Resting state functional connectivity in SLE patients and association with cognitive impairment and blood-brain barrier permeability.

OBJECTIVE: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment in SLE. This study aimed to examine the associations of brain functional connectivity (FC) with cognitive impairment and BBB dysfunction among patients with SLE. METHODS: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (n = 61). Differences in rsFC were compared between SLE patients with cognitive impairment (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls. RESULTS: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (P = 0.030) and healthy controls (P = 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (P = 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and cognitive impairment in SLE patients was mediated by alterations in FC. CONCLUSION: SLE patients with cognitive impairment had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and cognitive impairment.

Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment.

OBJECTIVES: To examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE). METHODS: A total of 65 ambulatory patients with SLE and 9 healthy controls underwent dynamic contrast-enhanced MRI scanning, for quantitative assessment of BBB permeability. Volumetric data were extracted using the VolBrain pipeline. Global cognitive function was evaluated using a screening battery consisting of tasks falling into five broad cognitive domains, and was compared between patients with normal versus extensive BBB leakage. RESULTS: Patients with SLE had significantly higher levels of BBB leakage compared with controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in patients with SLE (16/65; 24.6%), who also had smaller right and left cerebral grey matter volumes compared with controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment on one or more cognitive tasks (p=0.01). CONCLUSION: Our findings provide evidence for a link between extensive BBB leakage and changes in both brain structure and cognitive function in patients with SLE. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, validate the diagnostic utility of BBB imaging, and determine the potential of targeting the BBB as a therapeutic strategy in patients with SLE.

Maturation trajectories of cortical resting-state networks depend on the mediating frequency band.

The functional significance of resting state networks and their abnormal manifestations in psychiatric disorders are firmly established, as is the importance of the cortical rhythms in mediating these networks. Resting state networks are known to undergo substantial reorganization from childhood to adulthood, but whether distinct cortical rhythms, which are generated by separable neural mechanisms and are often manifested abnormally in psychiatric conditions, mediate maturation differentially, remains unknown. Using magnetoencephalography (MEG) to map frequency band specific maturation of resting state networks from age 7 to 29 in 162 participants (31 independent), we found significant changes with age in networks mediated by the beta (13-30 Hz) and gamma (31-80 Hz) bands. More specifically, gamma band mediated networks followed an expected asymptotic trajectory, but beta band mediated networks followed a linear trajectory. Network integration increased with age in gamma band mediated networks, while local segregation increased with age in beta band mediated networks. Spatially, the hubs that changed in importance with age in the beta band mediated networks had relatively little overlap with those that showed the greatest changes in the gamma band mediated networks. These findings are relevant for our understanding of the neural mechanisms of cortical maturation, in both typical and atypical development.

Dexmedetomidine Disrupts the Local and Global Efficiencies of Large-scale Brain Networks.

BACKGROUND: A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target. METHODS: Dexmedetomidine was administered as a 1-µg/kg bolus over 10 min, followed by a 0.7-µg · kg · h infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine-induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes. RESULTS: Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine. CONCLUSIONS: Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain.

Corticolimbic anatomical characteristics predetermine risk for chronic pain.

SEE TRACEY DOI101093/BRAIN/AWW147 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Mechanisms of chronic pain remain poorly understood. We tracked brain properties in subacute back pain patients longitudinally for 3 years as they either recovered from or transitioned to chronic pain. Whole-brain comparisons indicated corticolimbic, but not pain-related circuitry, white matter connections predisposed patients to chronic pain. Intra-corticolimbic white matter connectivity analysis identified three segregated communities: dorsal medial prefrontal cortex-amygdala-accumbens, ventral medial prefrontal cortex-amygdala, and orbitofrontal cortex-amygdala-hippocampus. Higher incidence of white matter and functional connections within the dorsal medial prefrontal cortex-amygdala-accumbens circuit, as well as smaller amygdala volume, represented independent risk factors, together accounting for 60% of the variance for pain persistence. Opioid gene polymorphisms and negative mood contributed indirectly through corticolimbic anatomical factors, to risk for chronic pain. Our results imply that persistence of chronic pain is predetermined by corticolimbic neuroanatomical factors.

The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients.

UNLABELLED: Recent advances in brain imaging have contributed to our understanding of the neural activity associated with acupuncture treatment. In this study, we investigated functional connectivity across longitudinal acupuncture treatments in older patients with knee osteoarthritis (OA). Over a period of 4 weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before and after their first, third and sixth treatments. Clinical outcome showed a significantly greater pain subscore on the Knee Injury and Osteoarthritis Outcome Score (KOOS) (indicative of improvement) with verum acupuncture than with sham acupuncture. Independent component analysis (ICA) of the resting state fMRI data showed that the right frontoparietal network (rFPN) and the executive control network (ECN) showed enhanced functional connectivity (FC) with the rostral anterior cingulate cortex/medial prefrontal cortex, a key region in the descending pain modulatory system, in the verum groups as compared to the sham group after treatments. We also found that the rFPN connectivity with the left insula is (1) significantly associated with changes in KOOS pain score after treatments, and (2) significantly enhanced after verum acupuncture treatments as compared to sham treatment. Analysis of the acupuncture needle stimulation scan showed that compared with sham treatment, verum acupuncture activated the left operculum/insula, which also overlaps with findings observed in resting state analysis. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by modulating functional connectivity between the rFPN, ECN and the descending pain modulatory pathway. CLINICAL TRIAL NUMBER: NCT01079390.

Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits.

Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.

White matter microstructure predicts measures of clinical symptoms in chronic back pain patients.

Chronic back pain (CBP) has extensive clinical and social implications for its sufferers and is a major source of disability. Chronic pain has previously been shown to have central neural factors underpinning it, including the loss of white matter (WM), however traditional methods of analyzing WM microstructure have produced mixed and unclear results. To better understand these factors, we assessed the WM microstructure of 50 patients and 40 healthy controls (HC) using diffusion-weighted imaging. The data were analyzed using fixel-based analysis (FBA), a higher-order diffusion modelling technique applied to CBP for the first time here. Subjects also answered questionnaires relating to pain, disability, catastrophizing, and mood disorders, to establish the relationship between fixelwise metrics and clinical symptoms. FBA determined that, compared to HC, CBP patients had: 1) lower fibre density (FD) in several tracts, specifically the right anterior and bilateral superior thalamic radiations, right spinothalamic tract, right middle cerebellar peduncle, and the body and splenium of corpus callosum; 2) higher FD in the genu of corpus callosum; and 3) lower FDC - a combined fibre density and cross-section measure - in the bilateral spinothalamic tracts and right anterior thalamic radiation. Exploratory correlations showed strong negative relationships between fixelwise metrics and clinical questionnaire scores, especially pain catastrophizing. These results have important implications for the intake and processing of sensory data in CBP that warrant further investigation.

Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study.

BACKGROUND: The 5% Lidocaine patch is used for treating chronic neuropathic pain conditions such as chronic back pain (CBP), diabetic neuropathy and complex regional pain syndrome, but is effective in a variable proportion of patients. Our lab has reported that this treatment reduces CBP intensity and associated brain activations when tested in an open labelled preliminary study. Notably, effectiveness of the 5% Lidocaine patch has not been tested against placebo for treating CBP. In this study, effectiveness of the 5% Lidocaine patch was compared with placebo in 30 CBP patients in a randomised double-blind study where 15 patients received 5% Lidocaine patches and the remaining patients received placebo patches. Functional MRI was used to identify brain activity for fluctuations of spontaneous pain, at baseline and at two time points after start of treatment (6 hours and 2 weeks). RESULTS: There was no significant difference between the treatment groups in either pain intensity, sensory and affective qualities of pain or in pain related brain activation at any time point. However, 50% patients in both the Lidocaine and placebo arms reported a greater than 50% decrease in pain suggesting a marked placebo effect. When tested against an untreated CBP group at similar time points, the patch treated subjects showed significantly greater decrease in pain compared to the untreated group (n = 15). CONCLUSIONS: These findings suggest that although the 5% Lidocaine is not better than placebo in its effectiveness for treating pain, the patch itself induces a potent placebo effect in a significant proportion of CBP patients.

Symptoms reported by Canadians posted in Havana are linked with reduced white matter fibre density.

Diplomats representing the USA have reported with unusual neurologic symptoms and MRI changes after being posted in Havana, Cuba between late 2016 and 2018. Here, we examined white matter microstructure and network connectivity of individuals stationed in Havana, using diffusion-weighted MRI, fixel-based analysis and structural connectomics as implemented in MRtrix3. MRI data acquisition and clinical assessments were done in a total of 24 diplomats and their family members and 40 healthy controls. The diplomat data were grouped into an exposed cohort (n = 16) and an unexposed cohort (n = 10), and among these, two individuals were assessed before and after potential exposure. Fixel-based analysis revealed a reduction in fibre density in two specific regions: the fornix and the splenium, in exposed individuals, relative to unexposed individuals and healthy controls. Post hoc analyses showed the effect remained present (P < 0.05) in both regions when comparing exposed and unexposed diplomats; and reduced fibre density was correlated with longer time period stationed in Cuba after age correction. Reduction of fibre density was also found to be linked with clinical symptoms of persistent migraine, tinnitus, sound sensitivity and fatigue. Network statistical comparisons revealed decreased structural connectivity in two distinct networks, comprising subcortical and cortical systems in exposed individuals, relative to unexposed and normative data. While the cause for the differences between the groups remains unknown, our results reveal region-specific white matter injury, that is, significantly correlated with clinical symptoms.

Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus.

OBJECTIVE: Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. METHODS: Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. RESULTS: There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. CONCLUSIONS: Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.

Hippocampal circuits underlie improvements in self-reported anxiety following mindfulness training.

INTRODUCTION: Mindfulness meditation has successfully been applied to cultivate skills in self-regulation of emotion, as it employs the unbiased present moment awareness of experience. This heightened attention to and awareness of sensory experience has been postulated to create an optimal therapeutic exposure condition and thereby improve extinction learning. We recently demonstrated increased connectivity in hippocampal circuits during the contextual retrieval of extinction memory following mindfulness training. METHODS: Here, we examine the role of structural changes in hippocampal subfields following mindfulness training in a randomized controlled longitudinal study using a two-day fear-conditioning and extinction protocol. RESULTS: We demonstrate an association between mindfulness training-related increases in subiculum and decreased hippocampal connectivity to lateral occipital regions during contextual retrieval of extinguished fear. Further, we demonstrate an association between decreased connectivity and decreases in self-reported anxiety following mindfulness training. CONCLUSIONS: The results highlight the role of the subiculum in gating interactions with contextual stimuli during memory retrieval and, also, the mechanisms through which mindfulness training may foster resilience.

Strengthened Hippocampal Circuits Underlie Enhanced Retrieval of Extinguished Fear Memories Following Mindfulness Training.

BACKGROUND: The role of hippocampus in context-dependent recall of extinction is well recognized. However, little is known about how intervention-induced changes in hippocampal networks relate to improvements in extinction learning. In this study, we hypothesized that mindfulness training creates an optimal exposure condition by heightening attention and awareness of present moment sensory experience, leading to enhanced extinction learning, improved emotion regulation, and reduced anxiety symptoms. METHODS: We tested this hypothesis in a randomized controlled longitudinal study design using a 2-day fear conditioning and extinction protocol. The mindfulness training group included 42 participants (28 women) and the control group included 25 participants (15 women). RESULTS: We show that mindfulness training is associated with differential engagement of the right supramarginal gyrus as well as hippocampal-cortical reorganization. We also report enhanced hippocampal connectivity to the primary sensory cortex during retrieval of extinguished stimuli following mindfulness training. CONCLUSIONS: These findings suggest hippocampal-dependent changes in contextual retrieval as one plausible neural mechanism through which mindfulness-based interventions enhance fear extinction and foster stress resilience.

Altered Onset Response Dynamics in Somatosensory Processing in Autism Spectrum Disorder.

Abnormalities in cortical connectivity and evoked responses have been extensively documented in autism spectrum disorder (ASD). However, specific signatures of these cortical abnormalities remain elusive, with data pointing toward abnormal patterns of both increased and reduced response amplitudes and functional connectivity. We have previously proposed, using magnetoencephalography (MEG) data, that apparent inconsistencies in prior studies could be reconciled if functional connectivity in ASD was reduced in the feedback (top-down) direction, but increased in the feedforward (bottom-up) direction. Here, we continue this line of investigation by assessing abnormalities restricted to the onset, feedforward inputs driven, component of the response to vibrotactile stimuli in somatosensory cortex in ASD. Using a novel method that measures the spatio-temporal divergence of cortical activation, we found that relative to typically developing participants, the ASD group was characterized by an increase in the initial onset component of the cortical response, and a faster spread of local activity. Given the early time window, the results could be interpreted as increased thalamocortical feedforward connectivity in ASD, and offer a plausible mechanism for the previously observed increased response variability in ASD, as well as for the commonly observed behaviorally measured tactile processing abnormalities associated with the disorder.

A longitudinal study of the reliability of acupuncture deqi sensations in knee osteoarthritis.

Deqi is one of the core concepts in acupuncture theory and encompasses a range of sensations. In this study, we used the MGH Acupuncture Sensation Scale (MASS) to measure and assess the reliability of the sensations evoked by acupuncture needle stimulation in a longitudinal clinical trial on knee osteoarthritis (OA) patients. The Knee injury and Osteoarthritis Outcome Score (KOOS) was used as the clinical outcome. Thirty OA patients were randomized into one of three groups (high dose, low dose, and sham acupuncture) for 4 weeks. We found that, compared with sham acupuncture, real acupuncture (combining high and low doses) produced significant improvement in knee pain (P = .025) and function in sport (P = .049). Intraclass correlation analysis showed that patients reliably rated 11 of the 12 acupuncture sensations listed on the MASS and that heaviness was rated most consistently. Overall perceived sensation (MASS Index) (P = .014), ratings of soreness (P = .002), and aching (P = .002) differed significantly across acupuncture groups. Compared to sham acupuncture, real acupuncture reliably evoked stronger deqi sensations and led to better clinical outcomes when measured in a chronic pain population. Our findings highlight the MASS as a useful tool for measuring deqi in acupuncture research.

Brain networks predicting placebo analgesia in a clinical trial for chronic back pain.

A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double-blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2 weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses--that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high-frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.

Noxious heat evokes stronger sharp and annoying sensations in women than men in hairy skin but not in glabrous skin.

Brief noxious heat evokes more intense pain in women than in men; however, sex differences in the intensity of pain sensations evoked in hairy and glabrous skins are not clearly understood. Glabrous skin putatively lacks the type of A-delta nociceptors that underlie heat-evoked sharp sensation. Therefore, we assessed whether noxious heat-evoked pain qualities differed for hairy and glabrous skins and whether sex differences exist in these evoked pains. We applied a prolonged (30s) ramped noxious heat stimulus to the dorsal and ventral aspects of the feet of 16 males and 16 females. Stimuli were calibrated in each subject to evoke a peak pain magnitude of 50/100. Subjects provided continuous online ratings of pain, annoyance, burning, sharp, stinging and cutting sensations in separate runs. The results indicate that both sex and skin type impact noxious heat-evoked sensations. Specifically, ratings of sharp sensations and annoyance evoked in hairy skin were significantly more intense in women than in men. Sharp, stinging and cutting sensations were evoked in glabrous skin, but the magnitude of these sensations was greater in hairy skin than glabrous skin; an effect only in females. Also, there was no sex difference in sharp sensation and annoyance in glabrous skin. These findings suggest that sharp sensations are evoked more prominently in hairy than in glabrous skin of women and that sharp sensations and annoyance play a prominent role in mediating aspects of pain-evoked from hairy skin in women.

Effects of temperature on heat pain adaptation and habituation in men and women.

We recently reported that women report greater pain adaptation and habituation to moderately painful heat stimuli than men (Hashmi and Davis [16]); but slightly lower temperatures were needed to evoke moderate pain in the women. Hardy et al (1962) and LaMotte (1979) suggested that pain adaptation is most prominent at modest noxious heat temperatures and may occur at temperatures close to pain thresholds. Thus, as a follow-up to our previous study, we examined the role of absolute temperature in pain adaptation and habituation in men and women and assessed whether pain threshold impacts these findings. We hypothesised that pain adaptation and habituation would be more prominent at low and moderate temperatures, and that higher temperatures would induce pain adaptation and habituation in women but not in men. We further hypothesized that pain adaptation would not be correlated with pain thresholds. To test this, we obtained continuous ratings of pain evoked by 44.5-47.5°C stimuli applied to the dorsal foot of men and women. Each run consisted of three 30s stimuli at the same temperature with a 60s inter-stimulus interval. Women showed within-stimulus adaptation of total pain at all temperatures, but men showed significant adaptation to temperatures less than 47°C. There were no sex differences in inter-stimulus habituation and both men and women reported habituation to temperatures less than 46°C. Pain thresholds did not correlate with pain adaptation. These data highlight the temperature-sensitivity and sex differences of pain adaptation and habituation.