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Background Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. Methods Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. Results A reduction of the total fractional power in both groups—specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex—was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). Conclusions These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M = 15.8, SD = 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR < 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS+>CS-; rp = 0.49, P = 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P < 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P < 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.

Post-traumatic headaches (PTHs) are associated with mild traumatic brain injuries (mTBI) and may predict the persistence of concussion symptoms. Altered brain networks implicated in brain injury and the affective components of headache-related pain may underlie the resolution of PTH. This is a hypothesis-generating investigation to evaluate the extent to which pain symptom reporting and functional brain changes are different in a cohort of young mTBI patients with resolved (PTH-R) and persistent (PTH-P) post-traumatic headache symptoms relative to healthy controls. This was a cross-sectional investigation involving 59 participants between the ages of 12-24 (PTH-P, n = 21; PTH-R, n = 18; healthy control, n = 20). Participants had no significant history of pre-existing headaches, chronic pain, or psychiatric neurological conditions. The primary outcome was resting-state functional connectivity (RS-Fc) alterations between cohorts. Secondary outcomes were self-reported pain-related symptoms. Elevated scores were reported for fear of pain in both PTH cohorts. Using a false discovery rate of p = 0.05, the PTH-P cohort showed altered connectivity relative to healthy controls in brain regions such as the frontal, temporal, and cerebellar regions, as well as sub-cortical regions including the amygdala and accumbens. The PTH-R cohort showed altered RS-Fc between cerebellar and temporal lobe sub-regions. Our results indicate that a core network of brain regions implicated in the affective pain response are functionally altered in PTH cohorts. Results should be interpreted given limitations on sample size and multiple comparisons. Despite the resolution of symptoms, persons who experience PTH may experience ongoing functional brain abnormalities, which may underlie symptom chronification.

Background and purpose Clinical comparisons do not usually take laterality into account and thus may report erroneous or misleading data. The concept of laterality, well evaluated in brain and motor systems, may also apply at the level of peripheral nerves. Therefore, we sought to evaluate the extent to which we could observe an effect of laterality in MRI-collected white matter indices of the sciatic nerve and its two branches (tibial and fibular). Materials and methods We enrolled 17 healthy persons and performed peripheral nerve diffusion weighted imaging (DWI) and magnetization transfer imaging (MTI) of the sciatic, tibial and fibular nerve. Participants were scanned bilaterally, and findings were divided into ipsilateral and contralateral nerve fibers relative to self-reporting of hand dominance. Generalized estimating equation modeling was used to evaluate nerve fiber differences between ipsilateral and contralateral legs while controlling for confounding variables. All findings controlled for age, sex and number of scans performed. Results A main effect of laterality was found in radial, axial, and mean diffusivity for the tibial nerve. Axial diffusivity was found to be lateralized in the sciatic nerve. When evaluating mean MTR, a main effect of laterality was found for each nerve division. A main effect of sex was found in the tibial and fibular nerve fiber bundles. Conclusion For the evaluation of nerve measures using DWI and MTI, in either healthy or disease states, consideration of underlying biological metrics of laterality in peripheral nerve fiber characteristics need to considered for data analysis. Integrating knowledge regarding biological laterality of peripheral nerve microstructure may be applied to improve how we diagnosis pain disorders, how we track patients’ recovery and how we forecast pain chronification.

Arrhythmic fluctuations in neural activity occur at many levels of the nervous system. Such activity does not have a characteristic temporal periodicity but can exhibit statistical similarities, most commonly power-law scaling behavior, which is indicative of scale-free dynamics. The recurrence of scaling laws across many different systems and its manifestation in behavior has prompted a search for unifying principles in human brain function. With this in mind, a focused search for abnormities in scale-free dynamics is of considerable clinical relevance to migraine and other clinical pain disorders. Here, we examined the scale-free properties of the resting-state functional magnetic resonance imaging (fMRI) signal in the broadband frequency range known to be related to spontaneous neural activity (0.01-0.1 Hz). In a large cohort of episodic migraine patients (N = 40), we observed that the strength of long-range temporal correlations in the fMRI signal (captured by the scaling exponent α) was significantly higher in the sensorimotor network compared with healthy controls. Increases in the scaling exponent were positively correlated with fMRI signal variance and negatively correlated with the patient's self-reported headache intensity. These changes in the fMRI signal suggest that the temporal structure of amplitude fluctuations carries valuable information about the dynamic state of the underlying neuronal networks and ensuing sensory impairments in migraine. The demonstrated scaling laws pose a novel quantitative approach for examining clinically relevant interindividual variability in migraine and other pain disorders.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

Background Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation. Methods and findings We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children’s Hospital from October 2016 to March 2020; 9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = −1.138, 95% CI = −2.062, −0.214, p = 0.002) and superior mFPC (MD = −0.999, 95% CI = −1.961, −0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1; MD = −0.342, 95% CI = −0.680, −0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = −0.092, 95% CI = −0.680, −0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers. Conclusions We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment. Trial registration ClinicalTrials.gov NCT02703090

In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)–to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as “switched off” in generalized allodynia.

OBJECTIVES Numbness associated with neuropathic pain suggests the loss of function in myelinated, large diameter sensory neurons. The purpose of this study was to examine the relationships between pain severity and subjective (ie, severity of numbness) and objective (ie, loss of light touch sensations, vibration thresholds) measures of loss of large fiber function in adult survivors with chemotherapy-induced peripheral neuropathy (CIPN, n=426) and breast cancer patients with persistent postsurgical pain (n=80). MATERIAL AND METHODS For both samples, average pain and numbness were evaluated using a 0 to 10 numeric rating scale. Loss of light touch sensations in the hands and feet of patients with CIPN and in the upper arm of patients at 5 and 6 months following breast cancer surgery were assessed using Semmes Weinstein monofilaments. Loss of vibration in the hands and feet of patients with CIPN was assessed using a biothesiometer. Pearson Product Moment correlation coefficients were calculated between average pain and the number or percentage of sites with loss of light touch sensations, mean vibration thresholds, and the severity of numbness. RESULTS For both pain conditions, average pain scores were significantly correlated with objective measures of large fiber function (r=0.12 to 0.34; all P

Complex regional pain syndrome (CRPS) develops after-limb injury, with persistent pain and deficits in movement frequently co-occurring. The striatum is critical for mediating multiple mechanisms that are often aberrant in CRPS, which includes sensory and pain processing, motor function, and goal-directed behaviors associated with movement. Yet, much remains unknown with regards to the morphological and functional properties of the striatum and its subregions in this disease. Thus, we investigated 20 patients (15 female, age 58 ± 9 years, right-handed) diagnosed with chronic (6+ months of pain duration) CRPS in the right hand and 20 matched, healthy controls with anatomical and resting-state, functional magnetic resonance imaging. In addition, a comprehensive clinical and behavioral evaluation was performed, where each participant's pain, motor function, and medical history were assessed. Complex regional pain syndrome patients harbored significant abnormalities in hand coordination, dexterity, and strength. These clinical pain- and movement-related findings in CRPS patients were concomitant with bilateral decreases in gray matter density in the putamen as well as functional connectivity increases and decreases among the putamen and pre-/postcentral gyri and cerebellum, respectively. Importantly, higher levels of clinical pain and motor impairment were associated with increased putamen-pre-/postcentral gyri functional connectivity strengths. Collectively, these findings suggest that putaminal alterations, specifically the functional interactions with sensorimotor structures, may underpin clinical pain and motor impairment in chronic CRPS patients.

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is classified as one of the most disabling symptoms that accompany an attack. Using subjective psychophysical assessments, we showed recently that migraine patients are more sensitive to all colors of light during the ictal than during the interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in the ictal and interictal phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b-wave, which was consistently larger (by 14-19% in the light-adapted and 18-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a-wave or the visual evoked potentials that differ most strikingly between the two groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that non-migraineurs feel as if they live in a cave.

Focused ultrasound (FUS) is a technology capable of delivering therapeutic levels of energy through the intact skull to a tightly localized brain region. Combining the FUS pressure wave with intravenously injected microbubbles creates forces on blood vessel walls that open the blood-brain barrier (BBB). This noninvasive and localized opening of the BBB allows for targeted delivery of pharmacological agents into the brain for use in therapeutic development. It is possible to use FUS power levels such that the BBB is opened without damaging local tissues. However, open questions remain related to the effects that FUS-induced BBB opening has on brain function including local physiology and vascular hemodynamics. We evaluated the effects that FUS-induced BBB opening has on resting state functional magnetic resonance imaging (rs-fMRI) metrics. Data from rs-fMRI was acquired in rats that underwent sham FUS BBB vs. FUS BBB opening targeted to the right primary somatosensory cortex hindlimb region (S1HL). FUS BBB opening reduced the functional connectivity between the right S1HL and other sensorimotor regions, including statistically significant reduction of connectivity to the homologous region in the left hemisphere (left S1HL). The effect was observed in all three metrics analyzed: functional connectivity between anatomically defined regions, whole brain voxel-wise correlation maps based on anatomical seeds, and spatial patterns from independent component analysis. Connectivity metrics for other regions where the BBB was not perturbed were not affected. While it is not clear whether the effect is vascular or neuronal in origin, these results suggest that even safe levels of FUS BBB opening have an effect on the physiological processes that drive the signals measured by BOLD fMRI. As such these effects must be accounted for when carrying out studies using fMRI to evaluate the effects of pharmacological agents delivered via FUS-induced BBB opening.

Pain interventions with no active ingredient, placebo, are sometimes effective in treating chronic pain conditions. Prior studies on the neurobiological underpinnings of placebo analgesia indicate endogenous opioid release and changes in brain responses and functional connectivity during pain anticipation and pain experience in healthy subjects. Here, we investigated placebo analgesia in healthy subjects and in interictal migraine patients (n = 9) and matched healthy controls (n = 9) using 11C-diprenoprhine Positron Emission Tomography (PET) and simultaneous functional Magnetic Resonance Imaging (fMRI). Intravenous saline injections (the placebo) led to lower pain ratings, but we did not find evidence for an altered placebo response in interictal migraine subjects as compared to healthy subjects., Highlights • Simultaneous fMRI and 11C-Diprenoprhine PET of migraineurs and controls before and after placebo analgesia • Placebo led to an overall reduction in pain ratings, with no significant differences between patients and controls • Structural changes in migraine, but no effects of placebo or diagnosis on pain fMRI or on opioid receptor binding.

Introduction Although migraine is a common headache complaint in children and adolescents there remains a significant gap in understanding the unique aspects of the disease in these age groups and their evolution with development. The aim of this retrospective cohort study was to identify migraine features that are influenced by age and sex. Methods The headache characteristics of 359 paediatric patients with a clinical diagnosis of migraine from a tertiary paediatric headache clinic were assessed. Patients retrospectively reported headache characteristics during a structured intake interview and clinical exam. Headache characteristics, description and associated symptoms were compared between children (age ≤ 12 years) and adolescents (age > 12 years), and between male and female migraineurs. Results Several migraine features differed significantly with age and/or sex, including: (i) a marked change from a 1:1 sex ratio in children to a 2:1 predominance of girls in adolescents; (ii) a higher frequency of headache attacks per month in adolescents and female migraineurs; (iii) a higher proportion of adolescents endorsed a ‘throbbing’ pain quality; (iv) a higher proportion of children reporting nausea and vomiting; and (v) a higher proportion of adolescents, particularly female migraineurs, had a diagnosis of a co-morbid anxiety. Conclusion The presentation of migraine, both in terms of its headache characteristics and associated symptoms, appear to vary as a function of age and sex. Given that migraine symptoms have a neural basis, it is not surprising that during the key period of neurodevelopment from childhood to adolescence this may impact their presentation.

Background Often concussion/mTBI triggers a chronic headache syndrome called persistent post-traumatic headache (P-PTH) that can last from months to years post-injury, and produce significant disruption of childhood education, social interaction and development. Although prevalent and highly disabling, P-PTH is underrepresented in headache and pain research and lacks clear definition and pathophysiology. Clinical presentation of P-PTH frequently resembles that of other headache disorders, like migraine, yet the pathophysiological mechanisms are distinct and not fully understood, making the disorder difficult to treat in the clinical setting. Methods In a retrospective analysis of 1506 pediatric patients attending Boston Children’s Hospital clinics, demographic trends, symptom features, and the influence of sex on clinical presentation of PTH are presented. We compare clinical characteristics of P-PTH with a published cohort of migraine patients to evaluate the clinical features that are unique to P-PTH. Results Findings show that despite equivalent representation of sex in the clinic, P-PTH is expressed more in females than males and is weighted towards somatic symptoms. Relative to migraine, PTH is less associated with a family history of headache. Conclusions The ability to identify persons with PTH can help manage risk factors and identify persons likely to develop persistent post-concussion symptoms.

Approximately 1.7 million youth suffer from debilitating chronic pain in the US alone, conferring risk of continued pain in adulthood. Aberrations in threat-safety (T-S) discrimination are proposed to contribute to pain chronicity in adults and youth by interacting with pain-related distress. Yet, few studies have examined the neural circuitry underlying T-S discrimination in patients with chronic pain or how T-S discrimination relates to pain-related distress. In this study, 91 adolescents (10-24 years; 78 females) including 30 chronic pain patients with high pain-related distress, 29 chronic pain patients with low pain-related distress, and 32 healthy peers without chronic pain completed a developmentally appropriate T-S learning paradigm. We measured self-reported fear, psychophysiology (skin conductance response), and functional magnetic resonance imaging responses (N = 72 after functional magnetic resonance imaging exclusions). After controlling for age and anxiety symptoms, patients with high pain-related distress showed altered self-reported fear and frontolimbic activity in response to learned threat and safety cues compared with both patients with low pain-related distress and healthy controls. Specifically, adolescent patients with high pain-related distress reported elevated fear and showed elevated limbic (hippocampus and amygdala) activation in response to a learned threat cue (CS+). In addition, they showed decreased frontal (vmPFC) activation and aberrant frontolimbic connectivity in response to a learned safety cue (CS-). Patients with low pain-related distress and healthy controls appeared strikingly similar across brain and behavior. These findings indicate that altered T-S discrimination, mediated by frontolimbic activation and connectivity, may be one mechanism maintaining pain chronicity in adolescents with high levels of pain-related distress.

Migraine is a debilitating condition; however, the pharmacological effects on central nervous system networks after successful therapy are poorly understood. Defining this neurocircuitry is critical to our understanding of the disorder and for the development of antimigraine drugs. Using an established inflammatory soup model of migraine-like pathophysiology (N = 12) compared with sham synthetic interstitial fluid migraine induction (N = 12), our aim was to evaluate changes in network-level functional connectivity after sumatriptan-naproxen infusion in awake, conscious rodents (Sprague-Dawley rats). Sumatriptan-naproxen infusion functional magnetic resonance imaging data were analyzed using an independent component analysis approach. Whole-brain analysis yielded significant between-group (inflammatory soup vs synthetic interstitial fluid) alterations in functional connectivity across the cerebellar, default mode, basal ganglia, autonomic, and salience networks. These results demonstrate the large-scale antimigraine effects of sumatriptan-naproxen co-administration after dural sensitization.

In patients with post-traumatic stress disorder (PTSD), a decrease in the brain reward function was reported in behavioral- and in neuroimaging studies. While pathophysiological mechanisms underlying this response are unclear, there are several lines of evidence suggesting over-recruitment of the brain reward regions by aversive stimuli rendering them unavailable to respond to reward-related content. The purpose of this study was to juxtapose brain responses to functional neuroimaging probes that reliably produce rewarding and aversive experiences in PTSD subjects and in healthy controls. The stimuli used were pleasant, aversive and neutral images selected from the International Affective Picture System (IAPS) along with pain-inducing heat applied to the dorsum of the left hand; all were administered during 3 T functional magnetic resonance imaging. Analyses of IAPS responses for the pleasant images revealed significantly decreased subjective ratings and brain activations in PTSD subjects that included striatum and medial prefrontal-, parietal- and temporal cortices. For the aversive images, decreased activations were observed in the amygdala and in the thalamus. PTSD and healthy subjects provided similar subjective ratings of thermal sensory thresholds and each of the temperatures. When 46 °C (hot) and 42 °C (neutral) temperatures were contrasted, voxelwise between-group comparison revealed greater activations in the striatum, amygdala, hippocampus and medial prefrontal cortex in the PTSD subjects. These latter findings were for the most part mirrored by the 44 vs. 42 °C contrast. Our data suggest different brain alterations patterns in PTSD, namely relatively diminished corticolimbic response to pleasant and aversive psychosocial stimuli in the face of exaggerated response to heat-related pain. The present findings support the hypothesis that brain sensitization to pain in PTSD may interfere with the processing of psychosocial stimuli whether they are of rewarding or aversive valence.

Alterations in fractional anisotropy (FA) have been considered to reflect microstructural white matter (WM) changes in disease conditions; however, no study to date has examined WM changes using diffusion tensor imaging (DTI) in adolescents with irritable bowel syndrome (IBS). The objective of the present study was two-fold: (1) to determine whether differences in FA, and other non-FA metrics, were present in adolescents with IBS compared to healthy controls using whole-brain, region of interest (ROI)-restricted tract-based spatial statistics (TBSS) and canonical ROI DTI analyses for the cingulum bundle, and (2) to determine whether these metrics were related to clinical measures of disease duration and pain intensity in the IBS group. A total of 16 adolescents with a Rome III diagnosis of IBS (females = 12; mean age = 16.29, age range: 11.96–18.5 years) and 16 age- and gender-matched healthy controls (females = 12; mean age = 16.24; age range: 11.71–20.32 years) participated in this study. Diffusion-weighted images were acquired using a Siemens 3-T Trio Tim Syngo MRI scanner with a 32-channel head coil. The ROI-restricted TBSS and canonical ROI-based DTI analyses revealed that adolescents with IBS showed decreased FA in the right dorsal cingulum bundle compared to controls. No relationship between FA and disease severity measures was found. Microstructural WM alterations in the right dorsal cingulum bundle in adolescents with IBS may reflect a premorbid brain state or the emergence of a disease-driven process that results from complex changes in pain- and affect-related processing via spinothalamic and corticolimbic pathways.

Aversion to light is common among migraineurs undergoing acute attacks. Using psychophysical assessments in patients with episodic migraine, we reported that white, blue, amber, and red lights exacerbate migraine headache in a significantly larger percentage of patients and to a greater extent compared with green light. This study aimed at determining whether these findings are phase-dependent-namely, manifested exclusively during migraine (ictally) but not in its absence (interictally), or condition-dependent-ie, expressed uniquely in migraineurs but not in healthy controls. To determine whether the color preference of migraine-type photophobia is phase- or condition-dependent, we compared the effects of each color of light in each intensity between migraineurs during and in-between attacks and healthy controls. During the ictal and interictal phases, the proportion of migraineurs reporting changes in headache severity when exposed to the different colors of light increased in accordance with elevated light intensities. During the ictal phase, white, blue, amber, and red lights exacerbated headaches in ∼80% of the patients; however, during the interictal phase, light initiated headache in only 16% to 19%. Notably, green light exacerbated headaches in 40% and triggered headaches in 3% of the patients studied during the ictal and interictal phases, respectively. With one exception (highest red light intensity), no control subject reported headache in response to the light stimuli. These findings suggest that color preference is unique to migraineurs-as it was not found in control subjects-and that it is independent of whether or not the patients are in their ictal or interictal phase.

Despite the prevalence of migraine, the pathophysiology of the disease remains unclear. Current understanding of migraine has alluded to the possibility of a hyperexcitable brain. The aim of the current study is to investigate human brain metabolite differences in the anterior cingulate cortex (ACC) during the interictal phase in migraine patients. We hypothesized that there may be differences in levels of excitatory neurotransmitters and/or their derivatives in the migraine cohort in support of the theory of hyperexcitability in migraine. 2D J-resolved proton magnetic resonance spectroscopy (1H-MRS) data were acquired on a 3 Tesla (3 T) MRI from a voxel placed over the ACC of 32 migraine patients (MP; 23 females, 9 males, age 33 ± 9.6 years) and 33 healthy controls (HC; 25 females, 8 males, age 32 ± 9.6 years). Amplitude correlation matrices were constructed for each subject to evaluate metabolite discriminability. ProFit-estimated metabolite peak areas were normalized to a water reference signal to assess subject differences. The initial analysis of variance (ANOVA) was performed to test for group differences for all metabolites/creatine (Cre) ratios between healthy controls and migraineurs but showed no statistically significant differences. In addition, we used a multivariate approach to distinguish migraineurs from healthy subjects based on the metabolite/Cre ratio. A quadratic discriminant analysis (QDA) model was used to identify 3 metabolite ratios sufficient to minimize minimum classification error (MCE). The 3 selected metabolite ratios were aspartate (Asp)/Cre, N-acetyl aspartate (NAA)/Cre, and glutamine (Gln)/Cre. These findings are in support of a ‘complex’ of metabolite alterations, which may underlie changes in neuronal chemistry in the migraine brain. Furthermore, the parallel changes in the three-metabolite ‘complex’ may confer more subtle but biological processes that are ongoing. The data also support the current theory that the migraine brain is hyperexcitable even in the interictal state., Highlights • 3 T MRI was used to acquire 2D J-resolved proton magnetic resonance spectroscopy. • Metabolite alterations are reported in the anterior cingulate cortex of episodic migraineurs. • The complex of metabolites may reflect multiple chemical changes in migraineurs. • The observed chemical changes support the theory that the brain of migraineurs is hyperexcitable.

Patients suffering from corneal neuropathy may present with photoallodynia; i.e., increased light sensitivity, frequently with a normal slit-lamp examination. This study aimed to evaluate the efficacy of autologous serum tears (AST) for treatment of severe photoallodynia in corneal neuropathy and to correlate clinical findings with corneal subbasal nerve alterations by in vivo confocal microscopy (IVCM).Retrospective case control study with 16 patients with neuropathy-induced severe photoallodynia compared to 16 normal controls. Symptom severity, clinical examination and bilateral corneal IVCM scans were recorded.All patients suffered from extreme photoallodynia (8.8±1.1) with no concurrent ocular surface disease. Subbasal nerves were significantly decreased at baseline in patients compared to controls; total nerve length (9208±1264 vs 24714±1056 μm/mm(2); P.0001) and total nerve number (9.6±1.4 vs 28.6±2.0; P.0001), respectively. Morphologically, significantly increased reflectivity (2.9±0.2 vs 1.8±0.1; P.0001), beading (in 93.7%), and neuromas (in 62.5%) were seen. AST (3.6±2.1 months) resulted in significantly decreased symptom severity (1.6±1.7; P=.02). IVCM demonstrated significantly improved nerve parameters (P.005), total nerve length (15451±1595 μm/mm(2)), number (13.9±2.1), and reflectivity (1.9±0.1). Beading and neuromas were seen in only 56.2% and 7.6% of patients.Patients with corneal neuropathy-induced photoallodynia show profound alterations in corneal nerves. AST restores nerve topography through nerve regeneration, and this correlated with improvement in patient-reported photoallodynia. The data support the notion that corneal nerve damage results in alterations in afferent trigeminal pathways to produce photoallodynia.

BACKGROUND: The experience of persistent pain in multiple locations is common in youth. Based on current literature, youth with multiple pain sites (MPS) are at risk of experiencing poorer emotional outcomes and a spread of symptoms into late adolescence and adulthood. Little is known regarding the association between MPS with physical and school functioning domains, particularly after initiation of multidisciplinary pain treatment. Therefore, the objective of this study was to examine the association of MPS with disability and school functioning among youth with chronic pain. METHODS: A total of 195 patients with chronic pain, aged 8–17, and their parents completed measures assessing patient distress and functioning at a multidisciplinary pain clinic evaluation and at 4-month follow-up. RESULTS: At evaluation, 63% of patients presented with MPS; 25% reporting MPS endorsed pain in five or more locations. When controlling for relevant demographic and emotional distress factors, MPS was associated with lower school functioning at evaluation with a persistent trend at follow-up. Although MPS was not a significant predictor of pain-related disability at evaluation, it emerged as significant at follow-up. CONCLUSIONS: Potentially due to the MPS load and the inverse effects that such a pain state has on function, such patients may be at-risk for poorer health and school-related outcomes. The mechanisms influencing these relationships appear to extend beyond psychological/emotional factors and warrant further investigation in order to aid in our understanding of youth with MPS. SIGNIFICANCE: Youth with MPS may be at risk for experiencing poorer physical and school functioning in comparison to single-site peers, despite treatment initiation. Further research is warranted in order to inform assessment and treatment approaches for this subgroup of patients.

Central sensitization is a condition in which there is an abnormal responsiveness to nociceptive stimuli. As such, the process may contribute to the development and maintenance of pain. Factors influencing the propensity for development of central sensitization have been a subject of intense debate and remain elusive. Injury-induced secondary hyperalgesia can be elicited by experimental pain models in humans, and is believed to be a result of central sensitization. Secondary hyperalgesia may thus reflect the individual level of central sensitization. The objective of this study was to investigate possible associations between increasing size of secondary hyperalgesia area and brain connectivity in known resting-state networks. We recruited 121 healthy participants (male, age 22, SD 3.35) who underwent resting-state functional magnetic resonance imaging. Prior to the scan session, areas of secondary hyperalgesia following brief thermal sensitization (3 min. 45 °C heat stimulation) were evaluated in all participants. 115 participants were included in the final analysis. We found a positive correlation (increasing connectivity) with increasing area of secondary hyperalgesia in the sensorimotor- and default mode networks. We also observed a negative correlation (decreasing connectivity) with increasing secondary hyperalgesia area in the sensorimotor-, fronto-parietal-, and default mode networks. Our findings indicate that increasing area of secondary hyperalgesia is associated with increasing and decreasing connectivity in multiple networks, suggesting that differences in the propensity for central sensitization, assessed as secondary hyperalgesia areas, may be expressed as differences in the resting-state central neuronal activity.

OBJECTIVE: Cortical spreading depression (CSD) has long been implicated in migraine attacks with aura. The process by which CSD, a cortical event that occurs within the blood brain barrier (BBB), results in nociceptor activation outside the BBB is likely mediated by multiple molecules and cells. The objective of this study was to determine whether CSD activates immune cells inside the BBB (pia), outside the BBB (dura), or in both, and if so, when. METHODS: Investigating cellular events in the meninges shortly after CSD, we used in-vivo 2-photon imaging to identify changes in macrophages and dendritic cells (DC) that reside in the pia, arachnoid, and dura, and their anatomical relationship to TRPV1 axons. RESULTS: We found that activated meningeal macrophages retract their processes and become circular, and that activated meningeal DC stop migrating. We found that CSD activates pial macrophages instantaneously, pial, subarachnoid and dural DC 6-12 minutes later, and dural macrophages 20 minutes later. Dural macrophages and DC can appear in close proximity to TRPV1-positive axons. INTERPRETATION: The findings suggest that activation of pial macrophages may be more relevant to cases where aura and migraine begin simultaneously, that activation of dural macrophages may be more relevant to cases where headache begins 20-30 minutes after aura, and that activation of dural macrophages may be mediated by activation of migratory DC in the SAS and dura. The anatomical relationship between TRPV1-positive meningeal nociceptors, and dural macrophages and dendritic cells support a role for these immune cells in the modulation of head pain.

Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions.

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.

Our understanding of chronic pain involves complex brain circuits that include sensory, emotional, cognitive and interoceptive processing. The feed-forward interactions between physical (e.g., trauma) and emotional pain and the consequences of altered psychological status on the expression of pain have made the evaluation and treatment of chronic pain a challenge in the clinic. By understanding the neural circuits involved in psychological processes, a mechanistic approach to the implementation of psychology-based treatments may be better understood. In this review we evaluate some of the principle processes that may be altered as a consequence of chronic pain in the context of localized and integrated neural networks. These changes are ongoing, vary in their magnitude, and their hierarchical manifestations, and may be temporally and sequentially altered by treatments, and all contribute to an overall pain phenotype. Furthermore, we link altered psychological processes to specific evidence-based treatments to put forth a model of pain neuroscience psychology.

Pediatric complex regional pain syndrome (P-CRPS) offers a unique model of chronic neuropathic pain as it either resolves spontaneously or through therapeutic interventions in most patients. Here we evaluated brain changes in well-characterized children and adolescents with P-CRPS by measuring resting state networks before and following a brief (median = 3 weeks) but intensive physical and psychological treatment program, and compared them to matched healthy controls. Differences in intrinsic brain networks were observed in P-CRPS compared to controls before treatment (disease state) with the most prominent differences in the fronto-parietal, salience, default mode, central executive, and sensorimotor networks. Following treatment, behavioral measures demonstrated a reduction of symptoms and improvement of physical state (pain levels and motor functioning). Correlation of network connectivities with spontaneous pain measures pre- and post-treatment indicated concomitant reductions in connectivity in salience, central executive, default mode and sensorimotor networks (treatment effects). These results suggest a rapid alteration in global brain networks with treatment and provide a venue to assess brain changes in CRPS pre- and post-treatment, and to evaluate therapeutic effects., Highlights • Pediatric complex regional pain syndrome (CRPS) alters brain networks. • Alterations are not equivalent to those observed in adults with CRPS. • Identifying alterations might be relevant to determine treatment modalities. • Intensive physical- and psycho-therapy reverses some but not all the changes.

In humans, functional magnetic resonance imaging (fMRI) activity in the anterior cingulate cortex (ACC) and the nucleus accumbens (NAc) appears to reflect affective and motivational aspects of pain. The responses of this reward-aversion circuit to relief of pain, however, have not been investigated in detail. Moreover, it is not clear whether brain processing of the affective qualities of pain in animals parallels the mechanisms observed in humans. In the present study, we analyzed fMRI blood oxygen level-dependent (BOLD) activity separately in response to an onset (aversion) and offset (reward) of a noxious heat stimulus to a dorsal part of a limb in both humans and rats. We show that pain onset results in negative activity change in the NAc and pain offset produces positive activity change in the ACC and NAc. These changes were analogous in humans and rats, suggesting that translational studies of brain circuits modulated by pain are plausible and may offer an opportunity for mechanistic investigation of pain and pain relief.

Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial µ-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

Intensive pain rehabilitation programs for children with chronic pain are effective for many patients. However, characteristics associated with treatment response have not been well documented. In this article we report trajectories of pain and functional impairment in patients with chronic pain up to 1 year after intensive pain rehabilitation and examine baseline factors associated with treatment response. Patients (n = 253) with chronic pain and functional disability were assessed at 5 time points (admission, discharge, 1-month, 4-month, and 12-month follow-ups). Individual trajectories were empirically grouped using SAS PROC TRAJ. For functional disability, 2 groups emerged: treatment responders (88%) and nonresponders (12%). Using a binomial logistic regression model to predict disability trajectory group, no baseline variables were significant predictors for the disability trajectory group. For pain, 3 groups emerged: early treatment responders (35%), late treatment responders (38%), and nonresponders (27%). Using multinomial regression analyses to predict pain trajectory group, older age, higher pain scores, fewer social difficulties, higher anxiety levels, and lower readiness to change were characteristics that distinguished nonresponders from responders; no significant predictors distinguished the late responders from the early responders. These results provide key information on the baseline factors that influence intensive pain rehabilitation outcomes, including risk factors that predict treatment nonresponse. Our findings have implications for developing more targeted treatment interventions. Perspective Deriving groups of individuals with differing treatment response trajectories stimulates new thinking regarding potential mechanisms that may be driving these outcomes.

The purpose of this study was to use functional near-infrared spectroscopy (fNIRS) to examine patterns of both activation and deactivation that occur in the frontal lobe in response to noxious stimuli. The frontal lobe was selected because it has been shown to be activated by noxious stimuli in functional magnetic resonance imaging studies. The brain region is located behind the forehead which is devoid of hair, providing a relative ease of placement for fNIRS probes on this area of the head. Based on functional magnetic resonance imaging studies showing blood-oxygenation-level dependent changes in the frontal lobes, we evaluated functional near-infrared spectroscopy measures in response to two levels of electrical pain in awake, healthy human subjects (n = 10; male = 10). Each subject underwent two recording sessions separated by a 30-minute resting period. Data collected from 7 subjects were analyzed, containing a total of 38/36 low/high intensity pain stimuli for the first recording session and 27/31 pain stimuli for the second session. Our results show that there is a robust and significant deactivation in sections of the frontal cortices. Further development and definition of the specificity and sensitivity of the approach may provide an objective measure of nociceptive activity in the brain that can be easily applied in the surgical setting.

For many years, neurobiological theories have emphasized the importance of neuronal oscillations in the emergence of brain function. At the same time, clinical studies have shown that disturbances or irregularities in brain rhythms may relate to various common neurological conditions, including migraine. Increasing evidence suggests that the CNS plays a fundamental role in the predisposition to develop different forms of headache. Here, we present human imaging data that strongly support the presence of abnormal low-frequency oscillations (LFOs) in thalamocortical networks of patients in the interictal phase of migraine. Our results show that the main source of arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus. In addition, spontaneous LFOs in the thalamus were selectively associated with the headache attack frequency, meaning that the varying amplitude of dysrhythmia could predispose patients to recurrent attacks. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability. We further speculate that the intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing and therefore could underlie important pathophysiological processes involved in multisensory integration. SIGNIFICANCE STATEMENT In many cases, migraine attacks are thought to begin centrally. A major obstacle to studying intrinsic brain activity has been the identification of the precise anatomical structures and functional networks that are involved in migraine. Here, we present imaging data that strongly support the presence of abnormal low-frequency oscillations in thalamocortical networks of patients in the interictal phase of migraine. This arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus and was selectively associated with headache attack frequency. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability and higher-level processes involved in multisensory integration.

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease-specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal.

Aim: Various animal and human studies have contributed to the idea of cortical structural–functional alterations in migraine. Defining concurrent cortical alterations may provide specific insights into the unfolding adaptive or maladaptive changes taking place in cortex in migraine.Methods: From a group of 60 episodic migraineurs, 20 were recruited to the study. Using high-resolution magnetic resonance imaging, structural and functional cortical measures were compared in migraineurs who experienced increased frequency of attacks (HF; 8–14 days/month; n = 10), to those who experienced less frequent migraine attacks (LF; Results: Parallel structural and functional differences were found as follows: (i) HF patients showed higher thickness in the area representing the face in the post-central gyrus, which correlated with the observed stronger functional activation, suggesting adaptation to repeated sensory drive; (ii) smaller cortical volume was observed in the cingulate cortex that correlated with lower activation in the HF group; and (iii) similarly significant structural and functional differences (HF > LF) were observed in the insula that may reflect potential alteration in affective processing.Conclusion: These results suggest differential response patterns in the sensory vs. affective processing regions in the brain that may be an adaptive response to repeated migraine attacks.

The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Children's Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human μ-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T-allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition.

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

During migraine attacks, alterations in sensation accompanying headache may manifest as allodynia and enhanced sensitivity to light, sound, and odors. Our objective was to identify physiological changes in cortical regions in migraine patients using painful heat and functional magnetic resonance imaging (fMRI) and the structural basis for such changes using diffusion tensor imaging (DTI). In 11 interictal patients, painful heat threshold + 1°C was applied unilaterally to the forehead during fMRI scanning. Significantly greater activation was identified in the medial temporal lobe in patients relative to healthy subjects, specifically in the anterior temporal pole (TP). In patients, TP showed significantly increased functional connectivity in several brain regions relative to controls, suggesting that TP hyperexcitability may contribute to functional abnormalities in migraine. In 9 healthy subjects, DTI identified white matter connectivity between TP and pulvinar nucleus, which has been related to migraine. In 8 patients, fMRI activation in TP with painful heat was exacerbated during migraine, suggesting that repeated migraines may sensitize TP. This article investigates a nonclassical role of TP in migraineurs. Observed temporal lobe abnormalities may provide a basis for many of the perceptual changes in migraineurs and may serve as a potential interictal biomarker for drug efficacy.

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n = 10); from a larger study on prescription opioid dependent patients (n = 133)] and matched healthy individuals (n = 10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

Using functional magnetic resonance imaging (fMRI) methods, we evaluated the effects of lamotrigine vs placebo in a double-blind 1:1 randomized trial. Six patients with neuropathic pain were recruited for the study. All subjects had baseline pain >4/10 on a visual analog scale (VAS) and allodynia to brush as inclusion criteria for the study. Patients underwent two fMRI sessions, with half of the subjects receiving placebo first and half receiving drug first (based on the blinding protocol). Lamotrigine decreased their average pain intensity level from 5.6 to 3.5 on a VAS. All subjects had brush, cold, and heat applied to the affected and mirror-unaffected sides of their face. The results show: 1) in a small cohort, lamotrigine had a significant effect on heat VAS but not on the other stimuli; and 2) contrast analysis of fMRI results for heat stimuli applied to the affected face for lamotrigine vs placebo produced an overall decrease in blood oxygen dependent level signal, suggesting a potential inhibitory effect of the drug on predominantly cortical regions (frontal, parietal, and temporal).

Purpose: To determine a simple yet robust method to generate parsimonious design matrices that accurately estimate the “pharmacological MRI” (phMRI) response amplitude in the presence of both confounding signals and variability in temporal profile. Variability in the temporal response profile of phMRI time series data is often observed. If not properly accounted for, this variation can result in inaccurate and unevenly biased signal amplitude estimates when modeled within a general linear model (GLM) framework. Materials and Methods: The approach uses a low-rank singular value decomposition (SVD) approximation to a set of vectors capturing anticipated variations of no interest around the signal model to generate additional regressors for the design matrix. The method is demonstrated for both plateau and bolus type phMRI response profiles in the presence of variation in signal onset and/or shape, and applied to an in vivo blood oxygenation level-dependent (BOLD) phMRI study of buprenorphine in healthy human subjects. Results: In general, 2–3 additional regressors, capturing >75% of the anticipated variance, resulted in robust and unbiased signal amplitude estimates in the presence of substantial variability. Conclusion: This method provides a simple and flexible means to provide robust phMRI amplitude estimates within a GLM framework. J. Magn. Reson. Imaging 2010;31:1445–1457. © 2010 Wiley-Liss, Inc.

Focal somatic pain can evolve into widespread hypersensitivity to nonpainful and painful skin stimuli (allodynia and hyperalgesia, respectively). We hypothesized that transformation of headache into whole-body allodynia/hyperalgesia during a migraine attack is mediated by sensitization of thalamic neurons that process converging sensory impulses from the cranial meninges and extracephalic skin.Extracephalic allodynia was assessed using single unit recording of thalamic trigeminovascular neurons in rats and contrast analysis of blood oxygenation level-dependent (BOLD) signals registered in functional magnetic resonance imaging (fMRI) scans of patients exhibiting extracephalic allodynia.Sensory neurons in the rat posterior thalamus that were activated and sensitized by chemical stimulation of the cranial dura exhibited long-lasting hyperexcitability to innocuous (brush, pressure) and noxious (pinch, heat) stimulation of the paws. Innocuous, extracephalic skin stimuli that did not produce neuronal firing at baseline (eg, brush) became as effective as noxious stimuli (eg, pinch) in eliciting large bouts of neuronal firing after sensitization was established. In migraine patients, fMRI assessment of BOLD signals showed that brush and heat stimulation at the skin of the dorsum of the hand produced larger BOLD responses in the posterior thalamus of subjects undergoing a migraine attack with extracephalic allodynia than the corresponding responses registered when the same patients were free of migraine and allodynia.We propose that the spreading of multimodal allodynia and hyperalgesia beyond the locus of migraine headache is mediated by sensitized thalamic neurons that process nociceptive information from the cranial meninges together with sensory information from the skin of the scalp, face, body, and limbs.

Pain and relief are at opposite ends of the reward-aversion continuum. Studying them provides an opportunity to evaluate dynamic changes in brain activity in reward-aversion pathways as measured by functional magnetic resonance imaging (fMRI). Of particular interest is the Nucleus Accumbens (NAc), a brain substrate known to be involved in reward-aversion processing, whose activation valence has been observed to be opposite in response to reward or aversive stimuli. Here we have used pain onset (aversive) and pain offset (rewarding) involving a prolonged stimulus applied to the dorsum of the hand in 10 male subjects over 120 seconds to study the NAc fMRI response. The results show a negative signal change with pain onset and a positive signal change with pain offset in the NAc contralateral to the stimulus. The study supports the idea that the NAc fMRI signal may provide a useful marker for the effects of pain and analgesia in healthy volunteers.

This pilot case-control study retrospectively assessed between-groups differences in subjective opioid effects in patients treated for the first time with opioids for chronic pain. Cases were individuals in an inpatient substance abuse treatment center for primary prescription opioid addiction whose initial exposure to prescription opioids was reported for chronic pain. Controls had not developed prescription opioid addiction as measured in part by close monitoring on long-term opioid therapy at a pain management center. Twenty subjects in each group completed a battery of measures to capture data related to the individual's first exposure to prescription opioids. The Morphine Benzedrine Group subscale of an adapted 49-item Addiction Center Research Inventory (ARCI), designed to measure euphoria and other drug effects, showed an average score of 8.70 (+/-4.18) in cases versus 2.55 (+/-3.36) in controls (p

Though human pain imaging studies almost always demonstrate activation in the cerebellum, the role of the cerebellum in pain function is not well understood. Here we present results from two studies on the effects of noxious thermal heat and brush applied to the right side of the face in a group of healthy subjects (Group I) and a group of patients with neuropathic pain (Group II) who are more sensitive to both thermal and mechanical stimuli. Statistically significant activations and volumes of activations were defined in the cerebellum. Activated cerebellar structures were identified by colocalization of fMRI activation with the 'MRI Atlas of the Human Cerebellum'. Functional data (obtained using a 3T magnet) were defined in terms of maximum voxels and volume of activation in the cerebellum. Volume maps were then mapped onto two millimeter serial slices taken through the cerebellum in order to identify activation within regions defined by the activation volume. The data indicate that different regions of the cerebellum are involved in acute and chronic pain processing. Heat produces greater contralateral activation compared with brush, while brush resulted in more ipsilateral/bilateral cerebellar activation. Further, innocuous brush stimuli in healthy subjects produced decreased cerebellar activation in lobules concerned with somatosensory processing. The data also suggest a dichotomy of innocuous stimuli/sensorimotor cerebellum activation versus noxious experience/cognitive/limbic cerebellum activation. These results lead us to propose that the cerebellum may modulate the emotional and cognitive experience that distinguishes the perception of pain from the appreciation of innocuous sensory stimulation.

The predictability of pain makes surgery an ideal model for the study of pain and the development of strategies for analgesia and reduction of perioperative pain. As functional near-infrared spectroscopy reproduces the known functional magnetic resonance imaging activations in response to a painful stimulus, we evaluated the feasibility of functional near-infrared spectroscopy to measure cortical responses to noxious stimulation during general anesthesia. A multichannel continuous wave near-infrared imager was used to measure somatosensory and frontal cortical activation in patients undergoing catheter ablation of arrhythmias under general anesthesia. Anesthetic technique was standardized and intraoperative NIRS signals recorded continuously with markers placed in the data set for the timing and duration of each cardiac ablation event. Frontal cortical signals only were suitable for analysis in five of eight patients studied (mean age 14 ± 1 years, weight 66.7 ± 17.6 kg, 2 males). Thirty ablative lesions were recorded for the five patients. Radiofrequency or cryoablation was temporally associated with a hemodynamic response function in the frontal cortex characterized by a significant decrease in oxyhemoglobin concentration (paired t-test, p

Colonoscopy is an invaluable tool for the screening and diagnosis of many colonic diseases. For most colonoscopies, moderate sedation is used during the procedure. However, insufflation of the colon produces a nociceptive stimulus that is usually accompanied by facial grimacing/groaning while under sedation. The objective of this study was to evaluate whether a nociceptive signal elicited by colonic insufflation could be measured from the brain. Seventeen otherwise healthy patients (age 54.8 ± 9.1; 6 female) undergoing routine colonoscopy (ie, no history of significant medical conditions) were monitored using near-infrared spectroscopy (NIRS). Moderate sedation was produced using standard clinical protocols for midazolam and meperidine, titrated to effect. Near-infrared spectroscopy data captured during the procedure was analyzed offline to evaluate the brains' responses to nociceptive stimuli evoked by the insufflation events (defined by physician or observing patients' facial responses). Analysis of NIRS data revealed a specific, reproducible prefrontal cortex activity corresponding to times when patients grimaced. The pattern of the activation is similar to that previously observed during nociceptive stimuli in awake healthy individuals, suggesting that this approach may be used to evaluate brain activity evoked by nociceptive stimuli under sedation, when there is incomplete analgesia. Although some patients report recollection of procedural pain after the procedure, the effects of repeated nociceptive stimuli in surgical patients may contribute to postoperative changes including chronic pain. The results from this study indicate that NIRS may be a suitable technology for continuous nociceptive afferent monitoring in patients undergoing sedation and could have applications under sedation or anesthesia.

The prevalence of migraine has an exponential trajectory that is most obvious in young females between puberty and early adulthood. Adult females are affected twice as much as males. During development, hormonal changes may act on predetermined brain circuits, increasing the probability of migraine. However, little is known about the pediatric migraine brain and migraine evolution. Using magnetic resonance imaging, we evaluated 28 children with migraine (14 females and 14 males) and 28 sex-matched healthy controls to determine differences in brain structure and function between (1) females and males with migraine and (2) females and males with migraine during earlier (10-11 years) vs later (14-16 years) developmental stages compared with matched healthy controls. Compared with males, females had more gray matter in the primary somatosensory cortex (S1), supplementary motor area, precuneus, basal ganglia, and amygdala, as well as greater precuneus resting state functional connectivity to the thalamus, amygdala, and basal ganglia and greater amygdala resting state functional connectivity to the thalamus, anterior midcingulate cortex, and supplementary motor area. Moreover, older females with migraine had more gray matter in the S1, amygdala, and caudate compared to older males with migraine and matched healthy controls. This is the first study showing sex and developmental differences in pediatric migraineurs in brain regions associated with sensory, motor, and affective functions, providing insight into the neural mechanisms underlying distinct migraine sex phenotypes and their evolution that could result in important clinical implications increasing treatment effectiveness.

A number of drugs, including triptans, promote migraine chronification in susceptible individuals. In rats, a period of triptan administration over 7 days can produce “latent sensitization” (14 days after discontinuation of drug) demonstrated as enhanced sensitivity to presumed migraine triggers such as environmental stress and lowered threshold for electrically induced cortical spreading depression (CSD). Here we have used fMRI to evaluate the early changes in brain networks at day 7 of sumatriptan administration that may induce latent sensitization as well as the potential response to stress. After continuous infusion of sumatriptan, rats were scanned to measure changes in resting state networks and the response to bright light environmental stress. Rats receiving sumatriptan, but not saline infusion, showed significant differences in default mode, autonomic, basal ganglia, salience, and sensorimotor networks. Bright light stress produced CSD-like responses in sumatriptan-treated but not control rats. Our data show the first brain-related changes in a rat model of medication overuse headache and suggest that this approach could be used to evaluate the multiple brain networks involved that may promote this condition.