Attitudes and Perceptions Toward Authorized Deception: A Pilot Comparison of Healthy Controls and Fibromyalgia Patients.

OBJECTIVE: Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. METHODS: An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). RESULTS: The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P < 0.001). CONCLUSIONS: Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.

Unique Autonomic Responses to Pain in Yoga Practitioners.

OBJECTIVE: Autonomic nervous system activity is associated with neurobehavioral aspects of pain. Yogis use breathing, relaxation, and mindfulness to tolerate pain, which could influence autonomic responses. To evaluate how the link between autonomic responses and pain is altered by other factors, we compared perceptual and autonomic responses to pain between yogis and controls. METHODS: Nineteen yogis and 15 controls rated warm and painfully hot stimuli (1-cm thermode on calf), with visual anticipatory cues indicating certainly painful, certainly nonpainful, or uncertainly either painful or nonpainful. Heart rate, skin conductance, respiration, and blood pressure were measured. RESULTS: At baseline, yogis breathed slower and deeper than did controls, with no differences in other autonomic measures. During the task, perceptual ratings did not differ between groups in either the certain or uncertain conditions. Nevertheless, yogis had higher phasic skin conductance responses in anticipation of and response to all stimuli, but particularly during painful heat in uncertain contexts (uncertain: 0.46 [0.34] µS; certain: 0.37 [0.28] µS; t(18) = 3.962, p = .001). Furthermore, controls showed a decrease in heart rate to warm (-2.51 [2.17] beats/min) versus painful stimuli (0.83 [1.63] beats/min; t(13) = 5.212, p < .001) and lower respiratory sinus arrhythmia during pain compared with warm trials, whereas yogis had similar reactions to painful and nonpainful stimuli. CONCLUSIONS: Autonomic responses to pain differed in yogis and healthy volunteers, despite similar pain ratings. Thus, autonomic reactivity to pain may be altered by environmental and psychological factors throughout an individual's life.

Cognitive and emotional control of pain and its disruption in chronic pain.

Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states - important components of mind-body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.

Encoding of Touch Intensity But Not Pleasantness in Human Primary Somatosensory Cortex.

UNLABELLED: Growing interest in affective touch has delineated a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, have cast doubt on the segregation of touch discrimination and affect, suggesting that S1 also encodes affective qualities. We used functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) to examine the role of S1 in processing touch intensity and pleasantness. Twenty-six healthy human adults rated brushing on the hand during fMRI. Intensity ratings significantly predicted activation in S1, whereas pleasantness ratings predicted activation only in the anterior cingulate cortex. Nineteen subjects also received inhibitory rTMS over right hemisphere S1 and the vertex (control). After S1 rTMS, but not after vertex rTMS, sensory discrimination was reduced and subjects with reduced sensory discrimination rated touch as more intense. In contrast, rTMS did not alter ratings of touch pleasantness. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. SIGNIFICANCE STATEMENT: Growing interest in affective touch has identified a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, cast doubt on the separation of touch discrimination and affect. We used functional magnetic resonance imaging and repetitive transcranial magnetic stimulation to demonstrate the representation of touch discrimination and intensity in S1, but the representation of pleasantness in the anterior cingulate cortex, not S1. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. Our study contributes to growing delineation of the affective touch system, a crucial step in understanding its dysregulation in numerous clinical conditions such as autism, eating disorders, depression, and chronic pain.

Is a Responsive Default Mode Network Required for Successful Working Memory Task Performance?

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or "negative" [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient. SIGNIFICANCE STATEMENT: We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks ["external-task positive" and "default-mode network" (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance.

Insular cortex mediates increased pain tolerance in yoga practitioners.

Yoga, an increasingly popular discipline among Westerners, is frequently used to improve painful conditions. We investigated possible neuroanatomical underpinnings of the beneficial effects of yoga using sensory testing and magnetic resonance imaging techniques. North American yogis tolerated pain more than twice as long as individually matched controls and had more gray matter (GM) in multiple brain regions. Across subjects, insular GM uniquely correlated with pain tolerance. Insular GM volume in yogis positively correlated with yoga experience, suggesting a causal relationship between yoga and insular size. Yogis also had increased left intrainsular white matter integrity, consistent with a strengthened insular integration of nociceptive input and parasympathetic autonomic regulation. Yogis, as opposed to controls, used cognitive strategies involving parasympathetic activation and interoceptive awareness to tolerate pain, which could have led to use-dependent hypertrophy of insular cortex. Together, these findings suggest that regular and long-term yoga practice improves pain tolerance in typical North Americans by teaching different ways to deal with sensory inputs and the potential emotional reactions attached to those inputs leading to a change in insular brain anatomy and connectivity.

Metabolic brain activity suggestive of persistent pain in a rat model of neuropathic pain.

Persistent pain is a central characteristic of neuropathic pain conditions in humans. Knowing whether rodent models of neuropathic pain produce persistent pain is therefore crucial to their translational applicability. We investigated the spared nerve injury (SNI) model of neuropathic pain and the formalin pain model in rats using positron emission tomography (PET) with the metabolic tracer [18F]fluorodeoxyglucose (FDG) to determine if there is ongoing brain activity suggestive of persistent pain. For the formalin model, under brief anesthesia we injected one hindpaw with 5% formalin and the FDG tracer into a tail vein. We then allowed the animals to awaken and observed pain behavior for 30min during the FDG uptake period. The rat was then anesthetized and placed in the scanner for static image acquisition, which took place between minutes 45 and 75 post-tracer injection. A single reference rat brain magnetic resonance image (MRI) was used to align the PET images with the Paxinos and Watson rat brain atlas. Increased glucose metabolism was observed in the somatosensory region associated with the injection site (S1 hindlimb contralateral), S1 jaw/upper lip and cingulate cortex. Decreases were observed in the prelimbic cortex and hippocampus. Second, SNI rats were scanned 3weeks post-surgery using the same scanning paradigm, and region-of-interest analyses revealed increased metabolic activity in the contralateral S1 hindlimb. Finally, a second cohort of SNI rats was scanned while anesthetized during the tracer uptake period, and the S1 hindlimb increase was not observed. Increased brain activity in the somatosensory cortex of SNI rats resembled the activity produced with the injection of formalin, suggesting that the SNI model may produce persistent pain. The lack of increased activity in S1 hindlimb with general anesthetic demonstrates that this effect can be blocked, as well as highlights the importance of investigating brain activity in awake and behaving rodents.

Anatomical and functional enhancements of the insula after loss of large primary somatosensory fibers.

Brain changes associated with the loss of a sensory modality such as vision and audition have previously been reported. Here, we examined the effect of loss of discriminative touch and proprioception on cortical thickness and functional connectivity. We performed structural magnetic resonance imaging and resting-state functional magnetic resonance imaging scans on a 60-year-old female who at age 31 suffered a selective loss of large-diameter myelinated primary afferents and, therefore, relies mainly on her intact thin-fiber senses (temperature, pain, itch, and C-fiber touch) and vision to negotiate her environment. The patient showed widespread cortical thinning compared with 12 age-matched female controls. In contrast, her right anterior insula was significantly thick. Seed-based resting-state analysis revealed that her right anterior insula had increased connectivity to bilateral posterior insula. A separate independent component analysis revealed the increased connectivity between the insula and visual cortex in the patient. As the insula is an important processing area for temperature and C-fiber tactile information, the increased intrainsular and insular-visual functional connectivity could be related to the patient's use of C-fiber (gentle) touch and temperature information in conjunction with visual information to navigate her environment. We, thus, demonstrated plasticity in networks involving the insular cortex following denervation of large-diameter somatosensory afferents.

International Association for the Study of Pain publications over the 50-year span.

ABSTRACT: The International Association for the Study of Pain (IASP) has a 50-year history of publishing educational and research materials, ranging from traditional print format books, journals, and other informational formats to online and electronic formats. Here we provide a historical overview of IASP publications and reflections from the perspective of 5 former or current Editors-in-Chief.

Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function.

Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n = 18) and 6 months after (spine surgery or facet joint injections; n = 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities-specifically in the left DLPFC-are reversible, suggesting that treating chronic pain can restore normal brain function in humans.

The ventral striatum is implicated in the analgesic effect of mood changes.

BACKGROUND: The ventral striatum, particularly the nucleus accumbens, is commonly associated with the processing of reward and positive stimuli, positive affect as well as antinociceptive processes. OBJECTIVES: The present study examined whether the ventral striatum is implicated in analgesia resulting from positive mood change induced by pleasant odours. METHODS: Functional magnetic resonance imaging studies were conducted in healthy individuals receiving painful heat stimuli in the presence of pleasant or unpleasant odours, which were used to induce positive and negative mood states. Ventral striatum activity was examined in the two mood states. RESULTS: For most subjects, pleasant odours improved mood and reduced pain unpleasantness perception relative to unpleasant odours. In the pleasant odour condition, the maximum activation of both the left and right ventral striatum was positively correlated with the amount of pain reduction. Furthermore, the left and right ventral striatum activations positively covaried with one another, and the right ventral striatum activation positively correlated with that in the periaqueductal grey matter. Both ventral striatum activations negatively covaried with the activation of the right mediodorsal thalamus, left dorsal anterior cingulate cortex, left medial prefrontal cortex and right ventrolateral prefrontal cortex. CONCLUSIONS: Because both the mediodorsal thalamus and anterior cingulate are involved in pain affect perception, and activation within the prefrontal areas and periaqueductal grey matter were previously shown to correlate with mood-related pain modulation, it is concluded that the ventral striatum is likely implicated in the analgesic effect of positive mood changes induced by pleasant odours on pain unpleasantness.

Biochemical and behavioral effects of decreasing dietary linoleic acid and increasing eicosapentaenoic acid and docosahexaenoic acid in a rat chronic monoarthrits model.

Clinical studies have demonstrated that decreasing linoleic acid (LA) while increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in diets evokes an analgesic effect in headache sufferers. We utilized a rat chronic monoarthritis model to determine if these analgesic effects can be reproduced in rats and to and further probe potential analgesic mechanisms. We fed 8 rats a control diet (with fatty acid levels similar to standard US diets) and 8 rats a low LA diet with added EPA and DHA (H3L6 diet) and after 10 weeks, performed a unilateral intraarticular injection of Complete's Freund Adjuvant (CFA). We evaluated thermal and mechanical sensitivity as well as hind paw weight bearing prior to and at 4 and 20 days post CFA injection. At 28 days post CFA injection rats were euthanized and tissue collected. H3L6 diet fed rats had higher concentrations of EPA and DHA, as well as higher concentrations of oxidized lipids derived from these fatty acids, in hind paw and plasma, compared to control fed rats. LA and oxidized LA metabolites were lower in the plasma and hind paw of H3L6 compared to control fed rats. Diet did not affect thermal or mechanical sensitivity, nor did it affect hind paw weight bearing. In conclusion, the H3L6 diet evoked biochemical changes in rats but did not impact pain related behavioral measures in this chronic monoarthritis model.

Regional gray matter density changes in brains of patients with irritable bowel syndrome.

BACKGROUND & AIMS: Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous. METHODS: We used magnetic resonance imaging-based techniques, voxel-based morphometry, and cortical thickness analysis to examine brain anatomical differences in a relatively large, tightly screened sample of IBS patients (n = 55); we compared data with that from healthy persons (controls; n = 48). RESULTS: IBS was associated with decreased gray matter density (GMD) in widespread areas of the brain, including medial prefrontal and ventrolateral prefrontal cortex, posterior parietal cortex, ventral striatum, and thalamus. Compared with controls, we observed increased GMD in patients with IBS in the pregenual anterior cingulate cortex and the orbitofrontal cortex, as well as trends in the posterior insula/secondary somatosensory cortex, (para)hippocampus, and left dorsolateral prefrontal cortex. In accounting for anxiety and depression, we found that several of the regions involved in affective processing no longer differed between patients with IBS and controls, whereas the differences in prefrontal and posterior parietal cortices remained. The areas of decreased GMD associated with IBS were largely consistent across clinical subgroups, based on predominant bowel habit and pain predominance of symptoms. No overall or regional differences were observed in cortical thickness between patients with IBS and controls. CONCLUSIONS: Changes in density of gray matter among regions involved in cognitive/evaluative functions are specifically observed in patients with IBS, whereas changes in other areas of the brain can be explained by levels of anxiety and depression.

Neural effects of placebo analgesia in fibromyalgia patients and healthy individuals.

ABSTRACT: Placebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the neurologic pain signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opioidergic prefrontal modulatory networks.

Pleasant Deep Pressure: Expanding the Social Touch Hypothesis.

Neuroscientific research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressure-driven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics.

Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aß fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aß afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection.

Mood influences supraspinal pain processing separately from attention.

Studies show that inducing a positive mood or diverting attention from pain decreases pain perception. Nevertheless, induction manipulations, such as viewing interesting movies or performing mathematical tasks, often influence both emotional and attentional states. Imaging studies have examined the neural basis of psychological pain modulation, but none has explicitly separated the effects of emotion and attention. Using odors to modulate mood and shift attention from pain, we previously showed that the perceptual consequences of changing mood differed from those of altering attention, with mood primarily altering pain unpleasantness and attention preferentially altering pain intensity. These findings suggest that brain circuits involved in pain modulation provoked by mood or attention are partially separable. Here we used functional magnetic resonance imaging to directly compare the neurocircuitry involved in mood- and attention-related pain modulation. We manipulated independently mood state and attention direction, using tasks involving heat pain and pleasant and unpleasant odors. Pleasant odors, independent of attentional focus, induced positive mood changes and decreased pain unpleasantness and pain-related activity within the anterior cingulate (ACC), medial thalamus, and primary and secondary somatosensory cortices. The effects of attentional state were less robust, with only the activity in anterior insular cortex (aIC) showing possible attentional modulation. Lateral inferior frontal cortex [LinfF; Brodmann's area (BA) 45/47] activity correlated with mood-related modulation, whereas superior posterior parietal (SPP; BA7) and entorhinal activity correlated with attention-related modulation. ACC activity covaried with LinfF and periacqueductal gray activity, whereas aIC activity covaried with SPP activity. These findings suggest that separate neuromodulatory circuits underlie emotional and attentional modulation of pain.

The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response.

The anticipation of clinical benefit, a crucial component of placebo analgesia, has been suggested to be a special case of reward anticipation. Since reward processing is closely linked to the ventral striatum and the neurotransmitter dopamine, we examined the relationships between brain gray matter, placebo analgesic response, and personality traits associated with dopaminergic neurotransmission. We report that dopamine-related traits predict a substantial portion of the pain relief an individual gains from a sham treatment. Voxel-based morphometry of magnetic resonance images shows that the magnitude of placebo analgesia is related to gray matter density (GMD) in several brain regions, including the ventral striatum, insula, and prefrontal cortex. Similarly, GMD in ventral striatum and prefrontal cortex is related to dopamine-related personality traits. Our findings highlight the relationship between placebo and reward and potentially offer ways of identifying subjects who are likely to show large placebo analgesic responses.

Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli.

Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is a rare recessive genetic disorder characterized by severe sensory loss affecting the tactile, thermal and nociceptive modalities. Although heterozygous carriers of nonsense mutations in the HSN2 gene, called with-no-lysine(K)-1 (WNK1), do not develop the disease, historical and experimental evidence suggests that these individuals might perceive somatosensory stimuli differently from others. Using the method-of-limits, we assessed the thresholds for warmth detection, cool detection, heat pain and cold pain in 25 mutation carriers and 35 controls. In group analyses, carriers displayed significantly lower warmth (p<0.001) and cool (p<0.05) difference thresholds, and also tended to report cold pain at higher temperatures (p=0.095), than controls. Similarly, matched-pair analyses showed that carriers are significantly more sensitive to warm stimuli (p<0.01) and cold pain stimuli (p<0.05), and tend to be more sensitive to cool stimuli (p=0.11). Furthermore, the differences between the warmth detection thresholds of the carriers and those of gender- and sex-matched wild types significantly increased with age (r=0.76, p=0.02), and in carriers cool detection thresholds did not increase with age (r=0.27, p=0.24) as expected and observed in controls (r=0.34, p=0.05). This study demonstrates that the carriers of a recessive mutation for HSAN2 display greater sensitivity to innocuous thermal stimuli, as well as for cold pain, suggesting a possible environmental adaptive advantage of the heterozygous state.

MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain.

In human conditions, chronic pain is associated with widespread anatomical changes in the brain. Nevertheless, little is known about the time course of these changes or the relationship of anatomical changes to perception and behaviour. In the present study, we use a rat model of neuropathic pain (spared nerve injury, SNI) and 7 T MRI to determine the longitudinal supraspinal changes associated with pain-like and anxiety-like behaviours. SNI rats and sham controls were scanned at seven time points, 1 week before surgery, 2 weeks after, and then once a month for 5 months. At each time point we performed behavioural tests, including thermal and mechanical sensitivity, and tests of locomotion and exploratory behaviour (open field and elevated plus maze). We found that SNI rats had early and sustained thermal and mechanical hyperalgesia, and developed anxiety-like behaviours several months after injury. Compared to sham controls, SNI rats had decreased frontal cortex volumes several months after surgery, coincident with the onset of anxiety-like behaviours. There was also decreased volume in retrosplenial and entorhinal cortices. We also explored areas that correlated with mechanical hyperalgesia and found that increased hyperalgesia was associated with decreased volumes in bilateral S1 hindlimb area, anterior cingulate cortex (ACC, areas 32 and 24), and insula. Overall, our results suggest that long-term neuropathic pain has widespread effects on brain anatomy related to the duration and magnitude of the pain.