14 research outputs found
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Reply to the Letter to the Editor by Dr. Lampman (âWhat is a proper control group in fibromyalgia study?â)
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Neural Correlates of Chronic Low Back Pain Measured by Arterial Spin Labeling
Background
The varying nature of chronic pain (CP) is difficult to correlate to neural activity using typical functional magnetic resonance imaging methods. Arterial spin labeling is a perfusion-based imaging technique allowing the absolute quantification of regional cerebral blood flow, which is a surrogate measure of neuronal activity.
Methods
Subjects with chronic low back and radicular pain and matched healthy normals, undergoing identical procedures, participated in three sessionsâa characterization and training session and two arterial spin labeling sessions. In the first imaging session CP (if any) was exacerbated using clinical maneuvers and in the second session noxious heat was applied to the affected leg dermatome, the intensity of which was matched to the pain intensity level of the CP exacerbations for each back pain subject.
Results
The clinically significant worsening of ongoing CP (â„30%, n=16) was associated with significant regional blood flow increases (6â10 mm/100gr of tissue/min, p<0.01) within brain regions known to activate with experimental pain (somatosensory, prefrontal, and insular cortices) and in other structures observed less frequently in experimental pain studies, such as the superior parietal lobule (part of the dorsal attention network). This effect is specific to changes in ongoing CP as it is observed during worsening CP, but it is not observed after thermal pain application, or in matched, pain-free healthy controls.
Conclusions
Our findings demonstrate the use of arterial spin labeling to investigate the neural processing of CP, and they are a step forward in the quest for objective biomarkers of the chronic pain experience
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The Somatosensory Link in Fibromyalgia: Functional Connectivity of the Primary Somatosensory Cortex Is Altered by Sustained Pain and Is Associated With Clinical/Autonomic Dysfunction
Objective
Fibromyalgia (FM) is a chronic functional pain syndrome characterized by widespread pain, significant pain catastrophizing, sympathovagal dysfunction, and amplified temporal summation for evoked pain. While several studies have found altered resting brain connectivity in FM, studies have not specifically probed the somatosensory system, and its role in both somatic and non-somatic FM symptomatology. Our objective was to evaluate resting primary somatosensory cortex (S1) connectivity, and explore how sustained, evoked deep-tissue pain modulates this connectivity.
Methods
We acquired fMRI and electrocardiography data from FM patients and healthy controls (HC) during rest (REST) and sustained mechanical pressure pain (PAIN) over the lower leg. Functional connectivity associated with different S1 subregions was calculated, while S1leg (leg representation) connectivity was contrast between REST and PAIN, and correlated with clinically-relevant measures in FM.
Results
At REST, FM showed decreased connectivity between multiple ipsilateral and cross-hemispheric S1 subregions, which was correlated with clinical pain severity. PAIN, compared to REST, produced increased S1legconnectivity to bilateral anterior insula in FM, but not in HC. Moreover, in FM, sustained pain-altered S1legconnectivity to anterior insula was correlated with clinical/behavioral pain measures and autonomic responses.
Conclusion
Our study demonstrates that both somatic and non-somatic dysfunction in FM, including clinical pain, pain catastrophizing, autonomic dysfunction, and amplified temporal summation, are all closely linked with the degree to which evoked deep-tissue pain alters S1 connectivity to salience/affective pain processing regions. Additionally, diminished connectivity between S1 subregions at REST in FM may result from ongoing widespread clinical pain
Pseudo-reference regions for glial imaging with (11)C-PBR28:investigation in two clinical cohorts
none14The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. While TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudo-reference approaches can minimize within-group variability, and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing two different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received (11)C-PBR28 PET scans. Occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudo-reference regions by testing for the absence of group differences in Standardized Uptake Value (SUV) and distribution volume (VT) estimated with an arterial input function (AIF). SUV from target regions (cLBP study - thalamus; ALS study - precentral gyrus) was normalized with SUV from candidate pseudo-reference regions to obtain SUVRoccip, SUVRcereb, and SUVRWB The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without AIF (refDVR), and VT Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudo-reference VT or SUV, excepting whole-brain VT, which was higher in cLBP patients than controls. Target VT elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVRoccip and SUVRWB, and by refDVR and blDVR (less reliably by SUVRcereb). In voxelwise analyses, SUVRoccip, but not SUVRcereb, identified regional group differences initially observed with SUVRWB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with VT While important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in (11)C-PBR28 signal as classic kinetic modeling techniques. Occipital cortex may be a suitable pseudo-reference region, at least for the populations evaluated, pending further validation in larger cohorts.noneAlbrecht, Daniel Strakis; Normandin, Marc David; Shcherbinin, Sergey; Wooten, Dustin W; Schwarz, Adam J; Zurcher, Nicole R; Barth, Vanessa N; Guehl, Nicolas J; Johnson-Akeju, Oluwaseun; Atassi, Nazem; Veronese, Mattia; Turkheimer, Federico; Hooker, Jacob M; Loggia, Marco LucianoAlbrecht, Daniel Strakis; Normandin, Marc David; Shcherbinin, Sergey; Wooten, Dustin W; Schwarz, Adam J; Zurcher, Nicole R; Barth, Vanessa N; Guehl, Nicolas J; Johnson-Akeju, Oluwaseun; Atassi, Nazem; Veronese, Mattia; Turkheimer, Federico; Hooker, Jacob M; Loggia, Marco Lucian
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Sustained deep-tissue pain alters functional brain connectivity
Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically-relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, fronto-parietal control and default mode networks; SMN, SLN, DAN, FCN and DMN) was evaluated with functional-connectivity MRI, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable with no significant changes of subjectsâ pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala, was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to inter-individual differences in pain sensitivity
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Phenotype Matters: The Absence of a Positive Association Between Cortical Thinning and Chronic Low Back Pain When Controlling for Salient Clinical Variables
Studies have associated chronic low back pain (cLBP) with grey matter thinning. But these studies have not controlled for important clinical variables (such as a comorbid affective disorder, pain medication, age, or pain phenotype), which may reduce or eliminate these associations. We conducted cortical thickness and voxel-based morphometry (VBM) analyses in 14 cLBP patients with a discogenic component to their pain, not taking opioids or benzodiazepines, and not depressed or anxious. They were age and gender matched to 14 healthy controls (HCs).
An ROI-driven analysis (regions of interest) was conducted, using 18 clusters from a previous arterial spin labeling study demonstrating greater regional cerebral blood flow (rCBF) in these cLBP subjects than the HCs. Cortical thickness and VBM-based gray matter volume measurements were obtained from a structural MRI scan and group contrasts were calculated. MANOVA showed a trend toward cortical thickening in the right paracentral lobule in cLBP subjects (F(1,17)=3.667, p<0.067), and significant thickening in the right rostral middle frontal gyrus (F(1,17)=6.880, p<0.014). These clusters were non-significant after including age as a covariate (p<0.891; p<0.279). A whole-brain cortical thickness and VBM analysis also did not identify significant clusters of thinning or thickening.
Exploratory analyses identified group differences for correlations between age and cortical thickness of the right rostral middle frontal gyrus (cLBP: R=-0.03, p=0.9; HCs: R=-0.81, p<0.001), i.e., HCs demonstrated age-related thinning while cLBP patients did not. Our pilot results suggest that controlling for affect, age, and concurrent medications may reduce or eliminate some of the previously reported structural brain alterations in cLBP
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Default mode network connectivity encodes clinical pain: An arterial spin labeling study
Neuroimaging studies have suggested the presence of alterations in the anatomo-functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroimaging markers for clinical pain have included resting brain connectivity, these cross-sectional studies have not examined sensitivity to within-subject exacerbation of pain. We used the dual regression probabilistic Independent Component Analysis approach to investigate resting-state connectivity on Arterial Spin Labeling (ASL) data. Brain connectivity was compared between patients with chronic low back pain (cLBP) and healthy controls, before and after the performance of maneuvers aimed at exacerbating clinical pain levels in the patients. Our analyses identified multiple resting state networks, including the Default Mode Network (DMN). At baseline, patients demonstrated stronger DMN connectivity to the pregenual anterior cingulate cortex (pgACC), left inferior parietal lobule and right insula (rINS). Patientsâ baseline clinical pain correlated positively with connectivity strength between the DMN and right insula (DMN-rINS). The performance of calibrated physical maneuvers induced changes in pain, which were paralleled by changes in DMN-rINS connectivity. Maneuvers also disrupted the DMN-pgACC connectivity, which at baseline was anti-correlated with pain. Finally, baseline DMN connectivity predicted maneuver-induced changes in both pain and DMN-rINS connectivity. Our results support the use of ASL to evaluate clinical pain, and the use of resting DMN connectivity as a potential neuroimaging biomarker for chronic pain perception
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The Lateral Prefrontal Cortex Mediates the Hyperalgesic Effects of Negative Cognitions in Chronic Pain Patients
While high levels of negative affect and cognitions have been associated in chronic pain conditions with greater pain sensitivity, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation, and that 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing, in fibromyalgia (FM) patients. Using functional Magnetic Resonance Imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex (IPFC). A bootstrapped mediation analysis revealed that pain-anticipatory activity in lateral prefrontal cortex (IPFC) mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of IPFC in the pathophysiology of FM related hyperalgesia, and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well validated measure of negative cognitions and psychological distress.
Perspective
This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions towards pain
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Disentangling linear and nonlinear brain responses to evoked deep tissue pain
Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional MRI, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that regionâs functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least five different, regionally-specific activity profiles in the brain. Linearly increasing (e.g., primary somatosensory/motor cortex, insulae) and intensity-independent (e.g., secondary somatosensory cortex) activation was noted in traditional pain processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (e.g., posterior cingulate cortex), linearly decreasing (e.g., contralateral inferior parietal lobule), and quadratic (U-shaped; e.g., medial prefrontal cortex). The latter observation suggests that: 1) different DMN subregions exhibit functional heterogeneity and 2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities in order to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing
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Disrupted Brain Circuitry for Pain-Related Reward/Punishment in Fibromyalgia
Objective
While patients suffering from fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. In this study we investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain such as anticipation of pain and of pain relief.
Methods
FMRI was performed on 31 FM patients and 14 controls while they received cuff pressure pain stimuli on their leg, calibrated to elicit a pain rating of âŒ50/100. During the scan, subjects also received visual cues informing them of impending pain onset (pain anticipation) and pain offset (relief anticipation).
Results
Patients exhibited less robust activations during both anticipation of pain and anticipation of relief within regions commonly thought to be involved in sensory, affective, cognitive and pain-modulatory processes. In healthy controls, direct searches and region-of-interest analyses in the ventral tegmental area (VTA) revealed a pattern of activity compatible with the encoding of punishment: activation during pain anticipation and pain stimulation, but deactivation during relief anticipation. In FM patients, however, VTA activity during pain and anticipation (of both pain and relief) periods was dramatically reduced or abolished.
Conclusion
FM patients exhibit disrupted brain responses to reward/punishment. The VTA is a source for reward-linked dopaminergic/GABAergic neurotransmission in the brain and our observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM. Reduced reward/punishment signaling in FM may relate to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients