Publications

2022
Bartolo, N.D., et al., 2022. Radiocaine: An Imaging Marker of Neuropathic Injury. ACS Chem. Neurosci. Publisher's VersionAbstract
Voltage-gated sodium channels (Navs) play a crucial electrical signaling role in neurons. Nav-isoforms present in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While these isoforms, particularly Nav1.7, are implicated in neuropathic pain disorders, changes in the functional state and expression levels of these channels have not been extensively studied in vivo. Radiocaine, a fluorine-18 radiotracer based on the local anesthetic lidocaine, a non-selective Nav blocker, has previously been used for cardiac Nav1.5 imaging using positron-emission tomography (PET). In the present study, we used Radiocaine to visualize changes in neuronal Nav expression after neuropathic injury. In rats that underwent unilateral spinal nerve ligation, PET/MR imaging demonstrated significantly higher uptake of Radiocaine into the injured sciatic nerve, as compared to the uninjured sciatic nerve, for up to 32 days post-surgery. Radiocaine, due to its high translational potential, may serve as a novel diagnostic tool for neuropathic pain conditions using PET imaging.
acschemneuro.2c00717_2.pdf
Zhu, Y., et al., 2022. Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery: Influence of Aromatase Inhibitor Therapy. Clin J Pain. , 38 (12) , pp. 721-729. Publisher's VersionAbstract

Objectives: Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy.

Methods: Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and nonsurgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses.

Results: Clinical pain and pain sensitivity were comparable between AI (n=49) and no-AI (n=106) groups preoperatively. After adjusting for body mass index, AI therapy was associated with a greater increase in the number of painful nonsurgical body sites (significant time by treatment interaction, P =0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group.

Conclusions: AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of aromatase inhibitor-associated musculoskeletal syndrome worthy of future investigation.

increased_clinical_pain_locations_and_pain.3.pdf
Turkheimer, F.E., et al., 2022. The art of pain: A quantitative color analysis of the self-portraits of Frida Kahlo. Front Hum Neurosci , 16 , pp. 1000656.Abstract
Frida Kahlo (1907-1954) was a Mexican artist who is remembered for her self-portraits, pain and passion, and bold, vibrant colors. This work aims to use her life story and her artistic production in a longitudinal study to examine with quantitative tools the effects of physical and emotional pain (rage) on artistic expression. Kahlo suffered from polio as a child, was involved in a bus accident as a teenager where she suffered multiple fractures of her spine and had 30 operations throughout her lifetime. She also had a tempestuous relationship with her painter husband, Diego Rivera. Her physical and personal troubles however became the texture of her vivid visual vocabulary-usually expressed through the depiction of Mexican and indigenous culture or the female experience and form. We applied color analysis to a series of Frida's self-portraits and revealed a very strong association of physical pain and emotional rage with low wavelength colors (red and yellow), indicating that the expression of her ailments was, consciously or not, achieved by increasing the perceived luminance of the canvas. Further quantitative analysis that used the fractal dimension identified "The broken column" as the portrait with higher compositional complexity, which matches previous critical acclaim of this portrait as the climax of her art. These results confirm the ability of color analysis to extract emotional and cognitive features from artistic work. We suggest that these tools could be used as markers to support artistic and creative interventions in mental health.
paper_.pdf
Zhu, Y., et al., 2022. Increased Clinical Pain Locations and Pain Sensitivity in Women after Breast Cancer Surgery: Influence of Aromatase Inhibitor Therapy. Clin J Pain.Abstract
OBJECTIVES: Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome, AIMSS). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy. METHODS: Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and non-surgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses. RESULTS: Clinical pain and pain sensitivity were comparable between AI(n=49) and no-AI(n=106) groups preoperatively. After adjusting for BMI, AI therapy was associated with a greater increase in number of painful non-surgical body sites (significant time by treatment interaction, P=0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group. CONCLUSION: AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of AIMSS worthy of future investigation.
paper.pdf
Barry, R.L., et al., 2022. Selective atrophy of the cervical enlargement in whole spinal cord MRI of amyotrophic lateral sclerosis. Neuroimage Clin , 36 , pp. 103199.Abstract
Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disorder affecting motor neurons in the spinal cord and brain. Studies have reported on atrophy within segments of the cervical cord, but we are not aware of previous investigations of the whole spinal cord. Herein we present our findings from a 3T MRI study involving 32 subjects (15 ALS participants and 17 healthy controls) characterizing cross-sectional area along the entire cord. We report atrophy of the cervical enlargement in ALS participants, but no evidence of atrophy of the thoracolumbar enlargement. These results suggest that MR-based analyses of the cervical cord may be sufficient for in vivo investigations of spinal cord atrophy in ALS, and that atrophy of the cervical enlargement (C4-C7) is a potential imaging marker for quantifying lower motor neuron degradation.
Pike, C.K., et al., 2022. Study protocol for a phase II, double-blind, randomised controlled trial of cannabidiol (CBD) compared with placebo for reduction of brain neuroinflammation in adults with chronic low back pain. BMJ Open , 12 (9) , pp. e063613.Abstract
INTRODUCTION: Chronic pain is a debilitating medical problem that is difficult to treat. Neuroinflammatory pathways have emerged as a potential therapeutic target, as preclinical studies have demonstrated that glial cells and neuroglial interactions play a role in the establishment and maintenance of pain. Recently, we used positron emission tomography (PET) to demonstrate increased levels of 18 kDa translocator protein (TSPO) binding, a marker of glial activation, in patients with chronic low back pain (cLBP). Cannabidiol (CBD) is a glial inhibitor in animal models, but studies have not assessed whether CBD reduces neuroinflammation in humans. The principal aim of this trial is to evaluate whether CBD, compared with placebo, affects neuroinflammation, as measured by TSPO levels. METHODS AND ANALYSIS: This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Eighty adults (aged 18-75) with cLBP for >6 months will be randomised to either an FDA-approved CBD medication (Epidiolex) or matching placebo for 4 weeks using a dose-escalation design. All participants will undergo integrated PET/MRI at baseline and after 4 weeks of treatment to evaluate neuroinflammation using [11C]PBR28, a second-generation radioligand for TSPO. Our primary hypothesis is that participants randomised to CBD will demonstrate larger reductions in thalamic [11C]PBR28 signal compared with those receiving placebo. We will also assess the effect of CBD on (1) [11C]PBR28 signal from limbic regions, which our prior work has linked to depressive symptoms and (2) striatal activation in response to a reward task. Additionally, we will evaluate self-report measures of cLBP intensity and bothersomeness, depression and quality of life at baseline and 4 weeks. ETHICS AND DISSEMINATION: This protocol is approved by the Massachusetts General Brigham Human Research Committee (protocol number: 2021P002617) and FDA (IND number: 143861) and registered with ClinicalTrials.gov. Results will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05066308; ClinicalTrials.gov.
cbd_paper.pdf
Schaechter, J.D., et al., 2022. Disruptions in Structural and Functional Connectivity Relate to Poststroke Fatigue. Brain Connect.Abstract
Introduction: Poststroke fatigue (PSF) is a disabling condition with unclear etiology. The brain lesion is thought to be an important causal factor in PSF, although focal lesion characteristics such as size and location have not proven to be predictive. Given that the stroke lesion results not only in focal tissue death but also in widespread changes in brain networks that are structurally and functionally connected to damaged tissue, we hypothesized that PSF relates to disruptions in structural and functional connectivity. Materials and Methods: Twelve patients who incurred an ischemic stroke in the middle cerebral artery (MCA) territory 1-3 years prior, and currently experiencing a range of fatigue severity, were enrolled. The patients underwent structural and resting-state functional magnetic resonance imaging (MRI). The structural MRI data were used to measure structural disconnection of gray matter resulting from lesion to white matter pathways. The functional MRI data were used to measure network functional connectivity. Results: The patients showed structural disconnection in varying cortical and subcortical regions. Fatigue severity correlated significantly with structural disconnection of several frontal cortex regions in the ipsilesional (IL) and contralesional hemispheres. Fatigue-related structural disconnection was most severe in the IL rostral middle frontal cortex. Greater structural disconnection of a subset of fatigue-related frontal cortex regions, including the IL rostral middle frontal cortex, trended toward correlating significantly with greater loss in functional connectivity. Among identified fatigue-related frontal cortex regions, only the IL rostral middle frontal cortex showed loss in functional connectivity correlating significantly with fatigue severity. Conclusion: Our results provide evidence that loss in structural and functional connectivity of bihemispheric frontal cortex regions plays a role in PSF after MCA stroke, with connectivity disruptions of the IL rostral middle frontal cortex having a central role. Impact statement Poststroke fatigue (PSF) is a common disabling condition with unclear etiology. We hypothesized that PSF relates to disruptions in structural and functional connectivity secondary to the focal lesion. Using structural and resting-state functional connectivity magnetic resonance imaging (MRI) in patients with chronic middle cerebral artery (MCA) stroke, we found frontal cortex regions in the ipsilesional (IL) and contralesional hemispheres with greater structural disconnection correlating with greater fatigue. Among these fatigue-related cortices, the IL rostral middle frontal cortex showed loss in functional connectivity correlating with fatigue. These findings suggest that disruptions in structural and functional connectivity play a role in PSF after MCA stroke.
judith_schaechter_paper.pdf
Carriere, J.S., et al., 2022. The Influence of Expectancies on Pain and Function Over Time After Total Knee Arthroplasty. Pain Med , 23 (10) , pp. 1767-1776.Abstract
OBJECTIVE: Expectancies have a well-documented influence on the experience of pain, responses to treatment, and postsurgical outcomes. In individuals with osteoarthritis, several studies have shown that expectations predict increased pain and disability after total knee replacement surgery. Despite the growing recognition of the importance of expectancies in clinical settings, few studies have examined the influence of expectancies throughout postsurgical recovery trajectories. The objective of the present study was to examine the role of presurgical expectancies on pain and function at 6-week, 6-month, and 1-year follow-ups after total knee arthroplasty. DESIGN AND PARTICIPANTS: Data were collected from patients scheduled for total knee arthroplasty 1 week before surgery and then at 6 weeks, 6 months, and 1 year after surgery. Correlational and multivariable regression analyses examined the influence of expectancies on patients' perceptions of pain reduction and functional improvement at each time point. Analyses controlled for age, sex, body mass index, presurgical pain intensity and function, pain catastrophizing, anxiety, and depression. RESULTS: Results revealed that expectancies significantly predicted pain reduction and functional improvement at 1-year follow-up. However, expectancies did not predict outcomes at the 6-week and 6-month follow-ups. Catastrophizing and depressive symptoms emerged as short-term predictors of postsurgical functional limitations at 6-week and 6-month follow-ups, respectively. CONCLUSIONS: The results suggest that targeting high levels of catastrophizing and depressive symptoms could optimize short-term recovery after total knee arthroplasty. However, the results demonstrate that targeting presurgical negative expectancies could prevent prolonged recovery trajectories, characterized by pain and loss of function up to 1 year after total knee arthroplasty.
1-s2.0-s1526590019306686-main.pdf
Ibinson, J.W., et al., 2022. Comparison of test-retest reliability of BOLD and pCASL fMRI in a two-center study. BMC Med Imaging , 22 (1) , pp. 62.Abstract
BACKGROUND: The establishment of test-retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BOLD) fMRI data acquired across two different scanners in a sample of healthy adults. While single site/single scanner studies have shown acceptable repeatability, TRR of both in a practical multisite study occurring in two facilities spread out across the country with weeks to months between scans is critically needed. METHODS: Ten subjects were imaged with similar 3 T MRI scanners at the University of Pittsburgh and Massachusetts General Hospital. Finger-tapping and Resting-state data were acquired for both techniques. Analysis of the resting state data for functional connectivity was performed with the Functional Connectivity Toolbox, while analysis of the finger tapping data was accomplished with FSL. pCASL Blood flow data was generated using AST Toolbox. Activated areas and networks were identified via pre-defined atlases and dual-regression techniques. Analysis for TRR was conducted by comparing pCASL and BOLD images in terms of Intraclass correlation coefficients, Dice Similarity Coefficients, and repeated measures ANOVA. RESULTS: Both BOLD and pCASL scans showed strong activation and correlation between the two locations for the finger tapping tasks. Functional connectivity analyses identified elements of the default mode network in all resting scans at both locations. Multivariate repeated measures ANOVA showed significant variability between subjects, but no significant variability for location. Global CBF was very similar between the two scanning locations, and repeated measures ANOVA showed no significant differences between the two scanning locations. CONCLUSIONS: The results of this study show that when similar scanner hardware and software is coupled with identical data analysis protocols, consistent and reproducible functional brain images can be acquired across sites. The variability seen in the activation maps is greater for pCASL versus BOLD images, as expected, however groups maps are remarkably similar despite the low number of subjects. This demonstrates that multi-site fMRI studies of task-based and resting state brain activity is feasible.
s12880-022-00791-9-2.pdf
Brusaferri, L., et al., 2022. The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic. Brain Behav Immun , 102 , pp. 89-97.Abstract
While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.
the_pandemic_brain_neuroinflammation_in_non-infected_individuals_during_the_covid-19_pandemic.pdf
Sari, H., et al., 2022. Multimodal Investigation of Neuroinflammation in Aviremic Patients With HIV on Antiretroviral Therapy and HIV Elite Controllers. Neurol Neuroimmunol Neuroinflamm , 9 (2).Abstract
BACKGROUND AND OBJECTIVES: The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radioligand; (2) the relationship between neuroinflammation and cognitive function in aviremic PWH; and (3) the relationship between [11C]-PBR28 signal and quantitative MRI (qMRI) measures of brain tissue integrity such as T1 and T2 relaxation times (rts). METHODS: [11C]-PBR28 (standard uptake value ratio, SUVR) images were generated in 36 participants (14 PWH, 6 ECs, and 16 healthy controls) using a statistically defined pseudoreference region. Group comparisons of [11C]-PBR28 SUVR were performed using region of interest-based and voxelwise analyses. The relationship between inflammation, qMRI measures, and cognitive function was studied. RESULTS: In region of interest analyses, ECs exhibited significantly lower [11C]-PBR28 signal in the thalamus, putamen, superior temporal gyrus, prefrontal cortex, and cerebellum compared with the PWH. In voxelwise analyses, differences were observed in the thalamus, precuneus cortex, inferior temporal gyrus, occipital cortex, cerebellum, and white matter (WM). [11C]-PBR28 signal in the WM and superior temporal gyrus was related to processing speed and selective attention in PWH. In a subset of PWH (n = 12), [11C]-PBR28 signal in the thalamus and WM regions was related to a decrease in T2 rt and to an increase in T1 rt suggesting a colocalization of increased glial metabolism, decrease in microstructural integrity, and iron accumulation. DISCUSSION: This study casts a new light onto the role of neuroinflammation and related microstructural alterations of HIV infection in the CNS and shows that ECs suppress neuroinflammation more effectively than PWH on therapy.
neurimminfl2021039288.pdf
Cheng, J.C., et al., 2022. Dynamic Functional Brain Connectivity Underlying Temporal Summation of Pain in Fibromyalgia. Arthritis Rheumatol , 74 (4) , pp. 700-710.Abstract
OBJECTIVE: Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e., summary) measures to examine the functional magnetic resonance imaging (fMRI) correlates of TSP in FM. However, functional brain activity rapidly and dynamically reorganizes over time, and, similarly, TSP is a temporally evolving process. This study was undertaken to demonstrate how a complete understanding of the neural circuitry supporting TSP in FM thus requires a dynamic measure that evolves over time. METHODS: We utilized novel methods for analyzing dynamic functional brain connectivity in patients with FM in order to examine how TSP-associated fluctuations are linked to the dynamic functional reconfiguration of the brain. In 84 FM patients and age- and sex-matched healthy controls, we collected high-temporal-resolution fMRI data during a resting state and during a state in which sustained cuff pressure pain was applied to the leg. RESULTS: FM patients experienced greater TSP than healthy controls (mean ± SD TSP score 17.93 ± 19.24 in FM patients versus 9.47 ± 14.06 in healthy controls; P = 0.028), but TSP scores varied substantially between patients. In the brain, the presence versus absence of TSP in patients with FM was marked by more sustained enmeshment between sensorimotor and salience networks during the pain period. Furthermore, dynamic enmeshment was noted solely in FM patients with high TSP, as interactions with all other brain networks were dampened during the pain period. CONCLUSION: This study elucidates the dynamic brain processes underlying facilitated central pain processing in FM. Our findings will enable future investigation of dynamic symptoms in FM.
arthritis_rheumatology_-_2021_-_cheng_-_dynamic_functional_brain_connectivity_underlying_temporal_summation_of_pain_in.pdf
Alshelh, Z., et al., 2022. Neuroimmune signatures in chronic low back pain subtypes. Brain , 145 (3) , pp. 1098-1110.Abstract
We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct 'neuroinflammatory signatures'. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. 'radicular' versus 'axial' back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of 'fibromyalgianess' (i.e. the degree of pain centralization, or 'nociplastic pain'). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of 'neuroinflammatory signatures' that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.
awab336_6.21.22.pdf
Martins, D., et al., 2022. Transcriptional and cellular signatures of cortical morphometric remodelling in chronic pain. Pain , 163 (6) , pp. e759-e773.Abstract
ABSTRACT: Chronic pain is a highly debilitating and difficult to treat condition, which affects the structure of the brain. Although the development of chronic pain is moderately heritable, how disease-related alterations at the microscopic genetic architecture drive macroscopic brain abnormalities is currently largely unknown. Here, we examined alterations in morphometric similarity (MS) and applied an integrative imaging transcriptomics approach to identify transcriptional and cellular correlates of these MS changes, in 3 independent small cohorts of patients with distinct chronic pain syndromes (knee osteoarthritis, low back pain, and fibromyalgia) and age-matched and sex-matched pain-free controls. We uncover a novel pattern of cortical MS remodelling involving mostly small-to-medium MS increases in the insula and limbic cortex (none of these changes survived stringent false discovery rate correction for the number of regions tested). This pattern of changes is different from that observed in patients with major depression and cuts across the boundaries of specific pain syndromes. By leveraging transcriptomic data from Allen Human Brain Atlas, we show that cortical MS remodelling in chronic pain spatially correlates with the brain-wide expression of genes related to pain and broadly involved in the glial immune response and neuronal plasticity. Our findings bridge levels to connect genes, cell classes, and biological pathways to in vivo imaging correlates of chronic pain. Although correlational, our data suggest that cortical remodelling in chronic pain might be shaped by multiple elements of the cellular architecture of the brain and identifies several pathways that could be prioritized in future genetic association or drug development studies.
transcriptional_and_cellular_signatures_of_cortical_morphometric_remodelling_in_chronic_pain.pdf
2021
Paschali, M., et al., 2021. The "self" in pain: high levels of schema-enmeshment worsen fibromyalgia impact. BMC Musculoskelet Disord , 22 (1) , pp. 871.Abstract
OBJECTIVE: Chronic pain can have detrimental effects on quality of life and a profound impact on one's identity. The Pictorial Representation of Illness- and Self-Measure (PRISM), is a visual tool designed to measure the self-illness separation (SIS) that represents the degree of schema-enmeshment (i.e., the degree to which the self-schema and the illness-schema come to overlap). Our aim was to investigate the relationship between schema-enmeshment and pain-related outcomes in patients with fibromyalgia. METHODS: In this cross-sectional study, 114 patients with fibromyalgia completed self-report assessments of pain catastrophizing, pain severity and interference, impact of symptoms, anxiety, and depression. SIS was assessed using an iPad version of PRISM. Mediation analyses evaluated the mediating role of schema-enmeshment on the association between pain catastrophizing and fibromyalgia impact. RESULTS: A higher degree of schema-enmeshment was associated with greater pain catastrophizing, pain severity and interference, impact of symptoms, and depression. Moreover, a mediation analysis revealed that schema-enmeshment significantly mediated the association between pain catastrophizing and fibromyalgia impact (p < 0.001). CONCLUSIONS: Our results indicate that schema-enmeshment is associated with greater intrusiveness of chronic pain on everyday life, thereby posing significant limitations on the emotional and physical well-being of fibromyalgia patients. Schema-enmeshment also appears to partly account for the deleterious effect of pain catastrophizing on disease impact. The PRISM is a simple tool that may uniquely capture the extent to which chronic pain and illness infiltrates and affects one's self-concept.
12891_2021_article_4740.pdf
Cheng, C.-H., et al., 2021. Association of the tissue microstructural diffusivity and translocator protein PET in Gulf War Illness. Brain Behav Immun Health , 18 , pp. 100364.Abstract
About a third of all United States veterans who served in the 1991 Gulf War (GW) report a range of chronic health symptoms including fatigue, neurocognitive symptoms, and musculoskeletal pain. There is growing evidence supporting the detrimental effects of maladaptive neuroimmune reactions in this multi-symptom illness. Indeed, recent studies using positron emission tomography (PET) using the radioligand [11C]PBR28, which binds the neuroinflammation marker 18 ​kDa translocator protein (TSPO), and diffusion magnetic resonance imaging (dMRI) have independently identified the anterior cingulate (ACC) and midcingulate cortices (MCC) as key regions for differentiating GWI veterans from healthy controls (HC). Here, we used integrated (i.e., simultaneous) PET/MRI imaging techniques, paired with dMRI processing methods (neurite density imaging, NDI, and free-water diffusion tensor model to single-shell high-order dMRI), to directly evaluate the relationship between ACC and MCC microstructural tissue parameters, TSPO signal and clinical parameters in the same cohorts of 10 GWI veterans and 19 ​HCs. Within the regions evaluated, TSPO signal elevations were associated with restricted diffusivity in the extracellular compartment, while clinical measures were best explained by neurite density and cellular structure complexity measures. Our study is the first to provide evidence of a relationship between PET and dMRI modalities in GWI and suggests that microstructural changes in the ACC and MCC are correlated to mood symptoms and cognitive performances in GWI veterans.
main_03.pdf
Barowsky, S., et al., 2021. Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain. Front Genet , 12 , pp. 687687.Abstract
Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (r g = 0.299 ± 0.026, p = 9.10 × 10-31), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (βOA → MD = 0.09, SE = 0.02, z-score p-value < 1.02 × 10-5; βMD → OA = 0.19, SE = 0.026, p < 2.67 × 10-13), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (P meta ≤ 5 × 10-8), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted "mechanosensory behavior" genes (GO:0007638; P gene_set = 2.45 × 10-8) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.
fgene-12-687687.pdf
Schaechter, J.D., et al., 2021. A pilot [C]PBR28 PET/MRI study of neuroinflammation and neurodegeneration in chronic stroke patients. Brain Behav Immun Health , 17 , pp. 100336.Abstract
Neuroinflammation occurs in response to acute ischemic stroke, and has been speculated to underlie secondary poststroke pathologies, such as depression, that often develop over time poststroke. However, no study has examined whether neuroinflammation is present in chronic stroke patients (e.g., ​≥ ​1 year poststroke). This study tested whether neuroinflammation is present in chronic stroke patients, and is associated with neurodegeneration, using [11C]PBR28 PET and diffusion MRI. Eight patients with middle cerebral artery (MCA) ischemic stroke incurred 1-3 years prior and 16 healthy controls underwent [11C]PBR28 PET to measure glial activation and diffusion MRI to measure microstructural integrity by mean diffusivity (MD) and fractional anisotropy (FA) using an integrated PET/MRI scanner. Group differences in [11C]PBR28 binding, MD and FA were analyzed voxelwise across the whole brain excluding the infarct zone defined as voxels containing the infarct in any patient. Compared to controls, patients showed elevations in [11C]PBR28 binding in several brain regions outside the infarct zone, including regions with presumed direct neuroanatomical connections to the infarct (e.g., ipsilesional internal capsule and thalamus) and those without known direct connections (e.g., contralesional thalamus and cingulate gyrus). Patients also showed widespread elevations in MD, with a subset of these regions having reduced FA. In patients, MD was more elevated in regions with co-localized elevations in [11C]PBR28 binding than in contralateral regions without elevations in [11C]PBR28 binding. This pilot study supports the presence of extensive glial activation along with widespread loss in microstructural integrity in non-infarcted tissue in a cohort of patients with chronic MCA stroke. The loss in microstructural integrity was greater in regions with co-localized glial activation. It is possible that stroke risk factors (e.g., hypertension) contributed to these tissue changes in patients.
1-s2.0-s2666354621001393-main.pdf
Keating, D., et al., 2021. Boston biorepository, recruitment and integrative network (BBRAIN): A resource for the Gulf War Illness scientific community. Life Sci , 284 , pp. 119903.Abstract
AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. MAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. KEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. SIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.
1-s2.0-s0024320521008900-main.pdf
Sander, C.Y., et al., 2021. [C]PBR28 radiotracer kinetics are not driven by alterations in cerebral blood flow. J Cereb Blood Flow Metab , 41 (11) , pp. 3069-3084.Abstract
The positron emission tomography (PET) radiotracer [11C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [11C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [11C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [11C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [11C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [11C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.
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