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.

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.

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.

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.

Magnetoencephalography: physics, techniques, and applications in the basic and clinical neurosciences.

Magnetoencephalography (MEG) is a technique used to measure the magnetic fields generated from neuronal activity in the brain. MEG has a high temporal resolution on the order of milliseconds and provides a more direct measure of brain activity when compared with hemodynamic-based neuroimaging methods such as magnetic resonance imaging and positron emission tomography. The current review focuses on basic features of MEG such as the instrumentation and the physics that are integral to the signals that can be measured, and the principles of source localization techniques, particularly the physics of beamforming and the techniques that are used to localize the signal of interest. In addition, we review several metrics that can be used to assess functional coupling in MEG and describe the advantages and disadvantages of each approach. Lastly, we discuss the current and future applications of MEG.

The Potential Clinical Utility of Pressure-Based vs. Heat-Based Paradigms to Measure Conditioned Pain Modulation in Healthy Individuals and Those With Chronic Pain.

Conditioned pain modulation (CPM) is a physiological measure thought to reflect an individual's endogenous pain modulation system. CPM varies across individuals and provides insight into chronic pain pathophysiology. There is growing evidence that CPM may help predict individual pain treatment outcome. However, paradigm variabilities and practical issues have impeded widespread clinical adoption of CPM assessment. This study aimed to compare two CPM paradigms in people with chronic pain and healthy individuals. A total of 30 individuals (12 chronic pain, 18 healthy) underwent two CPM paradigms. The heat CPM paradigm acquired pain intensity ratings evoked by a test stimulus (TS) applied before and during the conditioning stimulus (CS). The pressure CPM paradigm acquired continuous pain intensity ratings of a gradually increasing TS, before and during CS. Pain intensity was rated from 0 (no pain) to 100 (worst pain imaginable); Pain50 is the stimulus level for a response rated 50. Heat and pressure CPM were calculated as a change in TS pain intensity ratings at Pain50, where negative CPM scores indicate pain inhibition. We also determined CPM in the pressure paradigm as change in pressure pain detection threshold (PDT). We found that in healthy individuals the CPM effect was significantly more inhibitory using the pressure paradigm than the heat paradigm. The pressure CPM effect was also significantly more inhibitory when based on changes at Pain50 than at PDT. However, in individuals with chronic pain there was no significant difference in pressure CPM compared to heat or PDT CPM. There was no significant correlation between clinical pain measures (painDETECT and Brief Pain Inventory) and paradigm type (heat vs. pressure), although heat-based CPM and painDETECT scores showed a trend. Importantly, the pressure paradigm could be administered in less time than the heat paradigm. Thus, our study indicates that in healthy individuals, interpretation of CPM findings should consider potential modality-dependent effects. However, in individuals with chronic pain, either heat or pressure paradigms can similarly be used to assess CPM. Given the practical advantages of the pressure paradigm (e.g., short test time, ease of use), we propose this approach to be well-suited for clinical adoption.

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.

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.

Neural Oscillations: Understanding a Neural Code of Pain.

Neural oscillations play an important role in the integration and segregation of brain regions that are important for brain functions, including pain. Disturbances in oscillatory activity are associated with several disease states, including chronic pain. Studies of neural oscillations related to pain have identified several functional bands, especially alpha, beta, and gamma bands, implicated in nociceptive processing. In this review, we introduce several properties of neural oscillations that are important to understand the role of brain oscillations in nociceptive processing. We also discuss the role of neural oscillations in the maintenance of efficient communication in the brain. Finally, we discuss the role of neural oscillations in healthy and chronic pain nociceptive processing. These data and concepts illustrate the key role of regional and interregional neural oscillations in nociceptive processing underlying acute and chronic pains.

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.

Abnormal alpha band power in the dynamic pain connectome is a marker of chronic pain with a neuropathic component.

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.

Cross-network coupling of neural oscillations in the dynamic pain connectome reflects chronic neuropathic pain in multiple sclerosis.

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.

Plasticity in the dynamic pain connectome associated with ketamine-induced neuropathic pain relief.

Therapeutic interventions for neuropathic pain, such as the N-methyl-D-aspartate (NMDA) antagonist ketamine, can vary widely in effectiveness. In this study, we conducted a longitudinal functional MRI study to test the hypothesis that the pain-relieving effect of ketamine is the result of reversal of abnormalities in regional low-frequency brain oscillations (LFOs) and abnormal cross-network functional connectivity (FC) of the dynamic pain connectome. We found that (1) ketamine decreased regional LFOs in the posterior cingulate cortex of the default mode network, (2) a machine-learning algorithm demonstrated that treatment-induced brain changes could be used to make generalizable inferences about pain relief, (3) treatment responders exhibited a significant decrease in cross-network static FC between the posterior cingulate cortex and regions of the sensorimotor and salience networks following treatment, (4) the degree of reduced cross-network FC correlated with the amount of pain relief, and (5) ketamine treatment did not produce significant differences in static or dynamic FC within the ascending nociceptive or descending antinociceptive pathway. These findings support the proposition that regional LFOs contribute to cross-network connectivity that underlie the effectiveness of ketamine to produce significant relief from neuropathic pain. Together with our recent findings that pretreatment dynamic FC of the descending antinociceptive pathway can predict ketamine treatment outcomes, these new findings indicate that pain relief from ketamine arises from a combination of flexible pretreatment FC of the descending antinocieptive pathway together with plasticity (reduction) of cross-network connectivity of the default mode network with sensorimotor and salience networks.

Neuropathic pain and pain interference are linked to alpha-band slowing and reduced beta-band magnetoencephalography activity within the dynamic pain connectome in patients with multiple sclerosis.

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.

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.

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.

Dynamic pain connectome functional connectivity and oscillations reflect multiple sclerosis pain.

Pain is a prevalent and debilitating symptom of multiple sclerosis (MS); yet, the mechanisms underlying this pain are unknown. Previous studies have found that the functional relationships between the salience network (SN), specifically the right temporoparietal junction a SN node, and other components of the dynamic pain connectome (default mode network [DMN], ascending and descending pathways) are abnormal in many chronic pain conditions. Here, we use resting-state functional magnetic resonance imaging and measures of static and dynamic functional connectivity (sFC and dFC), and regional BOLD variability to test the hypothesis that patients with MS have abnormal DMN-SN cross-network sFC, dFC abnormalities in SN-ascending and SN-descending pathways, and disrupted BOLD variability in the dynamic pain connectome that relates to pain inference and neuropathic pain (NP). Thirty-one patients with MS and 31 controls completed questionnaires to characterize pain and pain interference, and underwent a resting-state functional magnetic resonance imaging scan from which measures of sFC, dFC, and BOLD variability were compared. We found that (1) ∼50% of our patients had NP features, (2) abnormalities in SN-DMN sFC were driven by the mixed-neuropathic subgroup, (3) in patients with mixed NP, dFC measures showed that there was a striking change in how the SN was engaged with the ascending nociceptive pathway and descending modulation pathway, (4) BOLD variability was increased in the DMN, and (5) the degrees of sFC and BOLD variability abnormalities were related to pain interference. We propose that abnormal SN-DMN cross-network FC and temporal dynamics within and between regions of the dynamic pain connectome reflect MS pain features.

Beyond Negative Pain-Related Psychological Factors: Resilience Is Related to Lower Pain Affect in Healthy Adults.

Resilience, a characteristic that enhances adaptation in response to stressful events, is a positive psychological factor that can predict and modulate health outcomes. However, resilience is rarely considered in pain research. Conversely, negative psychological factors (eg, anxiety, depression) are known to be related to the affective dimension of pain. It is critical to understand all potential psychological drivers of pain affect, a prominent component of chronic pain. We tested the hypothesis that higher resilience is associated with lower pain affect, above and beyond the predictive value of negative psychological factors. Healthy adults underwent psychophysical testing to acquire ratings of heat pain intensity and unpleasantness and completed the Resilience Scale, the State-Trait Anxiety Inventory (trait form), Beck Depression Inventory, Pain Catastrophizing Scale, and the Pain Vigilance and Attention Questionnaire. Multiple regression modeling (n = 68) showed resilience to be a negatively associated with pain affect (unpleasantness). Furthermore, in individuals with higher anxiety scores, resilience was protective against higher pain affect. This highlights the importance of resilience, a positive psychological factor, in the affective dimension of pain. This study is the first to assess a positive psychological factor and experimental pain affect, and has the potential to improve prediction of and treatment strategies for clinical pain. PERSPECTIVE: We report that resilience, a positive psychological factor, interacts with anxiety and is associated with heat pain affect (unpleasantness) in healthy individuals. Resilience may provide predictive value of chronic pain affect and treatment outcomes, and could be a target for behavioral therapy.

Reduced cerebrovascular reserve is regionally associated with cortical thickness reductions in children with sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder which adversely affects cerebrovascular health. Previous studies have demonstrated regional cortical thinning in SCD. However, the reason behind regional reductions in cortical thickness remains unclear. Therefore, we aimed to explore the possible link between the state of cerebrovascular health and cortical thickness. In this study, we obtained magnetic resonance (MR) based measures of cerebrovascular reactivity (CVR), a measure of vascular health, and cortical thickness in SCD patients (N=60) and controls of similar age and similar gender ratio (N=27). The group comparison analysis revealed significant regionally specific reductions in CVR and cortical thickness in the SCD group compared to the controls. In addition, a regional association analysis was performed between CVR and cortical thickness in the SCD group which revealed a significant regional association in several brain regions with the highest strength of association observed in the left cuneus, right post central gyrus and the right temporal pole. The regional association analysis revealed that significant associations were found in brain regions with high metabolic activity (anterior cingulate, posterior cingulate, occipital gyrus, precuneus) thus demonstrating that these regions could be most vulnerable to structural damage under hypoxic conditions.

Reproducibility of cerebrovascular reactivity measures in children using BOLD MRI.

PURPOSE: To evaluate the reproducibility of cerebrovascular reactivity (CVR) measurements acquired in children using magnetic resonance imaging (MRI) in combination with a computer-controlled carbon dioxide (CO2 ) stimulus. MATERIALS AND METHODS: Ten healthy children (age 16.1 ± 1.6 years) underwent CVR imaging on a 3T scanner using a blood-oxygen level-dependent (BOLD) MRI sequence. Targeted hypercapnia was induced during imaging with a CO2 gas challenge delivered using a specialized gas sequencer (RespirAct). A total of four BOLD scans were performed over 2 separate days to test within-day and between-day consistency of the data. CVR values were computed by correlating the relative change in BOLD signal in response to the CO2 stimulus delivered to the each subject. RESULTS: Intraclass correlation coefficients (ICCs) of within-day values show highly reproducible measures in both the gray matter (ICC = 0.857, P < 0.001) and white matter (ICC = 0.895, P < 0.001). Relatively lower between-day reproducibility was observed in both the gray matter (ICC = 0.776, P = 0.001) and white matter (ICC = 0.719, P = 0.004). CONCLUSION: Using a computer-controlled CO2 stimulus, we have demonstrated the reliability of BOLD-CVR measurements in pediatric subjects. Within-day and between-day metrics of reproducibility were comparable to adult data.