The experience of pain arises from spontaneous, dynamic activity within and between multiple brain regions, but the interaction underlying these patterns of communication and coordination are not well understood. Phase-amplitude coupling (PAC) of theta and gamma oscillations reflects complex interactions possibly involved in nociceptive processing and modulation at different points of interaction within the dynamic pain connectome (DPC) in the ascending nociceptive (Asc) and descending antinociceptive (Desc) pathways, default mode network (DMN), and salience network (SN). This study investigated whether PAC of intrinsic activity within the DPC is normally present and/or disrupted in people with chronic pain. We analyzed a previously published dataset to measure theta-gamma PAC in the DPC from resting-state magnetoencephalography in 38 healthy individuals (HCs: 20 M, 18 F) and 37 people with chronic pain associated with ankylosing spondylitis (20 M, 17 F). We also examined whether PAC was associated with chronic pain intensity, disease severity, and functional limitations. We found that over 80% of all individuals exhibited PAC in the main regions of the Asc, SN, and DMN but was less common (<45% of individuals) in the right subgenual anterior cingulate and left posterior cingulate cortices. Furthermore, PAC in the right midcingulate cortex was significantly decreased in individuals with chronic pain compared with HCs, and, in females with chronic pain, was correlated to functional limitations with a medium effect size. These novel findings implicate theta-gamma PAC as a means to shape nociceptive brain processes and point to PAC failures as a possible mechanistic contributor to chronic pain.NEW & NOTEWORTHY The experience of pain arises through the integration of information across brain regions and networks. Theta-gamma phase-amplitude coupling (PAC) reflects interactions between neuronal processes in the brain. We analyzed a previously published dataset to identify PAC of intrinsic brain activity in nociceptive processing/modulation regions and found sex-specific disruptions in people with chronic pain. This study implicates theta-gamma PAC as a means to shape nociception and PAC failures as a possible mechanistic contributor to chronic pain.

A fundamental issue in neuroscience is a lack of understanding regarding the relationship between brain function and the white matter architecture that supports it. Individuals with chronic neuropathic pain (NP) exhibit functional abnormalities throughout brain networks collectively termed the "dynamic pain connectome" (DPC), including the default mode network (DMN), salience network, and ascending nociceptive and descending pain modulation systems. These functional abnormalities are often observed in a sex-dependent fashion. However, the enigmatic white matter structural features underpinning these functional networks and the relationship between structure and function/dysfunction in NP remain poorly understood. Here we used fixel-based analysis of diffusion weighted imaging data in 80 individuals (40 with NP [21 female, 19 male] and 40 sex- and age-matched healthy controls [HCs]) to evaluate white matter microstructure (fiber density [FD]), macrostructure (fiber bundle cross section) and combined microstructure and macrostructure (fiber density and cross section) within anatomical connections that support the DPC. We additionally examined whether there are sex-specific abnormalities in NP white matter structure. We performed fixel-wise and connection-specific mean analyses and found three main ways in which individuals with NP differed from HCs: (1) people with NP exhibited abnormally low FD and FDC within the corona radiata consistent with the ascending nociceptive pathway between the sensory thalamus and primary somatosensory cortex (S1). Furthermore, the entire sensory thalamus-S1 pathway exhibited abnormally low FD and FDC in people with NP, and this effect was driven by the females with NP; (2) females, but not males, with NP had abnormally low FD within the cingulum consistent with the right medial prefrontal cortex-posterior cingulate cortex DMN pathway; and (3) individuals with NP had higher connection-specific mean FDC than HCs in the anterior insula-temporoparietal junction and sensory thalamus-posterior insula pathways. However, sex-specific analyses did not corroborate these connection-specific findings in either females or males with NP. Our findings suggest that females with NP exhibit microstructural and macrostructural white matter abnormalities within the DPC networks including the ascending nociceptive system and DMN. We propose that aberrant white matter structure contributes to or is driven by functional abnormalities associated with NP. Our sex-specific findings highlight the utility and importance of using sex-disaggregated analyses to identify white matter abnormalities in clinical conditions such as chronic pain.

ABSTRACTPurposePain is inherently salient and so draws our attention in addition to impacting performance on attention‐demanding tasks. Individual variability in pain–attention interactions can be assessed by two kinds of behavioral phenotypes that quantify how individuals prioritize pain versus attentional needs. The intrinsic attention to pain (IAP) measure quantifies the degree to which a person attends to pain (high‐IAP) or mind‐wanders away from pain (low‐IAP). The A/P categorization quantifies how pain impacts cognitive performance during an attention‐demanding task classifying individuals into P type (pain dominates, worse performance during pain in comparison to no pain) and A type (attention to task dominates, better performance during pain in comparison to no pain). Although previous MRI‐based studies have linked these phenotypes with the dynamic pain connectome (DPC), the underlying neural oscillations are not known. This paper aims to examine the brain–behavior relationship between alpha and theta oscillations within nodes of the DPC and pain–attention phenotypes.MethodFifty participants (27 F, 23 M) underwent resting‐state magnetoencephalography (MEG). Individual IAP scores were determined by assessing mind‐wandering during pain and A/P type was based on interference of pain with cognitive task performance.FindingThe main findings were: (1) peak alpha frequency (PAF) power did not differ between low/high‐IAP individuals or A/P‐type individuals within the nodes of the DPC; (2) compared to high‐IAP individuals, those with low‐IAP have slower PAF in the left primary somatosensory cortex, posterior cingulate cortex and precuneus and higher theta power in the ascending nociceptive pathway and default mode network; (3) males with low‐IAP, compared to females, had higher PAF power throughout the DPC.ConclusionAlpha and theta oscillations within the DPC may underlie aspects of attentional focus and pain–attention interactions.

Conditioned pain modulation (CPM), the change in pain evoked by a test stimulus at 1 body site by a conditioning stimulus at another site, varies across individuals, ranging from inhibition (pain decreases) to no CPM to facilitation (pain increases). Given the role of alpha oscillations in pain, we examined the relationship between CPM and peak alpha frequency (PAF) and power in the dynamic pain connectome (DPC). In 68 healthy individuals who underwent resting-state magnetoencephalography and a heat-based CPM evaluation, 32% had inhibitory CPM, 49% had facilitatory CPM, and 19% had no CPM. The facilitatory subgroup had lower alpha power in the medial prefrontal cortex (mPFC) compared with the inhibitory subgroup and across the DPC (mPFC, right thalamus, bilateral dorsolateral prefrontal cortex [dlPFC]) compared with the noCPM subgroup. Peak alpha frequency in the thalamus bilaterally was strongly correlated with inhibitory CPM (higher PAF with stronger inhibitory CPM). The subgenual anterior cingulate cortex (sgACC) PAF was correlated with inhibitory CPM in males and females in opposite directions, but not at the whole subgroup level. The pressure-based CPM evoked inhibitory CPM in 87% of the 45 individuals tested; the relationship with PAF in the right dlPFC and sgACC had medium-strong effect sizes driven by males (higher PAF with weaker inhibitory CPM). This study indicates that the role of alpha oscillations in CPM is paradigm- and sex-dependent. Our findings that healthy individuals exhibit an alpha-CPM relationship, particularly in the prefrontal regions and sgACC, provide insight into the potential therapeutic use of targeted neuromodulation for pain.

Abstract The perception of pain and ability to cope with it varies widely amongst people, which in part could be due to the presence of inhibitory (antinociceptive) or facilitatory (pronociceptive) effects in conditioned pain modulation (CPM). This study examined whether individual differences in CPM reflect functional connectivity (FC) strengths within nodes of the descending antinociceptive pathway (DAP). A heat-based CPM paradigm and resting-state functional magnetic resonance imaging (rs-fMRI) were used to test the hypothesis that an individual's capacity to exhibit inhibitory CPM (changes in test stimuli [TS] pain due to a conditioning stimulus [CS]) reflects FC of the subgenual anterior cingulate cortex (sgACC), periaqueductal gray (PAG), and rostral ventromedial medulla (RVM). A total of 151 healthy participants (72 men, 79 women) underwent CPM testing and rs-fMRI. Three types of CPM were identified based on the effect of the CS on TS pain: (1) Antinociception: CS reduced TS pain in 45% of participants, (2) No-CPM: CS did not change TS pain in 15% of participants, and (3) Pronociception: CS increased TS pain in 40% of participants. Only the Antinociceptive subgroup exhibited FC between the left sgACC and PAG, right sgACC and PAG, and RVM and PAG. Furthermore, only the Antinociceptive subgroup exhibited a correlation of both left and right sgACC-RVM FC (medium effect sizes) with CPM effect magnitude. Women, compared with men were more likely to be categorized as pronociceptive. These data support the proposition that FC of the DAP reflects or contributes to inhibitory CPM.

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 personalised treatment strategies, but white matter (WM) properties have been under-explored for this purpose. Here we assessed whether WM pathways of the default mode network (DMN: medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), precuneus (PCu)) 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 (FBA) 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 MRI 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 non-responders (n=17). We found that WM structure within the DMN and mPFC-PAG pathways did not differentiate responders from non-responders. However, pre-treatment FD in the anterior limb of the internal capsule correlated with pain relief (r=0.48). Moreover, pre-treatment FD in the DMN (left mPFC-PCu/PCC; r=0.52) and mPFC-PAG (r=0.42) 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.PerspectiveWe used advanced fixel-based analyses of MRI diffusion-weighted imaging data to identify pre-treatment white matter 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 neuropathic 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 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.

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.

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.

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.

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.

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.

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.

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.

We previously identified alpha frequency slowing and beta attenuation in the dynamic pain connectome related to pain severity and interference in patients with multiple sclerosis-related neuropathic pain (NP). Here, we determined whether these abnormalities, are markers of aberrant temporal dynamics in non-neuropathic inflammatory pain (non-NP) or when NP is also suspected. We measured resting-state magnetoencephalography (MEG) spectral density in 45 people (17 females, 28 males) with chronic back pain due to ankylosing spondylitis (AS) and 38 age/sex matched healthy controls. We used painDETECT scores to divide the chronic pain group into those with only non-NP (NNP) and those who likely also had a component of NP in addition to their inflammatory pain. We also assessed pain severity, pain interference, and disease activity with the Brief Pain Inventory and Bath AS Disease Activity Index (BASDAI). We examined spectral power in the dynamic pain connectome, including nodes of the ascending nociceptive pathway (ANP), default mode (DMN), and salience networks (SN). Compared to the healthy controls, the AS patients exhibited increased theta power in the DMN and decreased low-gamma power in the DMN and ANP, but did not exhibit beta-band attenuation or peak-alpha slowing. The NNP patients were not different from HCs. Compared to both healthy controls and NNP, NP patients had increased alpha power in the ANP. Increased alpha power within the ANP was associated with reduced BASDAI in the NNP group, and increased pain in the mixed-NP group within the DMN, SN, and ANP. Thus, high theta and low gamma activity may be markers of chronic pain but high alpha-band activity may relate to particular features of neuropathic chronic pain.

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.

Sensory perceptions are coded by complex neural dynamics of regional communication in the brain. Thus, sensory abnormalities such as chronic pain may occur when neural dynamics go awry. Previous studies of cross-network dynamic functional connectivity in chronic pain identified abnormalities but were based on functional MRI which only captures slow temporal features. Here we conducted a magnetoencephalography (MEG) study to investigate fine temporal dynamics of aberrant cross-regional and cross-network communication of the dynamic pain connectome in patients with chronic pain. We also introduced a novel measure, dynamic functional coupling, to quantify the variability of brain communication. The study was performed in 33 people who had chronic pain associated with multiple sclerosis and 30 healthy controls. We found that patients with chronic pain exhibited abnormalities in cross-network functional coupling across multiple frequency bands (theta, alpha, beta, gamma), between the salience network and 3 other networks: the ascending nociceptive pathway, descending anti-nociceptive pathway, and the default mode network. However, these cross-network abnormalities involved different frequency bands in patients with neuropathic versus non-neuropathic chronic pain. Furthermore, cross-network abnormalities were linked to pain severity and pain interference. Our findings implicate broadband cross-network abnormalities as hallmark features of chronic pain in multiple sclerosis.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of +/- 16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; ).

Chronic pain is a common occurrence in multiple sclerosis (MS) that severely affects quality of life, but the underlying brain mechanisms related to these symptoms are unknown. Previous electroencephalography studies have demonstrated a role of alpha-band and beta-band power in pain processing. However, how and where these brain signals change in MS-related chronic pain is unknown. Here, we used resting state magnetoencephalography to examine regional spectral power in the dynamic pain connectome—including areas of the ascending nociceptive pathway, default mode network (DMN), and the salience network (SN)—in patients with chronic MS pain and in healthy controls. Each patient was assessed for pain, neuropathic pain (NP), and pain interference with activities of daily living. We found that patients with MS exhibited an increase of alpha-band power and a decrease of beta-band power, most prominently in the thalamus and the posterior insula of the ascending nociceptive pathway and in the right temporoparietal junction of the SN. In addition, patients with mixed-NP exhibited slowing of alpha peak power within the thalamus and the posterior insula, and in the posterior cingulate cortex of the DMN. Finally, pain interference scores in patients with mixed-NP were strongly correlated with alpha and beta peak power in the thalamus and posterior insula. These novel findings reveal brain mechanisms of MS-related pain in the ascending nociceptive pathway, SN, and DMN, and that these spectral abnormalities reflect the impact of pain on quality of life measures.