Sex-differences in network level brain dynamics associated with pain sensitivity and pain interference.

Neural dynamics can shape human experience, including pain. Pain has been linked to dynamic functional connectivity within and across brain regions of the dynamic pain connectome (consisting of the ascending nociceptive pathway (Asc), descending antinociceptive pathway (Desc), salience network (SN), and the default mode network (DMN)), and also shows sex differences. These linkages are based on fMRI-derived slow hemodynamics. Here, we utilized the fine temporal resolution of magnetoencephalography (MEG) to measure resting state functional coupling (FCp) related to individual pain perception and pain interference in 50 healthy individuals (26 women, 24 men). We found that pain sensitivity and pain interference were linked to within- and cross-network broadband FCp across the Asc and SN. We also identified sex differences in these relationships: (a) women exhibited greater within-network static FCp, whereas men had greater dynamic FCp within the dynamic pain connectome; (b) relationship between pain sensitivity and pain interference with FCp in women was commonly found in theta, whereas in men, these relationships were predominantly in the beta and low gamma bands. These findings indicate that dynamic interactions of brain networks underlying pain involve fast brain communication in men but slower communication in women.

Abnormal Low-Frequency Oscillations Reflect Trait-Like Pain Ratings in Chronic Pain Patients Revealed through a Machine Learning Approach.

Measures of moment-to-moment fluctuations in brain activity of an individual at rest have been shown to be a sensitive and reliable metric for studying pathological brain mechanisms across various chronic pain patient populations. However, the relationship between pathological brain activity and clinical symptoms are not well defined. Therefore, we used regional BOLD signal variability/amplitude of low-frequency oscillations (LFOs) to identify functional brain abnormalities in the dynamic pain connectome in chronic pain patients that are related to chronic pain characteristics (i.e., pain intensity). Moreover, we examined whether there were sex-specific attributes of these functional brain abnormalities and whether functional brain abnormalities in patients is related to pain intensity characteristics on different time scales. We acquired resting-state functional MRI and quantified frequency-specific regional LFOs in chronic pain patients with ankylosing spondylitis. We found that patients exhibit frequency-specific aberrations in LFOs. Specifically, lower-frequency (slow-5) abnormalities were restricted to the ascending pain pathway (thalamus and S1), whereas higher-frequency abnormalities also included the default mode (i.e., posterior cingulate cortex; slow-3, slow-4) and salience (i.e., mid-cingulate cortex) networks (slow-4). Using a machine learning approach, we found that these abnormalities, in particular within higher frequencies (slow-3), can be used to make generalizable inferences about patients' average pain ratings (trait-like pain) but not current (i.e., state-like) pain levels. Furthermore, we identified sex differences in LFOs in patients that were not present in healthy controls. These novel findings reveal mechanistic brain abnormalities underlying the longer-lasting symptoms (trait pain intensity) in chronic pain.SIGNIFICANCE STATEMENT Measures of moment-to-moment fluctuations in brain activity of an individual at rest have been shown to be a reliable metric for studying functional brain associated with chronic pain. The current results demonstrate that dysfunction in these intrinsic fluctuations/oscillations in the ascending pain pathway, default mode network, and salience network during resting state display sex differences and can be used to make inferences about trait-like pain intensity ratings in chronic pain patients. These results provide robust and generalizable implications for investigating brain mechanisms associated with longer-lasting/trait-like chronic pain symptoms.

Brain Dynamics and Temporal Summation of Pain Predicts Neuropathic Pain Relief from Ketamine Infusion.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Ketamine is an N-methyl-D-aspartate receptor antagonist that reduces temporal summation of pain and modulates antinociception. Ketamine infusions can produce significant relief of neuropathic pain, but the treatment is resource intensive and can be associated with adverse effects. Thus, it is crucial to select patients who might benefit from this treatment. The authors tested the hypothesis that patients with enhanced temporal summation of pain and the capacity to modulate pain via the descending antinociceptive brain pathway are predisposed to obtain pain relief from ketamine. METHODS: Patients with refractory neuropathic pain (n = 30) and healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient intravenous ketamine (0.5 to 2 mg · kg · h; mean dose 1.1 mg · kg · h) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. Treatment response was defined as greater than or equal to 30% pain relief (i.e., reduction in pain scores). We determined the relationship between our primary outcome measure of pain relief with pretreatment temporal summation of pain and with brain imaging measures of dynamic functional connectivity between the default mode network and the descending antinociceptive brain pathway. RESULTS: Approximately 50% of patients achieved pain relief (mean ± SD; Responders, 61 ± 35%; Nonresponders, 7 ± 14%). Pretreatment temporal summation was associated with the effect of ketamine (ρ = -0.52, P = 0.003) and was significantly higher in Responders (median [25th, 75th] = 200 [100, 345]) compared with Nonresponders (44 [9, 92]; P = 0.001). Pretreatment dynamic connectivity was also associated with the clinical effect of ketamine (ρ = 0.51, P = 0.004) and was significantly higher in Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03; P = 0.006). Finally, the dynamic engagement of the descending antinociceptive system significantly mediated the relationship between pretreatment pain facilitation and pain relief (95% CI, 0.005 to 0.065). CONCLUSIONS: These findings suggest that brain and behavioral measures have the potential to prognosticate and develop ketamine-based personalized pain therapy.

FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients.

Fibromyalgia syndrome (FM) is a debilitating chronic pain condition, which afflicts primarily females. Although the etiology of this illness is not completely understood, FM pain is thought to rely on enhanced pain sensitivity maintained by central mechanisms. One of these mechanisms is central pain amplification, which is characterized by altered temporal summation of second pain (TSSP). Here we use a TSSP paradigm and functional MRI (fMRI) of the spinal cord, brainstem, and brain to noninvasively examine the central nervous system contributions to TSSP in FM patients and normal controls (NC). Functional MRI of pain-free female adults (N = 15) and FM patients (N = 14) was conducted while brief, repetitive heat pain stimuli (0.33 Hz) were applied to the thenar eminence of the hand (C6 dermatome). The stimulus intensity was adjusted to each participant's heat pain sensitivity to achieve moderate pain. Data were analyzed by means of a General Linear Model and region-of-interest analyses. All participants demonstrated significant pain summation in the TSSP condition. FM subjects, however, required significantly lower stimulus intensities than NC to achieve similar TSSP. fMRI analyses of perceptually equal TSSP identified similar brain activity in NC and FM subjects; however, multiple areas in the brainstem (rostral ventromedial medulla and periaqueductal grey region) and spinal cord (dorsal horn) exhibited greater activity in NC subjects. Finally, increased after-sensations and enhanced dorsal horn activity was demonstrated in FM patients. In conclusion, the spinal and brainstem BOLD responses to TSSP are different between NC and FM patients, which may indicate alterations to descending pain control mechanisms suggesting contributions of these mechanisms to central sensitization and pain of FM patients.

fMRI Localization of Spinal Cord Processing Underlying Female Sexual Arousal.

Using functional magnetic resonance imaging, the authors aimed to determine the roles of the human spinal cord in mediating sexual responses in women. Functional magnetic resonance imaging of the entire lower thoracic, lumbar, and sacral spinal cord was performed using a sexual stimulation paradigm designed to elicit psychological and physical components of sexual arousal. Responses were measured in 9 healthy adult women during 3 consecutive conditions: (a) erotic audiovisual, (b) manual clitoral, and (c) audiovisual plus manual stimulation. Functional magnetic resonance imaging results in healthy subjects demonstrate that this method is sensitive for mapping sexual function in the spinal cord, and identify several key regions involved in human sexual response, including the intermediolateral cell column, the dorsal commissural nucleus, and the sacral parasympathetic nucleus. Using spinal functional magnetic resonance imaging, this study identified many of the spinal cord regions involved in female sexual responses. Results from audiovisual and manual clitoral stimulation correspond with previous data regarding lumbar and sacral neurologic changes during sexual arousal. This study provides the first characterization of neural activity in the human spinal cord underlying healthy female sexual responses and sets a foundation for future studies aimed at mapping changes that result from sexual dysfunction, spinal cord trauma or disease.

Neural correlates of temporal summation of second pain in the human brainstem and spinal cord.

Temporal summation of second pain (TSSP) occurs when painful stimuli are presented repetitively (≥ 0.33 Hz) and results from a C-fibre evoked enhancement (or "wind-up") of the dorsal horn neurons. Based on electrophysiological studies in intact animals, windup is considered a purely central phenomenon. With advancements in functional MRI (fMRI), we can now probe the central mechanisms of this pain response in humans. The aim of this study is to characterize the fMRI responses in the healthy human brainstem and spinal cord that correspond to TSSP. Functional MRI of healthy female adults (N = 15) was conducted while brief, repetitive heat pain stimuli were applied to the right thenar eminence (C6 dermatome), and TSSP (0.33 Hz) and control (0.17 Hz) heat pain paradigms were employed. The stimulus intensity was adjusted to each participant's heat pain sensitivity. Data were analyzed by means of a general linear model, and region-of-interest analyses. As predicted, participants demonstrated significant behavioural summation of pain in the TSSP condition. FMRI results identified enhanced activity in the spinal cord dorsal horn at C6 in response to the TSSP condition. Additionally, multiple areas of the brainstem (RVM and PAG) showed greater responses with the TSSP condition. These results suggest that, in humans, increased pain perception in the TSSP condition is reflected by greater responses in the dorsal horn and in regions known to play a role in the descending modulation of pain, which may modulate the spinal cord response.

Spinal cord response to stepwise and block presentation of thermal stimuli: a functional MRI study.

PURPOSE: To examine the characteristics of the spinal cord and brainstem blood oxygenation level-dependent (BOLD) responses to peripheral stimulation in which the temperature is raised in a stepwise fashion, in order to enhance receptor responses, compared to a block design. MATERIALS AND METHODS: Functional magnetic resonance imaging (fMRI) studies of the spinal cord and brainstem were carried out in 14 healthy volunteers at 3T. Thermal sensory stimuli were applied to the right hand in a block-design paradigm, and in a stepwise paradigm to the same peak temperature. Data were analyzed by means of a general linear model, region of interest analyses, and by structural equation modeling. RESULTS: Results demonstrated BOLD responses in a number of consistent regions between the two paradigms as well as significant differences (P < .001) in the locations and magnitudes of some responses. Specifically, the BOLD response in the dorsal horn was significantly higher in the stepwise compared to the block condition (P < .001). However, more significant connections (T >2) between regions were observed in the block condition. CONCLUSION: Results from this study demonstrate the means to design thermal sensory paradigms to probe components of sensory processing in the brainstem and spinal cord.

Pretreatment Brain White Matter Integrity Associated With Neuropathic Pain Relief and Changes in Temporal Summation of Pain Following Ketamine.

Neuropathic pain (NP) is a prevalent condition often associated with heightened pain responsiveness suggestive of central sensitization. Neuroimaging biomarkers of treatment outcomes may help develop personalized treatment strategies, but white matter (WM) properties have been underexplored for this purpose. Here we assessed whether WM pathways of the default mode network (DMN: medial prefrontal cortex [mPFC], posterior cingulate cortex, and precuneus) and descending pain modulation system (periaqueductal gray [PAG]) are associated with ketamine analgesia and attenuated temporal summation of pain (TSP, reflecting central sensitization) in NP. We used a fixel-based analysis of diffusion-weighted imaging data to evaluate WM microstructure (fiber density [FD]) and macrostructure (fiber bundle cross-section) within the DMN and mPFC-PAG pathways in 70 individuals who underwent magnetic resonance imaging and TSP testing; 35 with NP who underwent ketamine treatment and 35 age- and sex-matched pain-free individuals. Individuals with NP were assessed before and 1 month after treatment; those with ≥30% pain relief were considered responders (n = 18), or otherwise as nonresponders (n = 17). We found that WM structure within the DMN and mPFC-PAG pathways did not differentiate responders from nonresponders. However, pretreatment FD in the anterior limb of the internal capsule correlated with pain relief (r=.48). Moreover, pretreatment FD in the DMN (left mPFC-precuneus/posterior cingulate cortex; r=.52) and mPFC-PAG (r=.42) negatively correlated with changes in TSP. This suggests that WM microstructure in the DMN and mPFC-PAG pathway is associated with the degree to which ketamine reduces central sensitization. Thus, fixel metrics of WM structure may hold promise to predict ketamine NP treatment outcomes. PERSPECTIVE: We used advanced fixel-based analyses of MRI diffusion-weighted imaging data to identify pretreatment WM microstructure associated with ketamine outcomes, including analgesia and markers of attenuated central sensitization. Exploring associations between brain structure and treatment outcomes could contribute to a personalized approach to treatment for individuals with NP.

Can we characterize A-P/IAP behavioural phenotypes in people with chronic pain?

Two behavioural phenotypes in healthy people have been delineated based on their intrinsic attention to pain (IAP) and whether their reaction times (RT) during a cognitively-demanding task are slower (P-type) or faster (A-type) during experimental pain. These behavioural phenotypes were not previously studied in chronic pain populations to avoid using experimental pain in a chronic pain context. Since pain rumination (PR) may serve as a supplement to IAP without needing noxious stimuli, we attempted to delineate A-P/IAP behavioural phenotypes in people with chronic pain and determined if PR can supplement IAP. Behavioural data acquired in 43 healthy controls (HCs) and 43 age-/sex-matched people with chronic pain associated with ankylosing spondylitis (AS) was retrospectively analyzed. A-P behavioural phenotypes were based on RT differences between pain and no-pain trials of a numeric interference task. IAP was quantified based on scores representing reported attention towards or mind-wandering away from experimental pain. PR was quantified using the pain catastrophizing scale, rumination subscale. The variability in RT was higher during no-pain trials in the AS group than HCs but was not significantly different in pain trials. There were no group differences in task RTs in no-pain and pain trials, IAP or PR scores. IAP and PR scores were marginally significantly positively correlated in the AS group. RT differences and variability were not significantly correlated with IAP or PR scores. Thus, we propose that experimental pain in the A-P/IAP protocols can confound testing in chronic pain populations, but that PR could be a supplement to IAP to quantify attention to pain.

Resilience is associated with cortical gray matter of the antinociceptive pathway in people with chronic pain.

Resilience is an important personal characteristic that influences health and recovery. Previous studies of chronic pain suggest that highly resilient people may be more effective at modulating their pain. Since brain gray matter in the antinociceptive pathway has also been shown to be abnormal in people with chronic pain, we examined whether resilience is related to gray matter in regions of interest (ROIs) of the antinociceptive pathway (rostral and subgenual anterior cingulate cortex (rACC, sgACC), anterior insula (aINS), dorsolateral prefrontal cortex (dlPFC)) normally and in people who are experiencing chronic pain. We extracted gray matter volume (GMV) and cortical thickness (CT) from 3T MRIs of 88 people with chronic pain (half males/females) and 86 healthy controls (HCs), who completed The Resilience Scale and Brief Pain Inventory. We found that resilience scores were significantly lower in people with chronic pain compared to HCs, whereas ROI GMV and CT were not different between groups. Resilience negatively correlated with average pain scores and positively correlated with GMV in the bilateral rACC, sgACC, and left dlPFC of people with chronic pain. Mediation analyses revealed that GMV in the right rACC and left sgACC partially co-mediated the relationship between resilience and average pain in people with chronic pain. The resilience-pain and some resilience-GMV relationships were sex-dependent. These findings suggest that the antinociceptive pathway may play a role in the impact of resilience on one's ability to modulate chronic pain. A better understanding of the brain-resilience relationship may help advance evidence-based approaches to pain management.

Somatotopic arrangement of thermal sensory regions in the healthy human spinal cord determined by means of spinal cord functional MRI.

Previous functional MRI studies of normal sensory function in the human spinal cord, including right-to-left symmetry of activity, have been influenced by order effects between repeated studies. In this study, we apply thermal sensory stimulation to four dermatomes within each functional MRI time-series acquisition. Each of the four dermatomes receives a unique stimulation paradigm, such that the four paradigms form a linearly independent set, enabling detection of each individual stimulus response. Functional MRI data are shown spanning the cervical spinal cord and brainstem in 10 healthy volunteers. Results of general linear model analysis demonstrate consistent patterns of activity within the spinal cord segments corresponding to each dermatome, and a high degree of symmetry between right-side and left-side stimulation. Connectivity analyses also demonstrate consistent areas of activity and connectivity between spinal cord and brainstem regions corresponding to known anatomy. However, right-side and left-side responses are not at precisely the same rostral-caudal positions, but are offset by several millimeters, with left-side responses consistently more caudal than right-side responses. The results confirm that distinct responses to multiple interleaved sensory stimuli can be distinguished, enabling studies of sensory responses within the spinal cord without the confounding effects of comparing sequential studies.

Neural correlates of sexual arousal in the spinal cords of able-bodied men: a spinal fMRI investigation.

The purpose of this study was to determine whether spinal cord functional magnetic resonance imaging could be used to map neural activity throughout the lower thoracic, lumbar, and sacral spinal cord regions during sexual arousal in healthy men. The authors found that viewing erotic films and genital self-stimulation elicited predominantly increased signal, indicative of amplified neuronal input to the dorsal and ventral horns and in the autonomic preganglionic nuclei of the lower thoracic, lumbar, and sacral spinal cord. In addition, linear regression analyses revealed a number of robust correlations (|R| ≥ 0.7) between signal intensity changes in these spinal cord regions and self-reported ratings of mental and physical sexual arousal. Taken together, these results demonstrate that spinal cord functional magnetic resonance imaging is an effective and sensitive technique for mapping the neural correlates of sexual arousal in the spinal cords of able-bodied men. Most important, the results from this study indicate that spinal cord functional magnetic resonance imaging may have important applications as a clinical tool for assessing and mapping the changes that occur in the spinal cords of men suffering from sexual dysfunction as a result of spinal cord trauma.

Empathy, defending, and functional connectivity while witnessing social exclusion.

Peers are present for most bullying episodes. Peers who witness bullying can play an important role in either stopping or perpetuating the behavior. Defending can greatly benefit victimized peers. Empathy is strongly associated with defending. Yet, less is known about defenders' neural response to witnessing social distress, and how this response may relate to the link between empathy and defending. Forty-six first-year undergraduate students (Mage = 17.7; 37 women), with varied history of peer defending, underwent fMRI scanning while witnessing a depiction of social exclusion. Functional connectivity analysis was performed across brain regions that are involved in cognitive empathy, empathetic distress, and compassion. History of defending was positively associated with functional connectivity (Exclusion > Inclusion) between the left orbitofrontal cortex (OFC) - medial prefrontal cortex (MPFC), and right OFC - left and right amygdalae. Defending was negatively associated with functional connectivity between the left OFC - anterior cingulate cortex. The relationship between history of defending and empathy (specifically, empathetic perspective taking) was moderated by functional connectivity of the right OFC - left amygdala. These findings suggest that coactivation of brain regions involved in compassionate emotion regulation and empathetic distress play a role in the relationship between empathy and peer defending.

Carpal tunnel surgery dampens thalamocortical and normalizes corticocortical functional connectivity.

Carpal tunnel syndrome is the most common entrapment neuropathy and is associated with altered brain function and structure. However, little is understood of the central mechanisms associated with its pain, symptom presentation, and treatment-related resolution. This longitudinal study evaluated carpal tunnel syndrome-related alterations in brain network communication and relationships to behavioural signs of central sensitization before and after carpal tunnel release surgery. We tested the hypothesis that carpal tunnel syndrome is associated with condition- and treatment-related plasticity in brain regions involved in somatosensation. We used quantitative sensory testing and clinical and pain questionnaires to assess sensory and pain function in 25 patients with carpal tunnel syndrome before (18 women, 7 men) and after (n = 16) surgery, and 25 sex- and age-matched healthy controls. We also acquired resting-state functional MRI to determine functional connectivity of two key nodes in the somatosensory system, the thalamus and primary somatosensory cortex. Seed-to-whole brain resting-state static functional connectivity analyses revealed abnormally low functional connectivity for the hand area of the primary somatosensory cortex with the contralateral somatosensory association cortex (supramarginal gyrus) before surgery (P < 0.01). After clinically effective surgery: (i) Primary somatosensory functional connectivity was normalized with the contralateral somatosensory association cortex and reduced with the dorsolateral prefrontal cortex (a region associated with cognitive and emotional modulation of pain) and primary visual areas (P < 0.001) from pre-op levels; and (ii) Functional connectivity of the thalamus with the primary somatosensory and motor cortices was attenuated from pre-op levels (P < 0.001) but did not correlate with temporal summation of pain (a behavioural measure of central sensitization) or clinical measures. This study is the first to reveal treatment-related neuroplasticity in resting-state functional connectivity of the somatosensory system in carpal tunnel syndrome. The findings of dysfunctional resting-state functional connectivity point to aberrant neural synchrony between the brain's representation of the hand with regions involved in processing and integrating tactile and nociceptive stimuli and proprioception in carpal tunnel syndrome. Aberrant neural communication between the primary somatosensory hand area and the dorsolateral prefrontal cortex could reflect increased attention to pain, paraesthesia, and altered sensation in the hand. Finally, reduced thalamocortical functional connectivity after surgery may reflect central plasticity in response to the resolution of abnormal sensory signals from the periphery. Our findings support the concept of underlying brain contributions to this peripheral neuropathy, specifically aberrant thalamocortical and corticocortical communication, and point to potential central therapeutic targets to complement peripheral treatments.

Exploring sex differences in alpha brain activity as a potential neuromarker associated with neuropathic pain.

ABSTRACT: Alpha oscillatory activity (8-13 Hz) is the dominant rhythm in the awake brain and is known to play an important role in pain states. Previous studies have identified alpha band slowing and increased power in the dynamic pain connectome (DPC) of people with chronic neuropathic pain. However, a link between alpha-band abnormalities and sex differences in brain organization in healthy individuals and those with chronic pain is not known. Here, we used resting-state magnetoencephalography to test the hypothesis that peak alpha frequency (PAF) abnormalities are general features across chronic central and peripheral conditions causing neuropathic pain but exhibit sex-specific differences in networks of the DPC (ascending nociceptive pathway [ANP], default mode network, salience network [SN], and subgenual anterior cingulate cortex). We found that neuropathic pain (N = 25 men and 25 women) was associated with increased PAF power in the DPC compared with 50 age- and sex-matched healthy controls, whereas slower PAF in nodes of the SN (temporoparietal junction) and the ANP (posterior insula) was associated with higher trait pain intensity. In the neuropathic pain group, women exhibited lower PAF power in the subgenual anterior cingulate cortex and faster PAF in the ANP and SN than men. The within-sex analyses indicated that women had neuropathic pain-related increased PAF power in the ANP, SN, and default mode network, whereas men with neuropathic pain had increased PAF power restricted to the ANP. These findings highlight neuropathic pain-related and sex-specific abnormalities in alpha oscillations across the DPC that could underlie aberrant neuronal communication in nociceptive processing and modulation.

A Hidden Markov Model reveals magnetoencephalography spectral frequency-specific abnormalities of brain state power and phase-coupling in neuropathic pain.

Neuronal populations in the brain are engaged in a temporally coordinated manner at rest. Here we show that spontaneous transitions between large-scale resting-state networks are altered in chronic neuropathic pain. We applied an approach based on the Hidden Markov Model to magnetoencephalography data to describe how the brain moves from one activity state to another. This identified 12 fast transient (~80 ms) brain states including the sensorimotor, ascending nociceptive pathway, salience, visual, and default mode networks. Compared to healthy controls, we found that people with neuropathic pain exhibited abnormal alpha power in the right ascending nociceptive pathway state, but higher power and coherence in the sensorimotor network state in the beta band, and shorter time intervals between visits of the sensorimotor network, indicating more active time in this state. Conversely, the neuropathic pain group showed lower coherence and spent less time in the frontal attentional state. Therefore, this study reveals a temporal imbalance and dysregulation of spectral frequency-specific brain microstates in patients with neuropathic pain. These findings can potentially impact the development of a mechanism-based therapeutic approach by identifying brain targets to stimulate using neuromodulation to modify abnormal activity and to restore effective neuronal synchrony between brain states.

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

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.

Sex differences in brain modular organization in chronic pain.

ABSTRACT: Men and women can exhibit different pain sensitivities, and many chronic pain conditions are more prevalent in one sex. Although there is evidence of sex differences in the brain, it is not known whether there are sex differences in the organization of large-scale functional brain networks in chronic pain. Here, we used graph theory with modular analysis and machine-learning of resting-state-functional magnetic resonance imaging data from 220 participants: 155 healthy controls and 65 individuals with chronic low back pain due to ankylosing spondylitis, a form of arthritis. We found an extensive overlap in the graph partitions with the major brain intrinsic systems (ie, default mode, central, visual, and sensorimotor modules), but also sex-specific network topological characteristics in healthy people and those with chronic pain. People with chronic pain exhibited higher cross-network connectivity, and sex-specific nodal graph properties changes (ie, hub disruption), some of which were associated with the severity of the chronic pain condition. Females exhibited atypically higher functional segregation in the mid cingulate cortex and subgenual anterior cingulate cortex and lower connectivity in the network with the default mode and frontoparietal modules, whereas males exhibited stronger connectivity with the sensorimotor module. Classification models on nodal graph metrics could classify an individual's sex and whether they have chronic pain with high accuracies (77%-92%). These findings highlight the organizational abnormalities of resting-state-brain networks in people with chronic pain and provide a framework to consider sex-specific pain therapeutics.

Abnormal subgenual anterior cingulate circuitry is unique to women but not men with chronic pain.

The subgenual anterior cingulate cortex (sgACC) plays an important role in pain modulation. We previously demonstrated sex differences in sgACC functional connectivity (FC) in healthy individuals. Given that many chronic pain conditions show sex differences in prevalence, here we tested the hypothesis that people with chronic pain exhibit a sex-specific pattern of abnormal sgACC FC. We acquired resting-state functional magnetic resonance imaging data from 156 (82 W: 74 M) healthy participants and 38 (19 W: 19 M) people with chronic low back pain resulting from ankylosing spondylitis, a condition that predominantly affects men. We confirmed that there are sex differences in sgACC FC in our large cohort of healthy adults; women had greater sgACC FC with the precuneus, a key node of the default mode network, and men had greater sgACC FC with the posterior insula and the operculum. Next, we identified an interaction effect between sex and pain status (healthy/chronic pain) for sgACC FC. Within the chronic pain group, women had greater sgACC FC than men to the default mode and sensorimotor networks. Compared to healthy women, women with chronic pain also had greater sgACC FC to the precuneus and lower FC to the hippocampus and frontal regions. No differences in sgACC FC were seen in men with vs without chronic pain. Our findings indicate that abnormal sgACC circuitry is unique to women but not men with ankylosing spondylitis-related chronic pain. These sex differences may impact the benefit of therapeutics that target the sgACC for chronic pain.

Individual variability and sex differences in conditioned pain modulation and the impact of resilience, and conditioning stimulus pain unpleasantness and salience.

Distinct pain experiences are shaped both by personal attributes and characteristics of noxious stimuli. An Individual's capacity for endogenous pain inhibition (reflected by conditioned pain modulation [CPM]), their resilience, and the pain unpleasantness and salience of painful stimuli can impact their pain perception. Here, we aimed to determine how individual variability in CPM relates to sex and resilience as personal attributes, and pain unpleasantness and salience of the CPM conditioning stimulus (CS). We evaluated CPM in 106 healthy participants (51 female and 55 male) based on the change in test stimulus pain applied concurrently with a painful CS, both delivered by painful heat. The CS reduced test stimulus pain in only half of the participants (CPM subgroup), but did not do so for the other half (no-CPM subgroup), many who exhibited pain facilitation. A regression model explained CPM effects after accounting for sex, resilience, CS pain unpleasantness and salience. In the CPM subgroup regression model, the CPM effect was positively related to CS pain unpleasantness, while the CPM effect was not related to any variable in the no-CPM subgroup model. Correlation analyses revealed that the CPM effect was anticorrelated with resilience in males with no-CPM. The CPM effect was correlated with CS pain unpleasantness in males with CPM and in females with no-CPM. The CPM effect and CS salience were correlated in the whole group more strongly than in the subgroups. These data reveal that the complexity of contributors to CPM variability include both personal attributes and attributes of the CS.