Secondary analysis: heat and self-report pain sensitivity associate with biological sex and racialized sociocultural group but may not be mediated by anxiety or pain catastrophizing.

Introduction: Previous studies have demonstrated associations between sex and racialized group on pain sensitivity and tolerance. We analyzed the association of sex and racialized group on heat pain sensitivity, sensibility to painful suprathreshold mechanical pain (STMP), and pain sensitivity questionnaire (PSQ). We hypothesized that anxiety and pain catastrophizing reported by racialized minority groups and women would mediate enhanced pain sensitivity. Our secondary aim was to evaluate validity of the PSQ in a diverse population. Methods: Using quantitative sensory testing for painful heat, STMP (forces: 64, 128, 256, and 512 mN), and PSQ, we evaluated pain sensitivity in 134 healthy participants [34 (18 women) Asian, 25 (13 women) Black, and 75 (41 women) White]. We used general linear and linear mixed models to analyze outcomes. We assessed mediation of state and trait anxiety and pain catastrophizing on pain sensitivity. Results: Racialized minority status was associated with greater heat pain sensitivity (F = 7.63; P = 0.00074) and PSQ scores (F = 15.45; P = 9.84 × 10-7) but not associated with STMP (F = 1.50; P = 0.23). Female sex was associated with greater heat pain sensitivity (F = 4.9; P = 0.029) and lower PSQ (F = 9.50; P = 0.0025) but not associated with STMP (F = 0.0018; P = 0.97). Neither anxiety nor pain catastrophizing mediated associations between sex or racialized group with heat pain threshold or PSQ. Differential experience of individual items (F = 19.87; P = 3.28 × 10-8) limited PSQ face validity in racialized minorities. Conclusion: Consistent with previous research, sensitivity to painful heat was associated with racialized minority status and female sex. By contrast, there was no significant effect of racialized minority status or female sex on STMP. Some PSQ items are inapplicable to participants from racialized minority groups.

Vigilance to Painful Laser Stimuli is Associated with Increased State Anxiety and Tense Arousal.

Introduction: Pain is frequently accompanied by enhanced arousal and hypervigilance to painful sensations. Here, we describe our findings in an experimental vigilance task requiring healthy participants to indicate when randomly timed moderately painful stimuli occur in a long train of mildly painful stimuli. Methods: During a continuous performance task with painful laser stimuli (CPTpain), 18 participants rated pain intensity, unpleasantness, and salience. We tested for a vigilance decrement over time using classical metrics including correct targets (hits), incorrectly identified non-targets (false alarms), hit reaction time, and false alarm reaction time. We measured state anxiety and tense arousal before and after the task. Results: We found a vigilance decrement across four 12.5-minute blocks of painful laser stimuli in hits [F3,51=2.91; p=0.043; time block 1>block 4 (t=2.77; p=0.035)]. Both self-report state anxiety (tpaired,17=3.34; p=0.0039) and tense arousal (tpaired,17=3.20; p=0.0053) increased after the task. We found a vigilance decrement during our laser pain vigilance task consistent with vigilance decrements found in other stimulus modalities. Furthermore, state anxiety positively correlated with tense arousal. Discussion: CPTpain acutely increased tense arousal and state anxiety, consistent with previous results implicating the reciprocal interaction of state anxiety and acute painful sensations and the role of pain in augmenting tense arousal. These results may indicate a psychological process which predisposes the hypervigilant to developing greater acute pain, resulting in positive feedback, greater pain and anxiety.

Biological sex influences psychological aspects of the biopsychosocial model related to chronic pain intensity and interference among South Korean patients with chronic secondary musculoskeletal pain in rheumatic diseases.

Introduction: Pain is a prominent contributor to negative personal and social outcomes, including increased disability and mortality, in many rheumatic diseases. In the Biopsychosocial model of chronic pain, psychological and social factors share roles with the biology of the injury in determining each patient's pain and suffering. The current study explored factors associated with clinical pain intensity and interference among patients with chronic secondary musculoskeletal pain in rheumatic diseases. Methods: In total, 220 patients experiencing chronic secondary musculoskeletal pain participated. Biological factors (age, biological sex, pain condition, pain duration, pain sensitivity, and comorbidity), socio-economic factors, psychological factors (pain catastrophizing and depressive symptoms), and pain intensity and interference were measured. Descriptive, multivariable linear regression and partial correlation analyses were conducted. Subgroup analysis by sex was conducted to examine differences in how different factors affect the pain experience. Results: The mean age of the participants was 52.3 years (SD = 12.07) and ranged from 22 to 78. Average pain intensity was 3.01 (0-10 scale) and average total pain interference score was 21.07 (0-70 scale). Partial correlation found positive correlations between pain intensity and interference with depression (intensity: R = 0.224; p = 0.0011; interference: R = 0.351; p < 0.001) and pain catastrophizing (intensity: R = 0.520; p < 0.001; interference: R = 0.464; p < 0.001). In males, pain condition (ß = -0.249, p = 0.032) and pain catastrophizing (R = 0.480, p < 0.001) were associated with pain intensity. In males, the simple correlation between pain intensity and depression (R = 0.519; p < 0.001) was driven by pain catastrophizing. In females, pain catastrophizing (R = 0.536, p < 0.001) and depressive symptoms (R = 0.228, p = 0.0077) were independently associated with pain intensity. Age (ß = -0.251, p = 0.042) and pain catastrophizing (R = 0.609, p < 0.001) were associated with pain interference in males, while depressive symptoms (R = 0.439, p < 0.001) and pain catastrophizing (R = 0.403, p < 0.001) were associated with pain interference in females. Again, in males, the simple correlation between pain interference and depression (R = 0.455; p < 0.001) was driven by pain catastrophizing. Discussion: In this study, females were more directly affected by depressive symptoms than males, regarding pain intensity and interference. Pain catastrophizing was a significant factor influencing chronic pain for both males and females. Based on these findings, a sex-specific approach to the Biopsychosocial model should be considered in understanding and managing pain among Asians with chronic secondary musculoskeletal pain.

Pandemic Fatigue and Anxiety Sensitivity as Associated Factors With Posttraumatic Stress Symptoms Among University Students in South Korea During the Prolonged COVID-19 Pandemic.

Objectives: The global impact of COVID-19 driven by new variants may add to the negative mental health consequences of the prolonged pandemic, including posttraumatic stress symptoms (PTSS). University students may be prone to develop a series of PTSS due to life plan disruptions as well as increased uncertainty caused by the pandemic. The purpose of this study was to assess the associations between pandemic fatigue, anxiety sensitivity (AS), and PTSS among university students in South Korea. Methods: Using convenience sampling, 400 students participated in this cross-sectional online survey. Descriptive statistics and linear mixed models were used to examine factors associated with PTSS. Results: About one-third (32.3%) of the participants reported clinically significant levels of PTSS. Multivariate analyses revealed that pandemic fatigue (ß = 0.124, p < 0.001) and AS (ß = 0.212, p < 0.001) were significantly associated with PTSS while controlling for other study variables. Conclusion: Young adults who feel more fatigue related to the COVID-19 pandemic and with high AS should be given access to mental health resources to better manage their mental health and reduce PTSS.

A Cross-Sectional Time Course of COVID-19 Related Worry, Perceived Stress, and General Anxiety in the Context of Post-Traumatic Stress Disorder-like Symptomatology.

The COVID-19 pandemic within the United States of America resulted in over 800,000 deaths as of February 2022 and has been addressed by social distancing or stay-at-home measures. Collective prolonged multimodal trauma on this scale is likely to elicit symptomatology in the general population consistent with post-traumatic stress disorder (PTSD), somatization, anxiety, and stress. The psychological component of this response contributes substantially to the burden of this disease worldwide. This cross-sectional study examines the relationship between COVID-19-related concern, anxiety, and perceived stress on PTSD-like symptomatology over the course of the COVID-19 pandemic. Participants were recruited via social media within the United States of America between 8th May 2020 and 11th August 2021 to complete an internet questionnaire including mood, personality, and COVID-19-specific scales. General anxiety and PTSD-like symptomatology were above the screening cutoffs for most respondents. These measures increased in severity over the pandemic, with the change point of our Concern scale preceding that of the other significant measures. Measures of COVID-19-related concern, generalized anxiety, and PTSD-like symptomatology were strongly correlated with each other. Anxiety, perceived stress, and PTSD-like symptomatology are strongly interrelated, increase with pandemic length, and are linked to reported levels of concern over COVID-19. These observations may aid future research and policy as the pandemic continues.

Brain responses to painful electrical stimuli and cognitive tasks interact in the precuneus, posterior cingulate cortex, and inferior parietal cortex and do not vary across the menstrual cycle.

INTRODUCTION: Bidirectional effects between cognition and pain have been extensively reported. Although brain regions involved in cognitive and pain processing seem to partly overlap, it is unknown what specific brain regions are involved in the interaction between pain and cognition. Furthermore, the role of gonadal hormones on these interacting effects has not been examined. This study investigated brain activation patterns of the interaction between pain and cognition over different phases of the naturally occurring menstrual cycle. METHODS: Fifteen healthy normally cycling females were examined over the course of 4 different cycle phases. Sensory stimulation was applied using electrical pulses and cognitive performance was assessed using the Multi-Source Interference Task. Brain imaging consisted of functional magnetic resonance imaging using a repeated measures ANOVA group analysis approach. RESULTS: Sensory stimulation was found to interact with task performance in the left precuneus, left posterior cingulate cortex and right inferior parietal lobule. No effects of cycle phase were observed to interact with main effects of stimulation, task or interaction effects between task performance and sensory stimulation. CONCLUSION: Potential neural correlates of shared resources between pain and cognition were demonstrated providing further insights into the potential mechanisms behind cognitive performance difficulties in pain patients and opening avenues for new treatment options including targeting specific cognitive factors in pain treatment such as cognitive interference.

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Pain Prevalence, Management and Interference Among University Students in South Korea: An Exploratory Cross-Sectional Study.

BACKGROUND: Pain is a global health issue with a significant impact on young adults. Adverse effects caused by inappropriate pain management among university students are related to poor mental/physical health. This study aimed to explore pain prevalence, management, and interference among university students in South Korea. METHODS: Pain intensity, painful body areas, pain management, and pain interference were measured in a convenience sample of 404 students. Descriptive statistics are reported, and a multivariable binomial logistic regression was conducted to reveal factors associated with pain interference. RESULTS: The prevalence of acute and chronic pain was 73.5%, while 7.8% reported chronic pain (≥ 3 months). Half of university students who experienced pain reported at least four painful body areas. The average pain intensity during the past 6 months was 4.8/10. About 56% of university students who experienced pain used over-the-counter pain pills for pain management. Rest and massage were the most used non-pharmacological pain management strategies. Mood was the most reported pain interference complaint amongst university students. Greater pain interference was associated with longer pain duration, more painful body areas, and greater pain intensity. DISCUSSION: Pain is highly prevalent among South Korean university students. Pain management programs, including education about appropriate methods of pain relief, should be developed for university students. Attention should be given to university students with widespread acute and chronic pain of high intensity to mitigate the negative impacts caused by pain interference.

During capsaicin-induced central sensitization, brush allodynia is associated with baseline warmth sensitivity, whereas mechanical hyperalgesia is associated with painful mechanical sensibility, anxiety and somatization.

BACKGROUND: Mechanical hyperalgesia and allodynia incidence varies considerably amongst neuropathic pain patients. This study explored whether sensory or psychological factors associate with mechanical hyperalgesia and brush allodynia in a human experimental model. METHODS: Sixty-six healthy volunteers (29 male) completed psychological questionnaires and participated in two quantitative sensory testing (QST) sessions. Warmth detection threshold (WDT), heat pain threshold (HPT) and suprathreshold mechanical pain (STMP) ratings were measured before exposure to a capsaicin-heat pain model (C-HP). After C-HP exposure, brush allodynia and STMP were measured in one session, whilst mechanical hyperalgesia was measured in another session. RESULTS: WDT and HPT measured in sessions separated by 1 month demonstrated significant but moderate levels of reliability (WDT: ICC = 0.5, 95%CI [0.28, 0.77]; HPT: ICC = 0.62, 95%CI [0.40, 0.77]). Brush allodynia associated with lower WDT (z = -3.06, p = 0.002; ϕ = 0.27). Those with allodynia showed greater hyperalgesia intensity (F = 7.044, p = 0.010, ηp 2  = 0.107) and area (F = 9.319, p = 0.004, ηp 2  = 0.163) than those without allodynia. No psychological self-report measures were significantly different between allodynic and nonallodynic groups. Intensity of hyperalgesia in response to lighter mechanical stimuli was associated with lower HPT, higher STMP ratings and higher Pain Sensitivity Questionnaire scores at baseline. Hyperalgesia to heavier probe stimuli associated with state anxiety and to a lesser extent somatic awareness. Hyperalgesic area associated with lower baseline HPT and higher STMP ratings. Hyperalgesic area was not correlated with allodynic area across individuals. CONCLUSIONS: These findings support research in neuropathic pain patients and human experimental models that peripheral sensory input and individual sensibility are related to development of mechanical allodynia and hyperalgesia during central sensitization, whilst psychological factors play a lesser role. SIGNIFICANCE: We evaluated differential relationships of psychological and perceptual sensitivity to the development of capsaicin-induced mechanical allodynia and hyperalgesia. Fifty percent of healthy volunteers failed to develop mechanical allodynia. Baseline pain sensitivity was greater in those developing allodynia and was related to the magnitude and area of hyperalgesia. State psychological factors, whilst unrelated to allodynia, were related to mechanical hyperalgesia. This supports that the intensity of peripheral sensory input and individual sensibility are related to development of mechanical allodynia and hyperalgesia during central sensitization, whilst psychological factors play a lesser role.

During vigilance to painful stimuli: slower response rate is related to high trait anxiety, whereas faster response rate is related to high state anxiety.

A pathological increase in vigilance, or hypervigilance, may be related to pain intensity in some clinical pain syndromes and may result from attention bias to salient stimuli mediated by anxiety. During a continuous performance task where subjects discriminated painful target stimuli from painful nontargets, we measured detected targets (hits), nondetected targets (misses), nondetected nontargets (correct rejections), and detected nontargets (false alarms). Using signal detection theory, we calculated response bias, the tendency to endorse a stimulus as a target, and discriminability, the ability to discriminate a target from nontarget. Owing to the relatively slow rate of stimulus presentation, our primary hypothesis was that sustained performance would result in a more conservative response bias reflecting a lower response rate over time on task. We found a more conservative response bias with time on task and no change in discriminability. We predicted that greater state and trait anxiety would lead to a more liberal response bias. A multivariable model provided partial support for our prediction; high trait anxiety related to a more conservative response bias (lower response rate), whereas high state anxiety related to a more liberal bias. This inverse relationship of state and trait anxiety is consistent with reports of effects of state and trait anxiety on reaction times to threatening stimuli. In sum, we report that sustained attention to painful stimuli was associated with a decrease in the tendency of the subject to respond to any stimulus over time on task, whereas the ability to discriminate target from nontarget remains unchanged.NEW & NOTEWORTHY During a series of painful stimuli requiring subjects to respond to targets, we separated response willingness from ability to discriminate targets from nontargets. Response willingness declined during the task, with no change in subjects' ability to discriminate, consistent with previous vigilance studies. High trait anxious subjects were less willing to respond and showed slower reaction times to hits than low anxious subjects. This study reveals an important role of trait anxiety in pain vigilance.

Behavioral, Physiological and EEG Activities Associated with Conditioned Fear as Sensors for Fear and Anxiety.

Anxiety disorders impose substantial costs upon public health and productivity in the USA and worldwide. At present, these conditions are quantified by self-report questionnaires that only apply to behaviors that are accessible to consciousness, or by the timing of responses to fear- and anxiety-related words that are indirect since they do not produce fear, e.g., Dot Probe Test and emotional Stroop. We now review the conditioned responses (CRs) to fear produced by a neutral stimulus (conditioned stimulus CS+) when it cues a painful laser unconditioned stimulus (US). These CRs include autonomic (Skin Conductance Response) and ratings of the CS+ unpleasantness, ability to command attention, and the recognition of the association of CS+ with US (expectancy). These CRs are directly related to fear, and some measure behaviors that are minimally accessible to consciousness e.g., economic scales. Fear-related CRs include non-phase-locked phase changes in oscillatory EEG power defined by frequency and time post-stimulus over baseline, and changes in phase-locked visual and laser evoked responses both of which include late potentials reflecting attention or expectancy, like the P300, or contingent negative variation. Increases (ERS) and decreases (ERD) in oscillatory power post-stimulus may be generalizable given their consistency across healthy subjects. ERS and ERD are related to the ratings above as well as to anxious personalities and clinical anxiety and can resolve activity over short time intervals like those for some moods and emotions. These results could be incorporated into an objective instrumented test that measures EEG and CRs of autonomic activity and psychological ratings related to conditioned fear, some of which are subliminal. As in the case of instrumented tests of vigilance, these results could be useful for the direct, objective measurement of multiple aspects of the risk, diagnosis, and monitoring of therapies for anxiety disorders and anxious personalities.

Menstrual Cycle Variations in Gray Matter Volume, White Matter Volume and Functional Connectivity: Critical Impact on Parietal Lobe.

The role of gonadal hormones in neural plasticity remains unclear. This study aimed to examine the effects of naturally fluctuating hormone levels over the menstrual cycle in healthy females. Gray matter, functional connectivity (FC) and white matter changes over the cycle were assessed by using functional magnetic resonance imaging (fMRI), resting state fMRI, and structural MRIs, respectively, and associated with serum gonadal hormone levels. Moreover, electrocutaneous sensitivity was evaluated in 14 women in four phases of their menstrual cycle (menstrual, follicular, ovulatory, and luteal). Electrocutaneous sensitivity was greater during follicular compared to menstrual phase. Additionally, pain unpleasantness was lower in follicular phase than other phases while pain intensity ratings did not change over the cycle. Significant variations in cycle phase effects on gray matter volume were found in the left inferior parietal lobule (IPL) using voxel-based morphometry. Subsequent Freesurfer analysis revealed greater thickness of left IPL during the menstrual phase when compared to other phases. Also, white matter volume fluctuated across phases in left IPL. Blood estradiol was positively correlated with white matter volume both in left parietal cortex and whole cortex. Seed-driven FC between left IPL and right secondary visual cortex was enhanced during ovulatory phase. A seed placed in right IPL revealed enhanced FC between left and right IPL during the ovulatory phase. Additionally, we found that somatosensory cortical gray matter was thinner during follicular compared to menstrual phase. We discuss these results in the context of likely evolutionary pressures selecting for enhanced perceptual sensitivity across modalities specifically during ovulation.

New Developments in Non-invasive Brain Stimulation in Chronic Pain.

PURPOSE OF REVIEW: The goal of this review is to present a summary of the recent literature of a non-invasive brain stimulation (NIBS) to alleviate pain in people with chronic pain syndromes. This article reviews the current evidence for the use of transcranial direct current (tDCS) and repetitive transcranial magnetic stimulation (rTMS) to improve outcomes in chronic pain. Finally, we introduce the reader to novel stimulation methods that may improve therapeutic outcomes in chronic pain. RECENT FINDINGS: While tDCS is approved for treatment of fibromyalgia in Canada and the European Union, no NIBS method is currently approved for chronic pain in the United States. Increasing sample sizes in randomized clinical trials (RCTs) seems the most efficient way to increase confidence in initial promising results. Trends at funding agencies reveal increased interest and support for NIBS such as recent Requests for Application from the National Institutes of Health. NIBS in conjunction with cognitive behavioral therapy and physical therapy may enhance outcomes in chronic pain. Novel stimulation methods, such as transcranial ultrasound stimulation, await rigorous study in chronic pain.

Decreased grey matter volume in mTBI patients with post-traumatic headache compared to headache-free mTBI patients and healthy controls: a longitudinal MRI study.

Traumatic brain injury (TBI) occurs in 1.7 million people annually and many patients go on to develop persistent disorders including post-traumatic headache (PTH). PTH is considered chronic if it continues past 3 months. In this study we aimed to identify changes in cerebral grey matter volume (GMV) associated with PTH in mild TBI patients. 50 mTBI patients (31 Non-PTH; 19 PTH) underwent MRI scans: within 10 days post-injury, 1 month, 6 months and 18 months. PTH was assessed at visit 4 by a post-TBI headache questionnaire. Healthy controls (n = 21) were scanned twice 6 months apart. Compared to non-PTH, PTH patients had decreased GMV across two large clusters described as the right anterior-parietal (p = 0.012) and left temporal-opercular (p = 0.027). Compared to healthy controls non-PTH patients had decreased GMV in the left thalamus (p = 0.047); PTH patients had decreased GMV in several extensive clusters: left temporal-opercular (p = 0.003), temporal-parietal (p = 0.041), superior frontal gyrus (p = 0.008) and right middle frontal/superior frontal gyrus (0.004) and anterior-parietal (p = 0.003). Differences between PTH and non-PTH patients were most striking at early time points. These early changes may be associated with an increased risk of PTH. Patients with these changes should be monitored for chronic PTH.

Missed targets, reaction times, and arousal are related to trait anxiety and attention to pain during an experimental vigilance task with a painful target.

Although hypervigilance may play a role in some clinical pain syndromes, experimental vigilance toward painful stimuli has been studied infrequently. We evaluated vigilance toward pain by using a continuous performance task (CPT), in which subjects responded to moderately intense painful target stimuli, occurring in a train of mildly painful nontargets. We assessed nondetected targets (misses), reaction times (RTs), and psychological activation (tense arousal). During time on task in CPTs of other sensory modalities, there is an increase in misses and RTs (vigilance decrement). We hypothesized that our CPT would influence vigilance performance related to pain, anxiety, and limitation of attentional resources. The results showed a decrement in vigilance over time as misses increased, although RTs were unchanged. While mind-wandering did not influence vigilance performance, intrinsic attention to pain drove both hit RTs and number of misses. This resulted in pain-focused subjects performing worse on the CPT pain task with slower RTs and more misses per block. During the CPT, the change in stimulus salience was related to the change in pain intensity, while pain unpleasantness correlated with tense arousal. CPT performance during experimental vigilance to pain and psychological activation were related to trait anxiety, as measured by the Spielberger State-Trait Anxiety Inventory and neuroticism, as measured by the NEO five factor inventory. Trait anxiety and neuroticism may play important roles in an individual's predisposition to dwell on pain and interpret pain as threatening.NEW & NOTEWORTHY Subjects detected moderately painful target stimuli in a train of mildly painful nontarget stimuli, which resulted in vigilance performance metrics including missed targets, reaction times, and psychological activation. These performance metrics were related to intrinsic attention to pain and trait anxiety. Subjects with high trait anxiety and neuroticism scores, with a predisposition to attend to pain, had greater tense arousal and poorer vigilance performance, which may be important psychological aspects of vigilance to pain.

Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network.

Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans.

Cerebral peak alpha frequency predicts individual differences in pain sensitivity.

The identification of neurobiological markers that predict individual predisposition to pain are not only important for development of effective pain treatments, but would also yield a more complete understanding of how pain is implemented in the brain. In the current study using electroencephalography (EEG), we investigated the relationship between the peak frequency of alpha activity over sensorimotor cortex and pain intensity during capsaicin-heat pain (C-HP), a prolonged pain model known to induce spinal central sensitization in primates. We found that peak alpha frequency (PAF) recorded during a pain-free period preceding the induction of prolonged pain correlated with subsequent pain intensity reports: slower peak frequency at pain-free state was associated with higher pain during the prolonged pain condition. Moreover, the degree to which PAF decreased between pain-free and prolonged pain states was correlated with pain intensity. These two metrics were statistically uncorrelated and in combination were able to account for 50% of the variability in pain intensity. Altogether, our findings suggest that pain-free state PAF over relevant sensory systems could serve as a marker of individual predisposition to prolonged pain. Moreover, slowing of PAF in response to prolonged pain could represent an objective marker for subjective pain intensity. Our findings potentially lead the way for investigations in clinical populations in which alpha oscillations and the brain areas contributing to their generation are used in identifying and formulating treatment strategies for patients more likely to develop chronic pain.

N-acetylaspartate as a reservoir for glutamate.

N-acetylaspartate (NAA) is an intermediary metabolite that is found in relatively high concentrations in the human brain. More specifically, NAA is so concentrated in the neurons that it generates one of the most visible peaks in nuclear magnetic resonance (NMR) spectra, thus allowing NAA to serve as "a neuronal marker". However, to date there is no generally accepted physiological (primary) role for NAA. Another molecule that is found at similar concentrations in the brain is glutamate. Glutamate is an amino acid and neurotransmitter with numerous functions in the brain. We propose that NAA, a six-carbon amino acid derivative, is converted to glutamate (five carbons) in an energetically favorable set of reactions. This set of reactions starts when aspartoacylase converts the six carbons of NAA to aspartate and acetate, which are subsequently converted to oxaloacetate and acetyl CoA, respectively. Aspartylacylase is found in astrocytes and oligodendrocytes. In the mitochondria, oxaloacetate and acetyl CoA are combined to form citrate. Requiring two steps, the citrate is oxidized in the Kreb's cycle to alpha-ketoglutarate, producing NADH. Finally, alpha-ketoglutarate is readily converted to glutamate by transaminating the alpha-keto to an amine. The resulting glutamate can be used by multiple cells types to provide optimal brain functional and structural needs. Thus, the abundant NAA in neuronal tissue can serve as a large reservoir for replenishing glutamate in times of rapid or dynamic signaling demands and stress. This is beneficial in that proper levels of glutamate serve critical functions for neurons, astrocytes, and oligodendrocytes including their survival. In conclusion, we hypothesize that NAA conversion to glutamate is a logical and favorable use of this highly concentrated metabolite. It is important for normal brain function because of the brain's relatively unique metabolic demands and metabolite fluxes. Knowing that NAA is converted to glutamate will be important for better understanding myriad neurodegenerative diseases such as Canavan's Disease and Multiple Sclerosis, to name a few. Future studies to demonstrate the chemical, metabolic and pathological links between NAA and glutamate will support this hypothesis.