Sex differences in brain modular organization in chronic pain

Fauchon, Camille; Meunier, David; Rogachov, Anton; Hemington, Kasey S.; Cheng, Jui‐Ching; Bosma, Rachael L.; Osborne, Natalie R.; Kim, Junseok A.; Hung, Peter Shih-Ping; Inman, Robert D.; Davis, Karen D.

doi:10.1097/j.pain.0000000000002104

Cited by 37 publications

(42 citation statements)

References 91 publications

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“…This study builds on previous work in our lab that identified sex differences in sgACC FC in both healthy adults and individuals with chronic pain (3,9,17,18). We found that women had increased sgACC FC with bilateral ventral PFC compared with men, while men had increased sgACC FC with the left parietal operculum.…”

Section: Fc Of the Sgacc Shows Sex Differences And Sex-specific Age Effectssupporting

confidence: 79%

“…Each question is scored from 0 to 3, with a total score range of 0-63 (42). Depression scores are classified as none to minimal (0-13), mild (14)(15)(16)(17)(18)(19), moderate (20)(21)(22)(23)(24)(25)(26)(27)(28), and severe .…”

Section: Questionnairesmentioning

confidence: 99%

“…A MEG study of patients with multiple sclerosis identified abnormal static and dynamic FC that was particularly pronounced in patients with neuropathic pain ( 16 ). In another study, a graph-theory analysis of rsFC in patients with low-back pain due to ankylosing spondylitis (AS) found atypical modular segregation in the mid cingulate cortex and sgACC in women with chronic pain, with stronger interactions between nodes within the sgACC module and weaker interactions with nodes outside of it ( 17 ). A FC study that focused on the sgACC in a subset of these chronic pain patients found abnormal sgACC FC only in the women.…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain

et al. 2021

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The subgenual anterior cingulate cortex (sgACC) is a key node of the descending antinociceptive system with sex differences in its functional connectivity (FC). We previously reported that, in a male-prevalent chronic pain condition, sgACC FC is abnormal in women but not in men. This raises the possibility that, within a sex, sgACC FC may be either protective or represent a vulnerability to develop a sex-dominant chronic pain condition. The aim of this study was to characterize sgACC FC in a female-dominant chronic pain condition, carpal tunnel syndrome (CTS), to investigate whether sgACC abnormalities are a common feature in women with chronic pain or unique to individuals with pain conditions that are more prevalent in the opposite sex. We used fMRI to determine the resting state FC of the sgACC in healthy controls (HCs, n = 25, 18 women; 7 men) and people with CTS before (n = 25, 18 women; 7 men) and after (n = 17, 13 women; 4 men) successful surgical treatment. We found reduced sgACC FC with the medial pre-frontal cortex (mPFC) and temporal lobe in CTS compared with HCs. The group-level sgACC-mPFC FC abnormality was driven by men with CTS, while women with CTS did not have sgACC FC abnormalities compared with healthy women. We also found that age and sex influenced sgACC FC in both CTS and HCs, with women showing greater FC with bilateral frontal poles and men showing greater FC with the parietal operculum. After surgery, there was reduced sgACC FC with the orbitofrontal cortex, striatum, and premotor areas and increased FC with the posterior insula and precuneus compared with pre-op scans. Abnormally reduced sgACC-mPFC FC in men but not women with a female-prevalent chronic pain condition suggests pain-related sgACC abnormalities may not be specific to women but rather to individuals who develop chronic pain conditions that are more dominant in the opposite sex. Our data suggest the sgACC plays a role in chronic pain in a sex-specific manner, and its communication with other regions of the dynamic pain connectome undergoes plasticity following pain-relieving treatment, supporting it as a potential therapeutic target for neuromodulation in chronic pain.

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Section: Fc Of the Sgacc Shows Sex Differences And Sex-specific Age Effectssupporting

confidence: 79%

Section: Questionnairesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain

et al. 2021

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“…Additionally, many neurobiological disorders impact males and females differently, for instance autism (Jack et al, 2021;Hernandez et al, 2020), attention deficit hyperactivity disorder (Rosch et al, 2018), and chronic pain (Fauchon et al, 2021). Thus, reliable methods for investigating sex differences in functional connectivity are needed to delineate the pathophysiology of these conditions.…”

Section: Brain-behavior Prediction Studymentioning

confidence: 99%

Less is more: balancing noise reduction and data retention in fMRI with projection scrubbing

Pham¹,

McDonald²,

Liu³

et al. 2021

Preprint

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Functional MRI (fMRI) data are subject to artifacts arising from a myriad of sources, including subject head motion, respiration, heartbeat, scanner drift, and thermal noise. These artifacts cause deviations from common distributional assumptions, introduce spatial and temporal outliers, and reduce the signal-to-noise ratio of the data-all of which can have negative consequences on the accuracy and power of statistical analyses. Scrubbing is a technique for excluding fMRI volumes thought to be contaminated by artifacts. Motion scrubbing based on subject head motion derived measures, while popular, suffers from a number of drawbacks, among them the need to choose a threshold, high rates of scrubbing, consequent exclusion of subjects, and a lack of sensitivity to non-motion related artifacts. Data-driven scrubbing methods, which are instead based on observed noise in the processed fMRI timeseries, may avoid many of these issues and achieve higher sensitivity and specificity to artifacts. Here we present "projection scrubbing", a new data-driven scrubbing method based on a statistical outlier detection framework. Projection scrubbing consists of two main steps: projection of the data onto directions likely to represent artifacts, and quantitative comparison of each volume's association with artifactual directions to identify volumes exhibiting artifacts. Compared with DVARS, which is also data-driven, a primary advantage of projection scrubbing is its use of a common reference to identify abnormal volumes, rather than differences between subsequent volumes. We assess the ability of projection scrubbing to improve the reliability and predictiveness of functional connectivity (FC) compared with motion scrubbing and DVARS.We also compare projection methods, including independent component analysis (ICA), principal component analysis (PCA), and a novel fused PCA method. We perform scrubbing in conjunction with regression-based denoising through CompCor, which we found to outperform alternative methods. Projection scrubbing and DVARS were both substantially more beneficial to FC reliability than motion scrubbing, illustrating the advantage of data-driven measures over head motion-based measures for identifying contaminated volumes. ICA-based projection scrubbing produced the most

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“…Until recently, the existence of physiological sex differences in pain was a contested issue (Mogil, 2012). Now there is a growing body of literature that shows sex differences in brain regions associated with descending pain modulation (Wang et al, 2014a), as well as differences in resting-state functional connectivity within the dynamic pain connectome that links the many brain areas that regulate pain, attention and cognition (Fauchon et al, 2021;Kim et al, 2021;Osborne et al, 2021). In the periphery, sex differences in immune modulation of high mobility group box 1 protein (HMGB1) have been observed in a mouse arthritis model, with macrophage TLR4 involvement in males, but not females (Rudjito et al, 2021).…”

Section: Sex Differences In Chronic Painmentioning

confidence: 99%

Molecular Determinants of Spinal Hyperexcitability in Rat and Human Models of Pathological Pain

Dedek¹

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Chronic pain is a health crisis with few safe and effective treatments. Understanding the mechanisms that drive chronic pain predicate the development of novel therapeutics for the disease. The superficial dorsal horn (SDH) is an integral part of the pain-processing circuit.Nociceptive output from the SDH is mediated by a homeostatic balance of inhibition and excitation, resulting in pain responses in healthy individuals that are proportional to noxious stimuli. In chronic pain, the balance between inhibition and excitation degrades, resulting in spinal hyperexcitability and an increase in pain outputs to the brain. To study the molecular processes that disrupt the balance of inhibition and excitation within SDH circuitry, we paired a male rat ex vivo pain model with in vivo models. We found that the loss of potassium-chloride cotransporter 2-dependent inhibition (disinhibition) and facilitated excitation (marked by potentiation of excitatory N-methyl-D-aspartate receptors, NMDARs) are linked. We determined that downregulation of the phosphatase STEP61 is the linker between disinhibition and NMDAR potentiation in male rats. To address the translational divide that exists between basic science rodent research and clinical trials, we developed an ex vivo pathological pain model using human organ donor tissue. Using this model, we found that the STEP61-mediated link between disinhibition and NMDAR potentiation is conserved in the SDH of male humans. Despite that chronic pain affects women more often than men, the molecular underpinnings of chronic pain have been studied almost exclusively in males. Surprisingly, we found that NMDARs are not potentiated in our female rodent pain models, and that protein markers of disinhibition and facilitated excitation remain unchanged. This demonstrates a sex difference in neuronal pain processing in rodents within the SDH. Further, we used human tissue models to discover that this sex difference is conserved between rats and humans. We conclude that loss of STEP61 links Thank you to the patient group of educators at Bell High School. It is thanks to their belief in me that I channelled my teenage angst into a passion for academics. Thank you especially to Lisa H, who has now become a dear friend. I thank the members, past and present, of the Hildebrand and Tsai labs, as well as the many members of the Neuroscience Department that have made the journey fun and made me look forward to long days in the lab.

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Sex differences in brain modular organization in chronic pain

Cited by 37 publications

References 91 publications

Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain

Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain

Less is more: balancing noise reduction and data retention in fMRI with projection scrubbing

Molecular Determinants of Spinal Hyperexcitability in Rat and Human Models of Pathological Pain

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