effective treatments challenging. Prior studies have shown that adults with SCI have body awareness deficits. Recent imaging studies, including ours, point to the parietal operculum and insula as key areas for both pain perception and body awareness. Cognitive multisensory rehabilitation (CMR) is a physical therapy approach that helps improve body awareness for pain reduction and sensorimotor recovery. Based on our prior brain imaging work in CMR in stroke, we hypothesized that improving body awareness through restoring parietal operculum network connectivity leads to neuropathic pain relief and improved sensorimotor and daily life function in adults with SCI. Thus, the objectives of this study were to (1) determine baseline differences in resting-state and task-based functional magnetic resonance imaging (fMRI) brain function in adults with SCI compared to healthy controls and (2) identify changes in brain function and behavioral pain and pain-associated outcomes in adults with SCI after CMR.MethodsHealthy adults underwent a one-time MRI scan and completed questionnaires. We recruited community-dwelling adults with SCI-related neuropathic pain, with complete or incomplete SCI >3 months, and highest neuropathic pain intensity level of >3 on the Numeric Pain Rating Scale (NPRS). Participants with SCI were randomized into two groups, according to a delayed treatment arm phase I randomized controlled trial (RCT): Group A immediately received CMR intervention, 3x/week, 45 min/session, followed by a 6-week and 1-year follow-up. Group B started with a 6-week observation period, then 6 weeks of CMR, and a 1-year follow-up. Highest, average, and lowest neuropathic pain intensity levels were assessed weekly with the NPRS as primary outcome. Other primary outcomes (fMRI resting-state and functional tasks; sensory and motor function with the INSCI AIS exam), as well as secondary outcomes (mood, function, spasms, and other SCI secondary conditions), were assessed at baseline, after the first and second 6-week period. The INSCI AIS exam and questionnaires were repeated at the 1-year follow-up.FindingsThirty-six healthy adults and 28 adults with SCI were recruited between September 2020 and August 2021, and of those, 31 healthy adults and 26 adults with SCI were enrolled in the study. All 26 participants with SCI completed the intervention and pre-post assessments. There were no study-related adverse events. Participants were 52±15 years of age, and 1-56 years post-SCI. During the observation period, group B did not show any reductions in neuropathic pain and did not have any changes in sensation or motor function (INSCI ASIA exam).However, both groups experienced a significant reduction in neuropathic pain after the 6-week CMR intervention. Their highest level ofneuropathic painof 7.81±1.33 on the NPRS at baseline was reduced to 2.88±2.92 after 6 weeks of CMR. Their change scores were 4.92±2.92 (large effect size Cohen’sd=1.68) for highest neuropathic pain, 4.12±2.23 (d=1.85) for average neuropathic pain, and 2.31±2.07 (d=1.00) for lowest neuropathic pain. Nine participants out of 26 were pain-free after the intervention (34.62%).The results of the INSCI AIS testing also showed significant improvements in sensation, muscle strength, and function after 6 weeks of CMR. Their INSCI AIS exam increased by 8.81±5.37 points (d=1.64) for touch sensation, 7.50±4.89 points (d=1.53) for pin prick sensation, and 3.87±2.81 (d=1.38) for lower limb muscle strength. Functional improvements after the intervention included improvements in balance for 17 out of 18 participants with balance problems at baseline; improved transfers for all of them and a returned ability to stand upright with minimal assistance in 12 out of 20 participants who were unable to stand at baseline. Those improvements were maintained at the 1-year follow-up.With regard to brain imaging, we confirmed that the resting-state parietal operculum and insula networks had weaker connections in adults with SCI-related neuropathic pain (n=20) compared to healthy adults (n=28). After CMR, stronger resting-state parietal operculum network connectivity was found in adults with SCI. Also, at baseline, as expected, right toe sensory stimulation elicited less brain activation in adults with SCI (n=22) compared to healthy adults (n=26). However, after CMR, there was increased brain activation in relevant sensorimotor and parietal areas related to pain and mental body representations (i.e., body awareness and visuospatial body maps) during the toe stimulation fMRI task. These brain function improvements aligned with the AIS results of improved touch sensation, including in the feet.InterpretationAdults with chronic SCI had significant neuropathic pain relief and functional improvements, attributed to the recovery of sensation and movement after CMR. The results indicate the preliminary efficacy of CMR for restoring function in adults with chronic SCI. CMR is easily implementable in current physical therapy practice. These encouraging impressive results pave the way for larger randomized clinical trials aimed at testing the efficacy of CMR to alleviate neuropathic pain in adults with SCI.Clinical Trial registrationClinicalTrials.govIdentifier:NCT04706208FundingAIRP2-IND-30: Academic Investment Research Program (AIRP) University of Minnesota School of Medicine. National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002494; the Biotechnology Research Center: P41EB015894, the National Institute of Neurological Disorders & Stroke Institutional Center Core Grants to Support Neuroscience Research: P30 NS076408; and theHigh-Performancee Connectome Upgrade for Human 3T MR Scanner: 1S10OD017974.

Humans commit more violent crimes when temperature and air pollution is higher. Here, we investigate if also the day-to-day rates of dogs biting humans is influenced by environmental factors. 69,525 reports of dogs biting humans, sourced from public records on animal control requests and from ER records, were analyzed. The impact of temperature and air pollutants were evaluated with a zero-inflated Poisson generalized additive model, while controlling for regional and calendar effects. Exposure-response curves were used to assess the association between outcome and major exposure variables. We find that the rates of dogs biting humans increases with increasing temperature and ozone, but not PM2.5 exposure. We also observed that higher UV irradiation levels were related to higher rats of dog bites. We conclude that dogs, or the interactions between humans and dogs, are more hostile on hot, sunny, and smoggy days, indicating that the societal burden of extreme heat and air pollution also includes the costs of animal aggression.

Neuropathic pain in spinal cord injury (SCI) is associated with inflammation in both the peripheral and central nervous system (CNS), which may contribute to the initiation and maintenance of persistent pain. An understanding of factors contributing to neuroinflammation may lead to new therapeutic targets for neuropathic pain. Moreover, novel circulating biomarkers of neuropathic pain may facilitate earlier and more effective treatment. MicroRNAs (miRNAs) are short, non-coding single-stranded RNA that have emerged as important biomarkers and molecular mediators in physiological and pathological conditions. Using a genome-wide miRNA screening approach, we studied differential miRNA expression in plasma from 68 healthy, community-dwelling adults with and without SCI enrolled in ongoing clinical studies. We detected 2367 distinct miRNAs. Of these, 383 miRNAs were differentially expressed in acute SCI or chronic SCI versus no SCI and 71 were differentially expressed in chronic neuropathic pain versus no neuropathic pain. We selected homo sapiens (hsa)-miR-19a-3p and hsa-miR-19b-3p for additional analysis based on p-value, fold change, and their known role as regulators of neuropathic pain and neuroinflammation. Both hsa-miR-19a-3p and hsa-miR-19b-3p levels were significantly higher in those with chronic SCI and severe neuropathic pain versus those with chronic SCI and no neuropathic pain. In confirmatory studies, both hsa-miR-19a-3p and hsa-miR-19b-3p have moderate to strong discriminative ability to distinguish between those with and without pain. After adjusting for opioid use, hsa-miR-19b-3p levels were positively associated with pain interference with mood. Because hsa-miR-19 levels have been shown to change in response to exercise, folic acid, and resveratrol, these studies suggest that miRNAs are potential targets of therapeutic interventions.

Background Tinnitus, the phantom perception of sound, shares many properties with phantom limb pain, in that both may arise as a consequence of sensory deprivation. Prediction errors in multisensory integration, such as induced with mirror box therapy in phantom pain, can reduce phantom percepts. Purpose We evaluated if a device that swaps sound from the right pinna to the left ear canal, and from the left pinna to the right ear canal, can reduce tinnitus. We call this auditory mirror therapy (AMT). Research Design Uncontrolled trial. Study Sample Twenty subjects with chronic tinnitus. Intervention An AMT device consisting of a modified ear defender device with microphones that swaps sounds from left pinna to the right ear canal and from the right pinna to the left ear canal. Participants used the device at home for 2 weeks. Data Collection and Analysis Tinnitus Handicap Inventory (THI), Tinnitus Reaction Questionnaire, and visual analog scale ratings of symptoms were collected at baseline and posttreatment. Repeated measures t-test were performed, Bonferroni corrected for multiple comparisons. Results There was a significant reduction in THI and in awareness of tinnitus after the AMT intervention. Conclusion Exposing the audiovisual integration system to prediction errors can help retrain phantom percepts and reduce tinnitus handicap. Further studies on this concept are warranted.

Pavlovian learning mechanisms are of great importance both for models of psychiatric disorders and treatment approaches, but understudied in obsessive-compulsive disorder (OCD). Using an established Pavlovian fear conditioning and reversal procedure, we studied skin conductance responses in 41 patients with OCD and in 32 matched healthy control participants. Within both groups, fear acquisition and reversal effects were evident. When comparing groups, patients showed impaired differential learning of threatening and safe stimuli, consistent with previous research. In contrast to prior findings, differential learning impairments were restricted to fear acquisition, and not observed in the reversal stage of the experiment. As previous and present fear reversal experiments in OCD differed in the use of color coding to facilitate stimulus discrimination, the studies converge to suggest that differential learning of threatening versus safe stimuli is impaired in OCD, but manifests itself differently depending on the difficulty of the association to be learned. When supported by the addition of color, patients with OCD previously appeared to acquire an association early but failed to reverse it according to changed contingencies. In absence of such color coding of stimuli, our data suggest that patients with OCD already show differential learning impairments during fear acquisition, which may relate to findings of altered coping with uncertainty previously observed in OCD. Impaired differential learning of threatening versus safe stimuli should be studied further in OCD, in order to determine whether impairments in differential learning predict treatment outcomes in patients, and whether they are etiologically relevant for OCD.

Introduction Functional networks develop throughout adolescence when anorexia nervosa (AN) normally debuts. In AN, cerebral structural alterations are found in most brain regions and may be related to the observed functional brain changes. Few studies have investigated the functional networks of the brain in adolescent AN patients.. The aim of this explorative study was to investigate multiple functional networks in adolescent AN patients compared to healthy age-matched controls (HC) and the relationship with age, eating disorder symptoms and structural alterations. Methods Included were 29 female inpatients with restrictive AN, and 27 HC. All participants were between the ages of 12 to 18 years. Independent component analysis (ICA) identified 21 functional networks that were analyzed with multivariate and univariate analyses of components and group affiliation (AN vs HC). Age, age × group interaction and AN symptoms were included as covariates. Follow-up correlational analyses of selected components and structural measures (cortical thickness and subcortical volume) were carried out. Results Decreased functional connectivity (FC) in AN patients was found in one cortical network, involving mainly the precuneus, and identified as a default mode network (DMN). Cortical thickness in the precuneus was significantly correlated with functional connectivity in this network. Significant group differences were also found in two subcortical networks involving mainly the hippocampus and the amygdala respectively, and a significant interaction effect of age and group was found in both these networks. There were no significant associations between FC and the clinical measures used in the study. Conclusion The findings from the present study may imply that functional alterations are related to structural alterations in selected regions and that the restricted food intake in AN patients disrupt normal age-related development of functional networks involving the amygdala and hippocampus.

Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.

Pavlovian learning mechanisms are of great importance both for models of psychiatric disorders and treatment approaches, but understudied in obsessive-compulsive disorder (OCD). Using an established Pavlovian fear conditioning and reversal procedure, we studied skin conductance responses (SCRs) in 41 patients with OCD and in 32 matched healthy control participants. Within both groups, fear acquisition and reversal effects were evident. When comparing groups, patients showed impaired differential learning of threatening and safe stimuli, consistent with previous research. In contrast to prior findings, differential learning impairments were restricted to fear acquisition, and not observed in the reversal stage of the experiment. As previous and present fear reversal experiments in OCD differed in the use of color coding to facilitate stimulus discrimination, the studies converge to suggest that differential learning of threatening versus safe stimuli is impaired in OCD, but manifests itself differently depending on the difficulty of the association to be learned. When supported by the addition of color, patients with OCD previously appeared to acquire an association early but failed to reverse it according to changed contingencies. In absence of such color coding of stimuli, our data suggest that patients with OCD already show differential learning impairments during fear acquisition, which may relate to findings of altered coping with uncertainty previously observed in OCD. Impaired differential learning of threatening versus safe stimuli should be studied further in OCD, in order to determine whether impairments in differential learning predict CBT treatment outcomes in patients, and whether they are etiologically relevant for OCD.

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K(+) channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K(+) channel PET tracer [(18)F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [(18)F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [(18)F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [(18)F]3F4AP for the focal brain injury was higher than [(18)F]FDG, [(11)C]PiB, and [(11)C]PBR28, and compared favorably to currently used MRI methods.

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [18F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [18F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [18F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [18F]3F4AP for the focal brain injury was higher than [18F]FDG, [11C]PiB and [11C]PBR28, and compared favorably to currently used MRI methods.

Spinal Cord Injuries (SCI) lead to alterations in brain structure and brain function by direct effects of nerve damage, by secondary mechanisms, and also by longer term injury consequences such as paralysis and neuropathic pain. Here, we review neuroimaging studies of patients with traumatic spinal cord injuries, perform a quantitative meta-analysis of motor and motor imagery studies, summarize structural studies, evidence of cortical reorganization, and provide an overview of diffusion and spectroscopy studies. The meta-analysis showed significantly altered motor cortex, as well as cerebellar and parietal lobe changes, and qualitatively consistent reports of alterations in somatosensory brain structure, cortical reorganization, white matter diffusion and thalamic metabolites. Larger samples in combination with standardized imaging protocols and data sharing will further our understanding of brain changes after SCI and help in defining short and long-term changes in brain systems in SCI patients. Such data would provide a basis for clinical trials, treatment outcomes, and guide novel interventions.

ObjectiveMeasures of spinal cord structure can be a useful phenotype to track disease severity and development; this observational study measures the hereditability of cervical spinal cord anatomy and its correlates in healthy human beings.MethodsTwin data from the Human Connectome Project were analyzed with semiautomated spinal cord segmentation, evaluating test-retest reliability and broad-sense heritability with an AE model. Relationships between spinal cord metrics, general physical measures, regional brain structural measures, and motor function were assessed.ResultsWe found that the spinal cord C2 cross-sectional area (CSA), left-right width (LRW), and anterior-posterior width (APW) are highly heritable (85%–91%). All measures were highly correlated with the brain volume, and CSA only was positively correlated with thalamic volumes (p = 0.005) but negatively correlated with the occipital cortex area (p = 0.001). LRW was correlated with the participant's height (p = 0.00027). The subjects' sex significantly influenced these metrics. Analyses of a test-retest data set confirmed validity of the approach.ConclusionsThis study provides the evidence of genetic influence on spinal cord structure. MRI metrics of cervical spinal cord anatomy are robust and not easily influenced by nonpathological environmental factors, providing a useful metric for monitoring normal development and progression of neurodegenerative disorders affecting the spinal cord, including—but not limited to—spinal cord injury and MS.

Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a ‘downward spiral’ fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification).

Positron emission tomography (PET) with the radioligand [Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [Acute [The data provide further support that [

The brain responds differently to environmental and internal signals that relates to the stage of development of neural systems. While genetic and epigenetic factors contribute to a premorbid state, hormonal fluctuations in women may alter the set point of migraine. The cyclic surges of gonadal hormones may directly alter neuronal, glial and astrocyte function throughout the brain. Estrogen is mainly excitatory and progesterone inhibitory on brain neuronal systems. These changes contribute to the allostatic load of the migraine condition that most notably starts at puberty in girls.

UNLABELLED: In patients with social anxiety disorder (SAD) it has been reported that selective serotonin reuptake inhibitors (SSRIs) and placebo induce anxiolytic effects by attenuating neural activity in overlapping amygdala subregions, i.e. left basolateral and right ventrolateral amygdala. However, it is not known whether these treatments inhibit amygdala subregions via similar or distinct brain pathways. As anxiolytic treatments may alter amygdala-frontal couplings we investigated differences and similarities in amygdala-frontal functional co-activation patterns between responders and nonresponders to SSRIs and placebo in patients with SAD. Positron emission tomography (PET) with oxygen-15-labeled water was used to measure anxiety-related regional cerebral blood flow in 72 patients with SAD before and after 6-8 wk of treatment under double-blind conditions. Functional couplings were evaluated with a seed region approach using voxel values from the left basolateral and right ventrolateral amygdala. Responders and nonresponders to SSRIs and placebo showed different treatment-induced co-activations between the left amygdala and the dorsolateral prefrontal cortex (dlPFC) as well as the rostral anterior cingulate cortex (ACC). Conjunction analysis suggested shared anxiolysis-dependent inverse co-activations in SSRI and placebo responders between the left amygdala-dlPFC and left amygdala-rostral ACC, and a shared positive co-activation between left amygdala-dorsal ACC. We demonstrate that amygdala-frontal co-activation patterns differentiate effective from ineffective anxiolytic treatments and that SSRI and placebo responders share overlapping neuromodulatory paths that may underlie improved emotion regulation and reduced expression of anxiety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00343707.

We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning.

Patients with schizophrenia may have altered pain perception, as suggested by clinical reports of pain insensitivity, and recent neuroimaging findings. Here, we examined neural responses to an aversive electrical stimulus and the immediate anticipation of such a stimulus using fMRI and a classical conditioning paradigm, which involved pairing an electrical shock with a neutral photograph. Fifteen men with schizophrenia and 13 healthy men, matched for demographic characteristics, electrical stimulation level and scan movement, were studied. The shock induced robust responses in midbrain, thalamus, cingulate gyrus, insula and somatosensory cortex in both groups. However, compared to controls, the schizophrenic patients displayed significantly lower activation of the middle insula (pFWE = 0.002, T=5.72, cluster size =24 voxels). Moreover, the lack of insula reactivity in the schizophrenia group was predicted by the magnitude of positive symptoms (r = −0.46, p=0.04). In contrast, there were no significant differences between the two groups in the magnitude of neural responses during anticipation of the shock. These findings provide support for the existence of a basic deficit in interoceptive perception in schizophrenia, which could play a role in the generation and/or maintenance of psychotic states.

The insula, a “cortical hub” buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new potential clinical perspectives for migraine treatment.

The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here, we summarize these studies by performing a coordinate-based meta-analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive-affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdala's role in pain processing.

The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to hum ...

This study investigated sex similarities and differences in pain-related functional connectivity in 60 healthy subjects. We used functional magnetic resonance imaging and psychophysiological interaction analysis to investigate how exposure to low vs high experimental pain modulates the functional connectivity of the periaqueductal gray (PAG). We found no sex differences in pain thresholds, and in both men and women, the PAG was more functionally connected with the somatosensory cortex, the supplemental motor area, cerebellum, and thalamus during high pain, consistent with anatomic predictions. Twenty-six men displayed a pain-induced increase in PAG functional connectivity with the amygdala caudate and putamen that was not observed in women. In an extensive literature search, we found that female animals have been largely overlooked when the connections between the PAG and the amygdala have been described, and that women are systematically understudied with regard to endogenous pain inhibition. Our results emphasize the importance of including both male and female subjects when studying basic mechanisms of pain processing, and point toward a possible sex difference in endogenous pain inhibition.

Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma-exposed subjects underwent a two-day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically-measured, cue-elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC.

This study investigated the effects of anxiety on nonverbal aspects of speech using data collected in the framework of a large study of social phobia treatment. The speech of social phobics (N = 71) was recorded during an anxiogenic public speaking task both before and after treatment. The speech samples were analyzed with respect to various acoustic parameters related to pitch, loudness, voice quality, and temporal aspects of speech. The samples were further content-masked by low-pass filtering (which obscures the linguistic content of the speech but preserves nonverbal affective cues) and subjected to listening tests. Results showed that a decrease in experienced state anxiety after treatment was accompanied by corresponding decreases in (a) several acoustic parameters (i.e., mean and maximum voice pitch, high-frequency components in the energy spectrum, and proportion of silent pauses), and (b) listeners’ perceived level of nervousness. Both speakers’ self-ratings of state anxiety and listeners’ ratings of perceived nervousness were further correlated with similar acoustic parameters. The results complement earlier studies on vocal affect expression which have been conducted on posed, rather than authentic, emotional speech.

Exposure-based therapy, an effective treatment for posttraumatic stress disorder (PTSD), relies on extinction learning principles. In PTSD patients, dysfunctional patterns in the neural circuitry underlying fear extinction have been observed using resting-state or functional activation measures. It remains undetermined whether resting activity predicts activations during extinction recall or PTSD symptom severity. Moreover, it remains unclear whether trauma exposure per se affects resting activity in this circuitry. The authors employed a multimodal approach to examine the relationships among resting metabolism, clinical symptoms, and activations during extinction recall.Three cohorts were recruited: PTSD patients (N=24), trauma-exposed individuals with no PTSD (TENP) (N=20), and trauma-unexposed healthy comparison subjects (N=21). Participants underwent a resting positron emission tomography scan 4 days before a functional MRI fear conditioning and extinction paradigm.Amygdala resting metabolism negatively correlated with clinical functioning (as measured by the Global Assessment of Functioning Scale) in the TENP group, and hippocampal resting metabolism negatively correlated with clinical functioning in the PTSD group. In the PTSD group, dorsal anterior cingulate cortex (dACC) resting metabolism positively correlated with PTSD symptom severity, and it predicted increased dACC activations but decreased hippocampal and ventromedial prefrontal cortex activations during extinction recall. The TENP group had lower amygdala resting metabolism compared with the PTSD and healthy comparison groups, and it exhibited lower hippocampus resting metabolism relative to the healthy comparison group.Resting metabolism in the fear circuitry correlated with functioning, PTSD symptoms, and extinction recall activations, further supporting the relevance of this network to the pathophysiology of PTSD. The study findings also highlight the fact that chronic dysfunction in the amygdala and hippocampus is demonstrable in PTSD and other trauma-exposed individuals, even without exposure to an evocative stimulus.

Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis). These ten subjects were examined by positron emission tomography (PET) with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA), was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP) / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment.

The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.

The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n=17) and healthy controls (n=17) using positron emission tomography and the radiotracer [11C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders.