Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape Task

Well-established methods are available to measure thermal and mechanical sensitivity in awake behaving rats. However, they require experimenter manipulations and tend to emphasize reflexive behaviors. Here we introduce a new behavioral test, with which we examine thermal sensitivity of rats with neuropathic injury. We contrast thermal hyperalgesia between spared nerve injury and chronic constriction injury rats. This device is a fully automated thermal sensitivity assessment tool designed to emphasize integrated learned responses to thermal painful and non-painful stimuli that are applied dynamically to a surface on which the animal is standing. It documents escape behavior in awake, unrestrained animals to innocuous and noxious heating of the floor where the animal is located. Animals learn to minimize pain by escaping to the opposite non-heated side; escape latency is recorded. On this device, thermal stimulus-response curves showed > 6°C leftward shift in both groups of neuropathic rats. In contrast, when these animals were tested on hotplate the stimulus-response shift was < 2°C. Spared nerve injury rats showed even less evidence for thermal hyperalgesia when thermal sensitivity was tested by measuring paw withdrawal to infrared heating, plantar test. The implications of test dependent magnitude of thermal hyperalgesia are discussed from the viewpoint of the tests used, as well as the animal models studied. It is argued that the dynamic thermal operant task reveals the relevance of the neuropathic injury associated pain-like behavior in relation to the whole organism

A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis

The effects of an analgesic treatment (lidocaine patches) on brain activity in chronic low back pain (CBP) and in knee osteoarthritis (OA) were investigated using serial fMRI (contrasting fMRI between before and after two weeks of treatment). Prior to treatment brain activity was distinct between the two groups: CBP spontaneous pain was associated mainly with activity in medial prefrontal cortex, while OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. After 5% lidocaine patches were applied to the painful body part for two weeks, CBP patients exhibited a significant decrease in clinical pain measures, while in OA clinical questionnaire based outcomes showed no treatment effect but stimulus evoked pain showed a borderline decrease. The lidocaine treatment resulted in significantly decreased brain activity in both patient groups with distinct brain regions responding in each group, and sub-regions within these areas were correlated with pain ratings specifically for each group (medial prefrontal cortex in CBP and thalamus in OA). We conclude that the two chronic pain conditions involve distinct brain regions, with OA pain engaging many brain regions commonly observed in acute pain. Moreover, lidocaine patch treatment modulates distinct brain circuitry in each condition, yet in OA we observe divergent results with fMRI and with questionnaire based instruments

Brain Morphological Signatures for Chronic Pain

Chronic pain can be understood not only as an altered functional state, but also as a consequence of neuronal plasticity. Here we use in vivo structural MRI to compare global, local, and architectural changes in gray matter properties in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA), relative to healthy controls. We find that different chronic pain types exhibit unique anatomical ‘brain signatures’. Only the CBP group showed altered whole-brain gray matter volume, while regional gray matter density was distinct for each group. Voxel-wise comparison of gray matter density showed that the impact on the extent of chronicity of pain was localized to a common set of regions across all conditions. When gray matter density was examined for large regions approximating Brodmann areas, it exhibited unique large-scale distributed networks for each group. We derived a barcode, summarized by a single index of within-subject co-variation of gray matter density, which enabled classification of individual brains to their conditions with high accuracy. This index also enabled calculating time constants and asymptotic amplitudes for an exponential increase in brain re-organization with pain chronicity, and showed that brain reorganization with pain chronicity was 6 times slower and twice as large in CBP in comparison to CRPS. The results show an exuberance of brain anatomical reorganization peculiar to each condition and as such reflecting the unique maladaptive physiology of different types of chronic pain

Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain,”The

Living with unrelenting pain (chronic pain) is maladaptive and is thought to be associated with physiological and psychological modifications, yet there is a lack of knowledge regarding brain elements involved in such conditions. Here, we identify brain regions involved in spontaneous pain of chronic back pain (CBP) in two separate groups of patients (n ϭ 13 and n ϭ 11), and contrast brain activity between spontaneous pain and thermal pain (CBP and healthy subjects, n ϭ 11 each). Continuous ratings of fluctuations of spontaneous pain during functional magnetic resonance imaging were separated into two components: high sustained pain and increasing pain. Sustained high pain of CBP resulted in increased activity in the medial prefrontal cortex (mPFC; including rostral anterior cingulate). This mPFC activity was strongly related to intensity of CBP, and the region is known to be involved in negative emotions, response conflict, and detection of unfavorable outcomes, especially in relation to the self. In contrast, the increasing phase of CBP transiently activated brain regions commonly observed for acute pain, best exemplified by the insula, which tightly reflected duration of CBP. When spontaneous pain of CBP was contrasted to thermal stimulation, we observe a double-dissociation between mPFC and insula with the former correlating only to intensity of spontaneous pain and the latter correlating only to pain intensity for thermal stimulation. These findings suggest that subjective spontaneous pain of CBP involves specific spatiotemporal neuronal mechanisms, distinct from those observed for acute experimental pain, implicating a salient role for emotional brain concerning the self

Scale-free brain functional networks

Functional magnetic resonance imaging (fMRI) is used to extract {\em functional networks} connecting correlated human brain sites. Analysis of the resulting networks in different tasks shows that: (a) the distribution of functional connections, and the probability of finding a link vs. distance are both scale-free, (b) the characteristic path length is small and comparable with those of equivalent random networks, and (c) the clustering coefficient is orders of magnitude larger than those of equivalent random networks. All these properties, typical of scale-free small world networks, reflect important functional information about brain states.Comment: 4 pages, 5 figures, 2 table

Influence of exercise on pain is associated with resting-state functional connections: A cross-sectional functional brain imaging study

Exercise is associated with lower prevalence and severity of pain, and is widely recommended for pain management. However, the mechanisms the exercise effect on pain remain unclear. In this study, we examined the association of exercise with pain and aimed to identify its neurobiological mediators. We utilized a baseline data of a clinical trial for people with low back pain. Participants reported pain intensity and exercise habit, as well as pain-related psychological and emotional assessments. We also obtained brain imaging data using a resting-state functional MRI and performed mediation analyses to identify brain regions mediating the exercise effect on pain. Forty-five people with low back pain (mean pain intensity = 59.6 and mean duration = 9.9 weeks) were included in this study. Participants with an exercise habit (n = 29) showed significant less pain compared to those without an exercise habit (n = 16). Mediation analysis using resting-state functional connectivity identified the left thalamus, right amygdala, and medial prefrontal cortex as statistical mediators of the exercise effect on pain (indirect effect = −0.460, 95% confidence interval = −0.767 to −0.153). In conclusion, our findings suggest that brain function of the specific regions is probably a neuro-mechanism of exercise alleviating pain

Reproducibility of structural, resting-state BOLD and DTI data between identical scanners.

Increasingly, clinical trials based on brain imaging are adopting multiple sites/centers to increase their subject pool and to expedite the studies, and more longitudinal studies are using multiple imaging methods to assess structural and functional changes. Careful investigation of the test-retest reliability and image quality of inter- or intra- scanner neuroimaging measurements are critical in the design, statistical analysis and interpretation of results. We propose a framework and specific metrics to quantify the reproducibility and image quality for neuroimaging studies (structural, BOLD and Diffusion Tensor Imaging) collected across identical scanners and following a major hardware repair (gradient coil replacement). We achieved consistent measures for the proposed metrics: structural (mean volume in specific regions and stretch factor), functional (temporal Signal-to-Noise ratio), diffusion (mean Fractional Anisotropy and Mean Diffusivity in multiple regions). The proposed frame work of imaging metrics should be used to perform daily quality assurance testing and incorporated into multi-center studies