Johnson P. Hampson

Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.

Background:Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment. Methods:To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia. Results:The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = −0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo. Conclusions:The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.

Altered Resting State Connectivity of the Insular Cortex in Individuals With Fibromyalgia

UNLABELLED The insular cortex (IC) and cingulate cortex (CC) are critically involved in pain perception. Previously we demonstrated that fibromyalgia (FM) patients have greater connectivity between the insula and default mode network at rest, and that changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain. In this study we more thoroughly evaluated the degree of resting-state connectivity to multiple regions of the IC in individuals with FM and healthy controls. We also investigated the relationship between connectivity, experimental pain, and current clinical chronic pain. Functional connectivity was assessed using resting-state functional magnetic resonance imaging in 18 FM patients and 18 age- and sex-matched healthy controls using predefined seed regions in the anterior, middle, and posterior IC. FM patients exhibited greater connectivity between 1) right mid IC and right mid/posterior CC and right mid IC, 2) right posterior IC and left CC, and 3) right anterior IC and left superior temporal gyrus. Healthy controls displayed greater connectivity between left anterior IC and bilateral medial frontal gyrus/anterior cingulate cortex; and left posterior IC and right superior frontal gyrus. Within the FM group, greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds. PERSPECTIVE These data provide further support for altered resting-state connectivity between the IC and other brain regions known to participate in pain perception/modulation, which may play a pathogenic role in conditions such as FM. We speculate that altered IC connectivity is associated with the experience of chronic pain in individuals with FM.

Augmented central pain processing in vulvodynia

UNLABELLED Vulvodynia (VVD) is a chronic pain disorder wherein women display sensitivity to evoked stimuli at the vulva and/or spontaneous vulvar pain. Our previous work suggests generalized hyperalgesia in this population; however, little is known about central neurobiological factors that may influence pain in VVD. Here we investigated local (vulvar) and remote (thumb) pressure-evoked pain processing in 24 VVD patients compared to 13 age-matched, pain-free healthy controls (HCs). As a positive control we also examined thumb pressure pain in 24 fibromyalgia patients. The VVD and fibromyalgia patients displayed overlapping insular brain activations that were greater than HCs in response to thumb stimulation (P < .005 corrected). Compared to HCs, VVD participants displayed greater levels of activation during thumb stimulation within the insula, dorsal midcingulate, posterior cingulate, and thalamus (P < .005 corrected). Significant differences between VVD subgroups (primary versus secondary and provoked versus unprovoked) were seen within the posterior cingulate with thumb stimulation and within the precuneus region with vulvar stimulation (provoked versus unprovoked only). The augmented brain activation in VVD patients in response to a stimulus remote from the vulva suggests central neural pathology in this disorder. Moreover, differing central activity between VVD subgroups suggests heterogeneous pathologies within this diagnosis. PERSPECTIVE The presence of augmented brain responses to pressure stimuli remote from the vulva was observed in vulvodynia patients. These findings may guide treatment decisions for better response, as brain mechanisms may be a factor in some VVD patients.

Resting state connectivity correlates with drug and placebo response in fibromyalgia patients

Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response. We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition. 15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex. This study indicates that ACC–IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response.

Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study.

Abstract Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P < 0.001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.

Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease

UNLABELLED Sickle cell disease (SCD) is a hemoglobinopathy that affects more than 100,000 individuals in the United States. The disease is characterized by the presence of sickle hemoglobin and recurrent episodes of pain. Some individuals with SCD experience frequent hospitalizations and a high burden of pain. The role of central mechanisms in SCD pain has not been explored. Twenty-five adolescents and young adults with SCD underwent functional magnetic resonance imaging. Participants were stratified into groups with high pain or low pain based on the number of hospitalizations for pain in the preceding 12 months. Resting state functional connectivity was analyzed using seed-based and dual regression independent component analysis. Intrinsic brain connectivity was compared between the high pain and low pain groups, and association with fetal hemoglobin, a known modifier of SCD, was explored. Patients in the high pain group displayed an excess of pronociceptive connectivity such as between anterior cingulate and default mode network structures, such as the precuneus, whereas patients in the low pain group showed more connectivity to antinociceptive structures such as the perigenual and subgenual cingulate. Although a similar proportion of patients in both groups reported that they were on hydroxyurea, the fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to antinociceptive structures. These findings support the role of central mechanisms in SCD pain. Intrinsic brain connectivity should be explored as a complementary and objective outcome measure in SCD pain research. PERSPECTIVE Altered connectivity patterns associated with high pain experience in patients with sickle cell disease suggest a possible role of central mechanisms in sickle cell pain. Resting state brain connectivity studies should be explored as an effective methodology to investigate pain in SCD.

Altered resting brain connectivity in persistent cancer related fatigue.

There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = −0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As the DMN is a network involved in self-referential thinking we speculate that enhanced connectivity between the DMN and the frontal gyrus may be related to mental fatigue and poor sleep quality. In contrast, enhanced connectivity between the DMN and regions in the subgenual cingulate and brainstem may serve a protective function in the non-fatigued group.

Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula.

Abstract Pain can be elicited through all mammalian sensory pathways yet cross-modal sensory integration, and its relationship to clinical pain, is largely unexplored. Centralized chronic pain conditions such as fibromyalgia are often associated with symptoms of multisensory hypersensitivity. In this study, female patients with fibromyalgia demonstrated cross-modal hypersensitivity to visual and pressure stimuli compared with age- and sex-matched healthy controls. Functional magnetic resonance imaging revealed that insular activity evoked by an aversive level of visual stimulation was associated with the intensity of fibromyalgia pain. Moreover, attenuation of this insular activity by the analgesic pregabalin was accompanied by concomitant reductions in clinical pain. A multivariate classification method using support vector machines (SVM) applied to visual-evoked brain activity distinguished patients with fibromyalgia from healthy controls with 82% accuracy. A separate SVM classification of treatment effects on visual-evoked activity reliably identified when patients were administered pregabalin as compared with placebo. Both SVM analyses identified significant weights within the insular cortex during aversive visual stimulation. These data suggest that abnormal integration of multisensory and pain pathways within the insula may represent a pathophysiological mechanism in some chronic pain conditions and that insular response to aversive visual stimulation may have utility as a marker for analgesic drug development.

Altered fMRI resting-state connectivity in individuals with fibromyalgia on acute pain stimulation

Fibromyalgia is a chronic widespread pain condition, with patients commonly reporting other symptoms such as sleep difficulties, memory complaints and fatigue. The use of magnetic resonance imaging (MRI) in fibromyalgia has allowed for the detection of neural abnormalities, with alterations in brain activation elicited by experimental pain and alterations in resting state connectivity related to clinical pain.

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (mapp) network study

Abstract Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.