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Background Native Americans (NAs) are more likely to experience chronic pain than non-Hispanic Whites (NHWs); however, the proximate causes predisposing NAs to chronic pain remain elusive. Likely due to centuries of adversity, discrimination, and marginalization, NAs report greater psychological stress than NHWs, which may place them at risk for sleep problems, a well-established risk factor for chronic pain onset. Purpose This study examined the effects of psychological stress and sleep problems on subjective and physiological measures of pain processing in NAs and NHWs. Methods Structural equation modeling was used to determine whether ethnicity (NA or NHW) was associated with psychological stress or sleep problems and whether these variables were related to conditioned pain modulation of pain perception (CPM-pain) and the nociceptive flexion reflex (CPM-NFR), temporal summation of pain (TS-pain) and NFR (TS-NFR), and pain tolerance in a sample of 302 (153 NAs) pain-free participants. Results NAs experienced more psychological stress (Estimate = 0.027, p = .009) and sleep problems (Estimate = 1.375, p = .015) than NHWs. When controlling for age, sex, physical activity, BMI, and general health, NA ethnicity was no longer related to greater sleep problems. Psychological stress was also related to sleep problems (Estimate = 30.173, p = Conclusions Sleep problems may contribute to chronic pain risk by facilitating pain perception without affecting facilitation of spinal neurons or endogenous inhibition of nociceptive processes. Since psychological stress promoted pain facilitation via enhanced sleep problems, efforts to reduce psychological stress and sleep problems among NAs may improve health outcomes.

Native Americans (NAs) have higher pain rates than the general U.S. population. It has been found that increased central sensitization and reduced pain inhibition are pronociceptive processes that increase pain risk; yet, little attention has focused on the influence of psychosocial factors. Discrimination is a psychosocial factor associated with increased pain in other minoritized groups; however, it is unclear whether it also promotes pain in NAs. This study analyzed data from 269 healthy, pain-free participants (N = 134 non-Hispanic whites [NHWs], N = 135 NAs) from the Oklahoma Study of Native American Pain Risk. Experienced discrimination was measured using the Everyday Discrimination Scale (EDS). Nociceptive processes were measured via static measures of spinal sensitivity (nociceptive flexion reflex [NFR] threshold, 3-stimulation NFR threshold), temporal summation of pain (TS-Pain) and nociceptive flexion reflex (TS-NFR), and conditioned pain modulation of pain (CPM-Pain) and NFR (CPM-NFR). Results demonstrated that greater discrimination was associated with enhanced TS-NFR and impaired CPM-NFR but not static measures of spinal sensitivity or measures of pain modulation (TS-Pain, CPM-Pain). Although the effects of discrimination on outcomes were similar in both groups (not moderated by ethnicity), NAs experienced higher levels of discrimination and therefore discrimination mediated a relationship between ethnicity and impaired CPM-NFR. This indicates experienced discrimination may promote a pain risk phenotype in NAs that involves spinal sensitization resulting from impaired inhibition of spinal nociception without sensitization of pain experience. PERSPECTIVE: This study found that discrimination was associated with spinal sensitization and impaired descending inhibition of spinal nociception. These findings bolster our understanding of how social stressors experienced disproportionately by minoritized groups can contribute to pain outcomes.

The nociceptive flexion reflex (NFR) is a spinally mediated withdrawal response and is used as an electrophysiological marker of descending modulation of spinal nociception. Chemical and pharmacological modulation of nociceptive neurotransmission at the spinal level has been evidenced by direct effects of neurotransmitters and pharmacological agents on the NFR. Largely unexplored are, however, the effects of nonpharmacological noninvasive conservative interventions on the NFR. Therefore, a systematic review and meta-analysis was performed and reported following the PRISMA guidelines to determine whether and to what extent spinal nociception measured through the assessment of the NFR is modulated by conservative therapy in patients and healthy individuals. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using the predefined inclusion criteria. Risk of bias was investigated according to Version 2 of the Cochrane risk-of-bias assessment tool for randomized trials. The evidence synthesis for this review was conducted in accordance with the Grading of Recommendations Assessment, Development and Evaluation. Thirty-six articles were included. Meta-analyses provided low-quality evidence showing that conservative therapy decreases NFR area and NFR magnitude and moderate-quality evidence for increases in NFR latency. This suggests that conservative interventions can exert immediate central effects by activating descending inhibitory pathways to reduce spinal nociception. Such interventions may help prevent and treat chronic pain characterized by enhanced spinal nociception. Furthermore, given the responsiveness of the NFR to conservative interventions, the NFR assessment seems to be an appropriate tool in empirical evaluations of treatment strategies.PROSPERO registration number: CRD42020164495.

Chronic pain results in considerable suffering, as well as significant economic and societal costs. Previous evidence suggests that Native Americans (NAs) have higher rates of chronic pain than other U.S. racial or ethnic groups, but the mechanisms contributing to this pain disparity are poorly understood. The Oklahoma Study of Native American Pain Risk was developed to address this issue and recruited healthy, pain-free NAs and non-Hispanic Whites. Cross-sectional analyses identified several measures of adversity (eg, trauma and discrimination), cognitive-affective factors (perceived stress and pain-related anxiety/catastrophizing), and cardiometabolic factors (eg, body mass index, blood pressure, and heart rate variability) that were associated with pronociceptive processes (eg, central sensitization, descending inhibition, and hyperalgesia). Every 6-months after enrollment, eligible participants (N = 277) were recontacted and assessed for the onset of chronic pain. This study examines predictors of chronic pain onset in the 222 participants (80%) who responded over the first 2 years. The results show that NAs developed chronic pain at a higher rate than non-Hispanic Whites (OR = 2.902, P0.05), even after controlling for age, sex, income, and education. Moreover, serial mediation models identified several potential pathways to chronic pain onset within the NA group. These paths included perceived discrimination, psychological stress, pain-related anxiety, a composite measure of cardiometabolic risk, and impaired descending inhibition of spinal nociception (assessed from conditioned pain modulation of the nociceptive flexion reflex). These results provide the first prospective evidence for a pain disparity in NAs that seems to be promoted by psychosocial, cardiometabolic, and pronociceptive mechanisms.

The most widely accepted definition of pain considers it a sensory and emotional experience associated with potential or actual physical harm. However, research tends to generalize findings from predominantly European American samples thereby assuming universality across cultures. Because of the high prevalence of pain within the AI group, it is important to consider whether their conceptualization of pain is similar to the universal definition. To accomplish this aim, a semi-structured interview was conducted with 152 AIs (primarily Southern Plains and eastern Oklahoma tribes) and 150 NHWs. Both groups were asked questions including what words describe hurtful experiences, the purpose of painful experiences, individual and culture-specific meanings of pain, and what constituted the opposite of pain. Many similarities were found between groups as well as differences. For example, NHWs used the word pain more often to describe physically hurtful experiences and were more likely to consider pain to be a signal or warning of an abnormality or pathology. By contrast, only AIs reported culture-specific meanings of pain, such as references to AI rituals or ceremonies. These observed differences are attenuated by small effect sizes. These findings are important to consider when hypothesizing the differences in pain among cultural groups.

Objectives Native Americans (NAs) have the highest prevalence of chronic pain of any racial/ethnic group. This issue has received little attention from the scientific community. One factor that may contribute to racial pain disparities is pain catastrophizing. Pain catastrophizing is a construct related to negative pain outcomes in persons with/without chronic pain. It has been suggested that the relationship between trait catastrophizing and pain is mediated by situation-specific (state) catastrophizing. The present study has 2 aims: (1) to investigate whether state pain catastrophizing mediates the relationship between trait catastrophizing and experimental pain (e.g., cold, ischemic, heat and electric tolerance), and (2) to investigate whether this relationship is stronger for NAs. Methods 145 non-Hispanic Whites (NHWs) and 137 NAs completed the study. Bootstrapped indirect effects were calculated for 4 unmoderated and 8 moderated mediation models (4 models with path a moderated and 4 with path b). Results Consistent with trait-activation theory, significant indirect effects indicated a tendency for trait catastrophizing to be associated with greater state catastrophizing which in turn is associated with reduced pain tolerance during tonic cold (a × b=−0.158) and ischemia stimuli (a × b=−0.126), but not during phasic electric and heat stimuli. Moderation was only noted for the prediction of cold tolerance (path a). Contrary to expectations, the indirect path was stronger for NHWs (a × b for NHW=−.142). Conclusions Together, these findings suggest that state catastrophizing mediates the relationship between trait catastrophizing and some measures of pain tolerance but this indirect effect was non-significant for NAs.

Native Americans (NAs) have a higher prevalence of chronic pain than other U.S. racial/ethnic groups, but there have been few attempts to understand the mechanisms of this pain disparity. This study used a comprehensive battery of laboratory tasks to assess peripheral fiber function (cool/warm detection thresholds), pain sensitivity (eg, thresholds/tolerances), central sensitization (eg, temporal summation), and pain inhibition (conditioned pain modulation) in healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Multiple pain stimulus modalities were used (eg, cold, heat, pressure, ischemic, and electric), and subjective (eg, pain ratings and pain tolerance) and physiological (eg, nociceptive flexion reflex) outcomes were measured. There were no group differences on any measure, except that NAs had lower cold-pressor pain thresholds and tolerances, indicating greater pain sensitivity than NHWs. These findings suggest that there are no group differences between healthy NAs and NHWs on peripheral fiber function, central sensitization, or central pain inhibition, but NAs may have greater sensitivity to cold pain. Future studies are needed to examine potential within-group factors that might contribute to NA pain risk.

Sexual assault (SA) is associated with an increased risk of chronic pain, but the mechanisms for this relationship are poorly understood. To explore whether disrupted descending inhibition is involved, this study used a conditioned pain modulation task to study the inhibition of pain and the nociceptive flexion reflex (NFR; a correlate of spinal nociception) in 32 pain-free SA survivors. This group was compared with 32 pain-free, trauma-exposed persons without SA and a group of 40 pain-free persons who reported no trauma exposure. Conditioned pain modulation was assessed from painful electric stimulations (test stimulus) delivered to the ankle before, during, and after participants submerged their hand in painful 10°C water (conditioning stimulus). Pain ratings and NFR were assessed in response to test stimuli. All groups demonstrated significant inhibition of pain during conditioned pain modulation. However, only the no trauma exposure group demonstrated significant inhibition of NFR. The persons without SA group showed no inhibition of NFR, whereas the SA group showed significant facilitation of the NFR. These findings suggest that trauma exposure may impair inhibitory cerebrospinal circuits, but that SA may specifically promote facilitation of spinal nociception. Perspective: This study suggests that trauma exposure disrupts the cerebrospinal inhibition of spinal nociception, but that exposure to SA further promotes chronic pain risk by facilitating spinal nociception. This finding help may help to elucidate the pain risk mechanisms in trauma survivors.

Objective This study investigated whether a brief psychotherapy for post-trauma nightmares (exposure, relaxation, and rescripting therapy [ERRT]), reduced suicidal ideation (SI). We hypothesized that: (a) nightmare frequency and severity, post-traumatic stress disorder (PTSD), depression, and sleep quality would be related to SI at pretreatment; (b) SI would decrease from pre- to post-treatment; and (c) the decrease in SI would remain after controlling for change in PTSD and depression. Method Seventy-five individuals exposed to a traumatic event and who experienced frequent nightmares (minimum one per week) participated in ERRT. Participants were not required to have a psychological diagnosis. Thirty percent endorsed SI at pretreatment. Results Depression and PTSD were related to SI at pretreatment. SI decreased following treatment; however, the third hypothesis was not supported. Conclusion Results suggest brief psychotherapy targeting post-trauma nightmares may decrease SI. More research is necessary to determine what factors contribute to decreases in SI.

Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing to assess pain experience in healthy, pain-free adults (n = 137 NAs (87 female), n = 145 non-Hispanic whites (NHW; 68 female)) after painful electric, heat, cold, ischemic, and pressure stimuli. After each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. The results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these finding were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (eg, pain → anxiety/catastrophizing → pain). Perspective NAs experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this characteristic may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.

Background The tendency to inhibit anger (anger-in) is associated with increased pain. This relationship may be explained by the negative affectivity hypothesis (anger-in increases negative affect that increases pain). Alternatively, it may be explained by the cognitive resource hypothesis (inhibiting anger limits attentional resources for pain modulation). Methods A well-validated picture-viewing paradigm was used in 98 healthy, pain-free individuals who were low or high on anger-in to study the effects of anger-in on emotional modulation of pain and attentional modulation of pain. Painful electrocutaneous stimulations were delivered during and in between pictures to evoke pain and the nociceptive flexion reflex (NFR; a physiological correlate of spinal nociception). Subjective and physiological measures of valence (ratings, facial/corrugator electromyogram) and arousal (ratings, skin conductance) were used to assess reactivity to pictures and emotional inhibition in the high anger-in group. Results The high anger-in group reported less unpleasantness, showed less facial displays of negative affect in response to unpleasant pictures, and reported greater arousal to the pleasant pictures. Despite this, both groups experienced similar emotional modulation of pain/NFR. By contrast, the high anger-in group did not show attentional modulation of pain. Conclusions These findings support the cognitive resource hypothesis and suggest that overuse of emotional inhibition in high anger-in individuals could contribute to cognitive resource deficits that in turn contribute to pain risk. Moreover, anger-in likely influenced pain processing predominantly via supraspinal (e.g., cortico-cortical) mechanisms because only pain, but not NFR, was associated with anger-in.

Native Americans (NAs) experience higher rates of chronic pain than the general U.S. population, but the risk factors for this pain disparity are unknown. NAs also experience high rates of stressors and cardiovascular and metabolic health disparities (eg, diabetes, cardiovascular disease) consistent with allostatic load (stress-related wear-and-tear on homeostatic systems). Given that allostatic load is associated with chronic pain, then allostatic load may contribute to their pain disparity. Data from 302 healthy, pain-free men and women (153 NAs, 149 non-Hispanic Whites [NHW]) were analyzed using structural equation modeling to determine whether cardiometabolic allostatic load (body mass index, blood pressure, heart rate variability) mediated the relationship between NA ethnicity and experimental measures of pronociceptive processes: temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR), conditioned pain modulation of pain (CPM-pain) and NFR (CPM-NFR), and pain tolerance. Results indicated that NAs experienced greater cardiometabolic allostatic load that was related to enhanced TS-NFR and impaired CPM-NFR. Cardiometabolic allostatic load was unrelated to measures of pain perception (CPM-pain, TS-pain, pain sensitivity). This suggests cardiometabolic allostatic load may promote spinal sensitization in healthy NAs, that is not concomitant with pain sensitization, perhaps representing a unique pain risk phenotype in NAs. Perspective: Healthy, pain-free Native Americans experienced greater cardiometabolic allostatic load that was associated with a pronociceptive pain phenotype indicative of latent spinal sensitization (ie, spinal sensitization not associated with hyperalgesia). This latent spinal sensitization could represent a pain risk phenotype for this population.

Threat-induced pain modulation can increase survival by amplifying physiological and behavioral reactions toward danger. Threat can also modulate spinal nociception, suggesting engagement of endogenous top-down circuitry. A unique method to assess spinal nociception is via reflex receptive fields (RRF) associated with the nociceptive withdrawal reflex (NWR, a protective spinally-mediated reflex). The size of nociceptive RRFs can be modulated by top-down circuitry with the enlargement of RRFs related to increased spinal nociception. Threat has been previously shown to enhance pain and spinal nociception, but the relationship between threat and RRFs has not been investigated. The present study investigated this issue in 25 healthy individuals. RRFs were determined from NWRs measured by electromyography of the tibialis anterior following electrocutaneous stimulations. RRFs and pain were assessed during periods in which participants were under threat of unpredictable painful abdominal stimulations and when they were not under threat. Results indicated that threat periods led to significantly higher pain, larger nociceptive RRFs and NWR magnitudes. These findings imply that threat produces changes in protective reflexes related to spinal nociceptive sensitivity and increased pain perception. This is likely mediated by top-down circuitry that enhances dorsal horn nociceptive neurons by enlarging RRFs and amplifying ascending pain signals. PERSPECTIVE: This article presents the enlargement of RRF during periods of threat. The results from this study may help clarify the mechanism underlining emotional modulation of spinal nociception.

Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n = 124) and non-Hispanic Whites (n = 129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. Perspective This study found that adverse life events were associated with impaired descending inhibition of spinal nociception in a sample of Native Americans and non-Hispanic Whites. These findings expand on previous research linking adversity to chronic pain risk by identifying a proximate physiological mechanism for this association.

Compared to other racial/ethnic groups, Native Americans (NAs) are more likely to develop health conditions associated with allostatic load (stress-related wear-and-tear). Psychosocial factors (i.e., adverse life events, discrimination, psychological distress) often promote stress and may help explain greater allostatic load in NAs. Moreover, previous research suggests sleep may either mediate or moderate the effects of some psychosocial stressors, like discrimination, on allostatic load. The current study investigated the relationship between adverse life events, discrimination, psychological stress, sleep, and cardiometabolic load.Using a sample of 302 healthy, chronic pain-free NAs and non-Hispanic White (NHW) participants, bootstrapped mediation analyses were conducted to determine whether the relationship between NA race/ethnicity and cardiometabolic allostatic load (composite score of body mass index, mean arterial pressure, and heart rate variability) was mediated by psychosocial stressors. Models also assessed whether sleep disturbance served as an additional mediator or a moderator to the effects.Consistent with prior research, we found that NAs experienced greater discrimination, adverse life events (potentially traumatic events), and cardiometabolic allostatic load than NHWs. Further, discrimination was associated with increased psychological stress for NAs, but this did not explain why NAs experience higher cardiometabolic allostatic load. A moderating effect of sleep on discrimination was found, such that discrimination partially contributed to the relationship between NA race/ethnicity and cardiometabolic allostatic load, but only for participants reporting greater sleep disturbance. Implications These findings highlight that good sleep can buffer the effect of psychosocial stress on cardiometabolic allostatic load in Native Americans.

Native Americans (NAs) experience higher rates of chronic pain. To examine the mechanisms for this pain inequity, we have previously shown that NAs report higher levels of pain-related anxiety and pain catastrophizing, which are in turn related to pronociceptive (pain-promoting) processes. But, it is currently unclear why NAs would report greater pain-related anxiety and catastrophizing. Given that NAs are also more likely to experience adverse life events (ALEs) and associated psychological distress, it was hypothesized that higher anxiety/catastrophizing in NAs would be partially explained by higher rates of ALEs and psychological distress. Structural equation modeling was used to analyze these pathways (NA ethnicity ➔ ALEs ➔ psychological distress ➔ pain anxiety/catastrophizing) in 305 healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Pain-related anxiety and situational pain catastrophizing were assessed in response to a variety of painful tasks. The Life Events Checklist was used to assess cumulative exposure to ALEs that directly happened to each participant. A latent psychological distress variable was modeled from self-reported perceived stress and psychological symptoms. Results found that NAs experienced more ALEs and greater psychological distress which was associated with higher rates of pain-related anxiety and pain catastrophizing. Notably, NAs did not report greater psychological distress when controlling for ALE exposure. This suggests that a higher risk of chronic pain in NAs may be due, in part, to psychological distress, pain-related anxiety, and pain catastrophizing that are promoted by exposure to ALEs. These results highlight several targets for intervention to decrease NA pain risk.

Poor sleep quality is often comorbid with chronic pain. Research has also shown that poor and disrupted sleep may increase risk for chronic pain by promoting pronociceptive processes. This could occur through disrupted emotional modulation of pain since poor sleep can impact emotional experience and emotional experience modulates pain and nociception. To assess the pain system, nociceptive flexion reflexes (spinal level), pain-evoked potentials (supraspinal level), and perceived pain were recorded during an emotional picture-viewing task in which 37 healthy individuals received painful electric stimulations. The Pittsburgh Sleep Quality Index assessed sleep quality. Individuals with poor sleep quality were unable to inhibit signals at the spinal level in response to positive pictures, whereas emotional modulation of supraspinal nociception and pain perception remained unaffected by sleep quality. This suggests poor sleep quality may promote pronociception by impairing descending, emotional modulation of spinal nociception.

Native Americans (NAs) are at increased risk for chronic pain. One mechanism contributing to this pain disparity could be personal pain beliefs, which may influence actual pain sensitivity. Thus, we examined whether self-evaluated pain sensitivity (SEPS) mediates the relationship between ethnicity [NAs vs. non-Hispanic Whites (NHWs)] and objectively-measured pain tolerance, and whether catastrophic thinking and pain-related anxiety influence these pain beliefs. 232 healthy, pain-free NAs and NHWs completed questionnaires measuring SEPS, catastrophizing, and anxiety. Objective pain tolerance was also assessed. Results suggested: (1) NAs reported higher levels of SEPS, catastrophizing, and anxiety, (2) catastrophizing may have enhanced anxiety and both catastrophizing and anxiety were associated with higher SEPS, and (3) anxiety and SEPS were associated with lower pain tolerance. A significant bootstrapped mediation analysis suggested NAs experienced higher pain-related anxiety, which may have promoted higher SEPS, that in turn reduced pain tolerance. Longitudinal research is needed to confirm this.

Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, P= .04, with the expected linear slope following anodal stimulation (ie, pleasantneutralunpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts. PERSPECTIVE: This study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.

BackgroundConditioned pain modulation (CPM) is a task that involves measuring pain in response to a test stimulus before and during a painful conditioning stimulus (CS). The CS pain typically inhibits pain elicited by the test stimulus; thus, this task is used to assess endogenous pain inhibition. Moreover, less efficient CPM-related inhibition is associated with chronic pain risk. Pain catastrophizing is a cognitive-emotional process associated with negative pain sequelae, and some studies have found that catastrophizing reduces CPM efficiency.PurposeThe current study examined the relationship between catastrophizing (dispositional and situation specific) and CPM-related inhibition of pain and the nociceptive flexion reflex (NFR; a marker of spinal nociception) to determine whether the catastrophizing–CPM relationship might contribute to the higher risk of chronic pain in Native Americans (NAs).MethodsCPM of pain and NFR was assessed in 124 NAs and 129 non-Hispanic Whites. Dispositional catastrophizing was assessed at the beginning of the test day, whereas situation-specific catastrophizing was assessed in response to the CS, as well as painful electric stimuli.ResultsSituation-specific, but not dispositional, catastrophizing led to less NFR inhibition but more pain inhibition. These effects were not moderated by race, but mediation analyses found that: (a) the NA race was associated with greater situation-specific catastrophizing, which led to less NFR inhibition and more pain inhibition, and (b) situation-specific catastrophizing was associated with greater CS pain, which led to more pain inhibition.ConclusionsCatastrophizing may contribute to NA pain risk by disrupting descending inhibition.

Several studies have recently suggested that an abnormal processing of respiratory interoceptive and nociceptive (painful) stimuli may contribute to eating disorder (ED) pathophysiology. Mood and anxiety disorders (MA) are also characterized by abnormal respiratory symptoms, and show substantial comorbidity with ED. However, no studies have examined both respiratory and pain processing simultaneously within ED and MA. The present study systematically evaluated responses to perturbations of respiratory and nociceptive signals across the levels of physiology, behavior, and symptom report in a transdiagnostic ED sample (n = 51) that was individually matched to MA individuals (n = 51) and healthy comparisons (HC; n = 51). Participants underwent an inspiratory breath-holding challenge as a probe of respiratory interoception and a cold pressor challenge as a probe of pain processing. We expected both clinical groups to report greater stress and fear in response to respiratory and nociceptive perturbation than HCs, in the absence of differential physiological and behavioral responses. During breath-holding, both the ED and MA groups reported significantly more stress, feelings of suffocation, and suffocation fear than HC, with the ED group reporting the most severe symptoms. Moreover, anxiety sensitivity was related to suffocation fear only in the ED group. The heightened affective responses in the current study occurred in the absence of group differences in behavioral (breath hold duration, cold pressor duration) and physiological (end-tidal carbon dioxide, end-tidal oxygen, heart rate, skin conductance) responses. Against our expectations, there were no group differences in the response to cold pain stimulation. A matched-subgroup analysis focusing on individuals with anorexia nervosa (n = 30) produced similar results. These findings underscore the presence of abnormal respiratory interoception in MA and suggest that hyperreactivity to respiratory signals may be a potentially overlooked clinical feature of ED.

OBJECTIVE Sexual assault (SA) is associated with an increased risk for chronic pain and affective distress. Given that emotional processes modulate pain (e.g., negative emotions enhance pain, positive emotions inhibit pain), increased pain risk in SA survivors could stem from a disruption of emotional modulation processes. METHODS A well-validated affective picture-viewing paradigm was used to study emotional modulation of pain in 33 healthy, pain-free SA survivors and a control group of 33 healthy, pain-free individuals with no reported history of SA (matched on age, sex, race, and number of non-SA traumas). Unpleasant (mutilation), neutral, and pleasant (erotic) pictures were presented, while painful electrocutaneous stimulations were delivered at the ankle. Pain intensity ratings and nociceptive flexion reflex (NFR) magnitudes (a physiologic measure of spinal nociception) were recorded in response to electric stimuli. Multilevel models were used to analyze the data with group (SA versus non-SA) and content (mutilation, neutral, erotic) as independent variables. RESULTS Both groups demonstrated similar emotional modulation of pain (FGroupbyContent(2,646.52) = 0.44, p = .65), but a main effect of group (FGroup(1,65.42) = 4.24, p = .043) indicated the SA group experienced more overall pain from electric stimuli (hyperalgesia). A significant group by content interaction for NFR (p = .035) indicated that emotional modulation of NFR was present for the non-SA group (FContentSimpleEffect(2,684.55) = 12.43, p < .001), but not the SA group (FContentSimpleEffect(2,683.38) = 1.71, p = .18). CONCLUSIONS These findings suggest that SA survivors have difficulty emotionally engaging brain-to-spinal cord mechanisms to modulate spinal nociception. A disruption of descending inhibition plus hyperalgesia could contribute to comorbidity between sexual trauma and chronic pain.

Negative affect is considered an important factor in the etiology of depression and anxiety, and is highly related to pain. However, negative affect is not a unitary construct. To identify specific targets for treatment development, we aimed to derive latent variables of negative affect and test their unique contributions to affective processing during anticipation of unpredictable, painful shock. Eighty-three subjects (43 with depression and anxiety spectrum disorders and 40 healthy controls) completed self-report measures of negative valence and underwent neuroimaging while exploring computer-simulated contexts with and without the threat of a painful, but tolerable, shock. Principal component analysis (PCA) extracted distinct components of general negative affect (GNA) and pain-related negative affect (PNA). While elevated GNA and PNA were both indicative of depression and anxiety disorders, greater PNA was more strongly related to task-specific anxious reactivity during shock anticipation. GNA was associated with increased precuneus and middle frontal gyrus activity, whereas PNA was related to increased bilateral anterior insula activity. Anterior insula activity mediated the relationship between PNA and task-specific anxious reactivity. In conclusion, GNA and PNA have distinct neural signatures and uniquely contribute to anxious anticipation. PNA, via insula activity, may relate to arousal in ways that could contribute to affective dysregulation, and thus may be an important treatment target.

Biological Psychiatry, 3 (6), ISSN:0006-3223, ISSN:1873-2402

Habituation (ie, decreases in responding) and sensitization (ie, increases in responding) after prolonged or repeated exposures to a fixed stimulus have been identified as important in adaptation to repeated or prolonged noxious stimulation. Determinants of habituation or sensitization are poorly understood, and experimental investigation of habituation of pain ratings have generally relied on pain reports and statistical techniques that average responses across a group of participants. Using a cross-sectional design, the current study used multilevel growth curve analyses to examine changes in the nociceptive flexion reflex (NFR), a spinal nociceptive withdrawal reflex, and pain ratings in response to 12 repeated, constant intensity, noxious electrocutaneous stimuli. Unconditional growth curve models indicated that, on average, participants evidenced habituation of the NFR and sensitization of pain ratings. However, a substantial subgroup of participants exhibited the opposite pattern of change. In conditional models, behavioral inhibition, b = .10, P = .003, and behavioral activation, b = −.07, P = .07, independently interacted with the growth curve to predict changes in NFR, but not pain ratings, across the 12 stimuli. These findings provide preliminary experimental support for Jensen and colleagues' 2-factor model of pain experience and implicate a role for approach and avoidance motivations in descending modulation of NFR. Perspective Using repeated NFR stimulation, this study showed that most participants exhibited NFR habituation and pain sensitization; however, a substantial subgroup showed an opposite pattern of pain habituation (25.0%) and NFR sensitization (31.4%). Further, NFR habituation was moderated by individual differences in behavioral activation and behavioral inhibition.

Objective To assess conditioned pain modulation efficiency in persons with and without migraine headaches. Design Cross-sectional assessment of experimental pain. Setting University campus and surrounding community in a large Midwestern US city. Subjects Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Participants were mostly female (N = 40) with an average age of 23 years. Methods Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering four more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Depression and pain catastrophizing were assessed to control for the potential influence of these variables on pain modulation. Results Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes. Pain report was inhibited by conditioned pain modulation in both the migraine and control groups. However, unlike nonmigraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task. This pattern persisted after controlling for level of pain catastrophizing and depression. Conclusions Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches.

Adverse life experiences (ALEs) are associated with hyperalgesia and chronic pain, but the underlying mechanisms are poorly understood. One potential mechanism is hyperexcitability of spinal neurons (i.e., central sensitization). Given that Native Americans (NA) are more likely to have ALEs, and have a higher prevalence of chronic pain, the relationship between ALEs and spinal hyperexcitability might contribute to their pain risk. The present study assessed temporal summation of the nociceptive flexion reflex (TS-NFR; correlate of spinal hyperexcitability) and pain (TS-Pain) in 246 healthy, pain-free non-Hispanic whites (NHW) and Native Americans (NA). The Life Events Checklist (LEC-4) assessed the number of ALEs. Multilevel growth models were used to predict TS-NFR and TS-Pain, after controlling for age, perceived stress, psychological problems, negative and positive affect, and painful stimulus intensity. ALEs and negative affect were significantly associated with higher pain, but not enhanced TS-Pain. By contrast, ALEs were associated with enhanced TS-NFR. Race did not moderate these relationships. This implies that ALEs promote hyperalgesia as a result of increased spinal neuron excitability. Although relationships between ALEs and NFR/pain were not stronger in NAs, given prior evidence that NAs experience more ALEs, this might contribute to the higher prevalence of chronic pain in NAs. PERSPECTIVE: This study found a dose-dependent relationship between adverse life experiences (ALE) and spinal neuron excitability. Although the relationship was not stronger in Native Americans (NA) than non-Hispanic whites, given prior evidence that NAs experience more ALEs, this could contribute to the higher prevalence of chronic pain in NAs.

Pain catastrophizing is associated with enhanced pain; however, the mechanisms by which it modulates pain are poorly understood. Evidence suggests that catastrophizing modulates supraspinal processing of pain but does not modulate spinal nociception (as assessed by nociceptive flexion reflex [NFR]). Unfortunately, most NFR studies have been correlational. To address this, this study experimentally reduced catastrophizing to determine whether it modulates spinal nociception (NFR). Healthy pain-free participants (N = 113) were randomly assigned to a brief 30-minute catastrophizing reduction manipulation or a control group that received pain education. Before and after manipulations, 2 types of painful stimuli were delivered to elicit (1) NFR (single trains of stimuli) and (2) temporal summation of NFR (3 stimulations at 2 Hz). After each set of stimuli, participants were asked to report their pain intensity and unpleasantness, as well as their situation-specific catastrophizing. Manipulation checks verified that catastrophizing was effectively reduced. Furthermore, pain intensity and unpleasantness to both stimulation types were reduced by the catastrophizing manipulation, effects that were mediated by catastrophizing. Although NFRs were not affected by the catastrophizing manipulation, temporal summation of NFR was reduced. However, this effect was not mediated by catastrophizing. These results indicate that reductions in catastrophizing lead to reductions in pain perception but do not modulate spinal nociception and provides further evidence that catastrophizing modulates pain at the supraspinal, not the spinal, level.

OBJECTIVE Premenstrual dysphoric disorder (PMDD) is associated with increased pain, but there has been a lack of well-controlled research assessing pain responsivity, sex hormones, and their relationships in this group. This study was designed to address this gap in the literature. MATERIALS AND METHODS Healthy, regularly cycling participants (14 PMDD, 14 non-PMDD) attended pain testing sessions during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (order counterbalanced) and salivary estradiol, progesterone, and testosterone were assessed at each testing session. Pain sensitivity was measured from electrocutaneous threshold/tolerance, ischemic threshold/tolerance, sensory and affective ratings of electrocutaneous and ischemic stimuli, and the nociceptive flexion reflex threshold (NFR, a measure of spinal nociception). RESULTS Women with PMDD had higher sensory pain ratings of electrocutaneous stimuli and trends for lower ischemic thresholds and higher affective pain ratings of electrocutaneous stimuli. However, there were no group differences observed in NFR threshold. Testosterone levels were also lower during the mid-follicular and ovulatory phases in PMDD. Correlations between pain outcomes and estradiol and testosterone indicated that these hormones are hypoalgesic, with estradiol having a greater hypoalgesic effect within the PMDD group. DISCUSSION Overall, women with PMDD may have a phase-independent hyperalgesia, with pain amplification likely occurring at the supraspinal level rather than the spinal level, given the lack of group differences in NFR threshold. Because testosterone was hypoalgesic and lower in women with PMDD, and there were strong associations between pain and estradiol in PMDD, sex hormones may play a role in PMDD-related hyperalgesia.

In healthy individuals, emotions modulate pain and spinal nociception according to a valence linear trend (ie, pain/nociception is highest during negative emotions and lowest during positive emotions). However, emerging evidence suggests that emotional modulation of pain (but not spinal nociception) is disrupted in fibromyalgia and disorders associated with chronic pain risk (eg, major depression, insomnia). The present study attempted to extend this work and to examine whether women with premenstrual dysphoric disorder (PMDD), a cyclical syndrome associated with debilitating affective symptoms during the late-luteal (premenstrual) phase of the menstrual cycle, is also associated with disrupted emotional modulation of pain. To do so, an affective picture-viewing procedure was used to study emotional modulation of pain and spinal nociception in 14 women with PMDD and 14 control women during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (verified by salivary hormone levels and luteinizing hormone tests). At each phase, mutilation, neutral, and erotic pictures were presented to manipulate emotion. During picture viewing, suprathreshold electrocutaneous stimuli were presented to evoke pain and the nociceptive flexion reflex (NFR; a physiological measure of spinal nociception). Statistically powerful linear mixed model analyses confirmed that pictures evoked the intended emotional states in both groups across all menstrual phases. Furthermore, emotion modulated pain and NFR according to a valence linear trend in both groups and across all menstrual phases. Thus, PMDD-related affective disturbance is not associated with a failure to emotionally modulate pain, suggesting that PMDD does not share this pain phenotype with major depression, insomnia, and fibromyalgia.

Sex hormones may contribute to inter- and intra-individual differences in pain by influencing emotional modulation of pain and nociception. To study this, a well-validated picture-viewing paradigm was used to assess emotional modulation of pain and the nociceptive flexion reflex (NFR; physiologic measure of nociception) during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle in healthy normally cycling women (n=40). Salivary estradiol, progesterone, and testosterone were assessed at each testing session. Emotional modulation of pain/NFR did not differ across menstrual phases, but low estradiol was associated with weaker emotional modulation of NFR (during all phases) and emotional modulation of pain (ovulatory and late-luteal phases). Given evidence that a failure to emotionally modulate pain might be a risk factor for chronic pain, low estradiol may promote chronic pain via this mechanism. However, future research is needed to extend these findings to women with disturbances of pain, emotion, and/or sex hormones.

Pain problems are more prevalent in Native Americans than in any other group in the U.S., and this might result from group differences in pain modulation. This study was designed to examine emotional modulation of pain and spinal nociception in healthy, pain-free Native Americans (n = 21) relative to non-Hispanic Whites (n = 20). To assess emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception), participants underwent a well-validated emotional picture-viewing paradigm during which suprathreshold pain stimuli were delivered to the ankle. Compared to Whites, Native Americans reported less pleasure to erotic pictures and failed to show corrugator reactivity to mutilation pictures. Unlike Whites, Native Americans only evidenced pain inhibition in response to erotica, but no pain facilitation (disinhibition) to mutilation pictures. Emotional modulation of NFR was similar in both groups. These preliminary findings suggest that Native Americans failed to disinhibit pain, perhaps due to over-activation of pain inhibitory mechanisms. Chronic over-activation of this system could ultimately exhaust it, thus putting Native Americans at future risk for chronic pain.

Objective The aim of this study was to conduct a preliminary dismantling study of exposure, relaxation, and rescripting therapy (ERRT) for nightmares. Method Participants (N = 70) were randomized to 1 of 2 conditions: ERRT with nightmare exposure and rescripting (full protocol; EX) or ERRT without nightmare exposure and rescripting (NEX). Participants completed follow-ups at 1 week, 3 months, and 6 months posttreatment. Results Both conditions yielded statistically significant improvements with medium to large effect sizes on primary outcomes related to nightmares (i.e., nights with nightmares, nightmares per week, and nightmare severity). Both conditions also yielded statistically significant improvements on secondary outcomes with medium to large effect sizes on fear of sleep, sleep quality, insomnia severity, daytime sleepiness, posttraumatic stress disorder symptom severity, and depression severity. The conditions did not differ at any time point. Conclusions Findings indicate that ERRT with and without nightmare exposure and rescripting can significantly alleviate nightmares and related distress. The addition of nightmare exposure and rescription did not contribute incrementally to outcomes in this sample. It is possible that the dose of exposure was not sufficient to result in group differences or that the treatment components included in both conditions (i.e., psychoeducation about trauma, nightmares, and sleep; sleep habit modification; and relaxation training) may adequately treat factors that maintain nightmares for some individuals. Theoretical implications of findings are discussed. The reduction of symptoms of other conditions following this brief intervention provides further evidence for the primary role of nightmares and sleep disturbances posttrauma. (PsycINFO Database Record

Nightmares and sleep disturbances are gaining attention as targets of treatment interventions for trauma-exposed populations. Measures in trials evaluating these interventions tend to utilize proprietary measures of nightmare characteristics, which makes it challenging to compare findings across studies. The Trauma-Related Nightmare Survey is a questionnaire that was initially developed for utilization in efficacy studies of Exposure, Relaxation, and Rescripting Therapy. Preliminary examinations of the psychometric properties have demonstrated good test-retest reliability and convergent validity. The present brief report provides an updated examination of these properties and offers the first open publication of the measure for general use. Results support previous findings that the Trauma-Related Nightmare Survey demonstrates good test-retest reliability (r = .73) and moderate to strong convergent validity (rs = .44-.78) with other commonly utilized measures of sleep and mood symptoms.

Slow breathing is used as a means to reduce pain, yet the mechanisms responsible for respiration-induced hypoalgesia are poorly understood. The present study asked 30 healthy partici- pants (Mage = 21 years, Meducation = 15 years, 80% white non-Hispanic) to breathe at normal, slow (50% normal), and fast (125% normal) rates while constant-intensity, suprathreshold electric stimu- lations were delivered to the sural nerve to elicit pain and the nociceptive flexion reflex (NFR, a mea- sure of spinal nociception). Stimulations were equally balanced across inhalations and exhalations to determine whether parasympathetic activation during exhalations contributes to hypoalgesia. Respi- ration rate, heart rate variability (HRV, a measure of parasympathetic activity), heart rate, and subjec- tive arousal were assessed as manipulation checks. Slow breathing reduced pain relative to normal breathing and fast breathing, but NFR was not influenced by breathing. Further, pain and NFR did not differ between exhalations and inhalations, and changes in HRV did not correlate with changes in pain or NFR. Together, these findings suggest that respiration-induced hypoalgesia does not re- quire gating of spinal nociception or changes in parasympathetic activity. Perspective: Slow breathing reduced pain relative to normal and fast breathing. This respiration- induced hypoalgesia does not appear to be due to gating of spinal nociception or changes in para- sympathetic activity.

The menstrual cycle influences pain, with symptoms often increasing during the premenstrual (late-luteal) phase. Deficiencies in endogenous inhibition of afferent nociception at the spinal level might contribute to menstrual phase-related changes in pain. This study assessed whether conditioned pain modulation (CPM) of spinal nociception differs between mid-follicular and late-luteal phases. CPM was evoked by a blood pressure cuff affixed to the right forearm and inflated to induce ischemia in 41 healthy women during both menstrual phases. Suprathreshold electric stimuli were delivered to the left sural nerve to evoke pain and the nociceptive flexion reflex (NFR) before, during, and after forearm ischemia. Forearm ischemia produced CPM of electrocutaneous pain and NFR, but inhibition did not differ across mid-follicular and late-luteal phases. Mechanisms contributing to changes in experimental pain across mid-follicular and late-luteal phases in healthy women are not due to deficits in CPM of spinal nociception.

Study Objectives: Evidence supports the use of cognitive behavioral therapies for nightmares in trauma-exposed individuals. This randomized clinical trial replicated a study of exposure, relaxation, and rescripting therapy (ERRT) and extended prior research by including broad measures of mental health diffi culties, self-reported physical health problems, and quality of life. Additionally, physiological correlates of treatment-related change assessed from a script-driven imagery paradigm were examined. Methods: Forty-seven individuals were randomized to treatment or waitlist control. Results: The treatment group demonstrated improvements relative to the control group at the one-week post-treatment assessment. At the 6-month follow-up assessment, signifi cant improvements were found for frequency and severity of nightmares, posttraumatic stress disorder symptoms, depression, sleep quality and quantity, physical health symptoms, anger, dissociation, and tension reduction behaviors. Participants also reported improved quality of life. Treatment-related decreases in heart rate to nightmare imagery were correlated with improvements in sleep quality and quantity; treatment-related decreases in skin conductance to nightmare imagery were correlated with improvements in nightmare severity, posttraumatic stress disorder symptom severity, sleep quality, and fear of sleep; and treatment-related decreases in corrugator activity to nightmare imagery were correlated with improved physical health. Conclusions: Findings provide additional support for the use of ERRT in treating nightmares and related diffi culties and im

The nociceptive flexion reflex (NFR) is a physiological tool to study spinal nociception. However, NFR assessment can take several minutes and expose participants to repeated suprathreshold stimulations. The 4 studies reported here assessed the reliability and validity of a brief method to assess NFR threshold that uses a single ascending series of stimulations (Peak 1 NFR), by comparing it to a well-validated method that uses 3 ascending/descending staircases of stimulations (Staircase NFR). Correlations between the NFR definitions were high, were on par with test-retest correlations of Staircase NFR, and were not affected by participant sex or chronic pain status. Results also indicated the test-retest reliabilities for the 2 definitions were similar. Using larger stimulus increments (4 mAs) to assess Peak 1 NFR tended to result in higher NFR threshold estimates than using the Staircase NFR definition, whereas smaller stimulus increments (2 mAs) tended to result in lower NFR threshold estimates than the Staircase NFR definition. Neither NFR definition was correlated with anxiety, pain catastrophizing, or anxiety sensitivity. In sum, a single ascending series of electrical stimulations results in a reliable and valid estimate of NFR threshold. However, caution may be warranted when comparing NFR thresholds across studies that differ in the ascending stimulus increments. Perspective This brief method to assess NFR threshold is reliable and valid; therefore, it should be useful to clinical pain researchers interested in quickly assessing inter- and intra-individual differences in spinal nociceptive processes.

Pain catastrophizing is associated with enhanced temporal summation of pain (TS-Pain). However, because prior studies have found that pain catastrophizing is not associated with a measure of spinal nociception (nociceptive flexion reflex [NFR] threshold), this association may not result from changes in spinal nociceptive processes. The goal of the present study in healthy participants was to examine the relationship between trait (traditional) and state (situation-specific) pain catastrophizing and temporal summation of NFR (TS-NFR) and TS-Pain. A secondary goal was to replicate prior findings concerning relationships between catastrophizing and NFR threshold, electrocutaneous pain threshold, and sensory and affective ratings of electrocutaneous stimuli. All analyses controlled for depression symptoms, pain-related anxiety, and participant sex. As expected, multiple regression analyses indicated that neither trait nor situation-specific catastrophizing was associated with NFR threshold, but that situation-specific catastrophizing was associated with pain ratings. Multilevel linear growth models of TS data indicated that situation-specific catastrophizing was associated with TS-Pain but not TS-NFR. Trait catastrophizing was not related to TS-Pain or TS-NFR. Together, these results confirm prior studies that indicate that catastrophizing enhances pain via supraspinal processes rather than spinal processes. Moreover, because catastrophizing was associated with TS-Pain but not TS-NFR, caution is warranted when using pain ratings to infer temporal summation of spinal nociceptive processes.

Research indicates pain may be influenced by the menstrual cycle. While the mechanisms underlying these effects are unclear, it is possible that menstrual phase-related changes in endogenous pain modulation contribute. The present study used well-validated methods to study affective modulation of pain and the nociceptive flexion reflex (NFR) in healthy women during two menstrual phases (mid-follicular vs. late-luteal). Women (N = 41) tracked their menstrual phases for three complete cycles and were asked to attend two laboratory testing sessions in the second and third cycles to assess affective modulation of pain and nociception (testing order counterbalanced). Menstrual phase was assessed from daily diaries, luteinizing hormone tests, and basal body temperature. At each session, emotionally charged pictures were presented and suprathreshold electrocutaneous stimulations were delivered during and in between pictures. Subjective and physiological emotional reactions were recorded in response to each picture and pain ratings and NFRs were recorded in response to each suprathreshold stimulus. Results suggested pictures effectively manipulated emotion in both menstrual phases. Moreover, arousing unpleasant pictures enhanced pain and NFR, whereas arousing pleasant pictures inhibited pain and NFR. These modulatory effects were similar in both menstrual phases. Together, these findings suggest that affective engagement of corticospinal mechanisms does not differ across these phases of the menstrual cycle. However, future research is needed to directly assess the relationship between affective modulation of pain/nociception and inter- and intra-individual differences in ovarian hormones and to extend these findings to women who suffer from menstrual cycle-related pain (e.g., premenstrual dysphoric disorder, fibromyalgia).

Fibromyalgia syndrome (FMS) is a chronic pain disorder associated with widespread musculoskeletal pain, tenderness, and fatigue. Additionally, correlational research suggests negative affect (eg, depression, anxiety) and deficits in positive affect may contribute to FMS symptomatology. However, well-controlled, experimental research is necessary to ascertain whether patients with FMS have problems in affective processing. The present study used a well-validated picture-viewing paradigm to evoke emotional responses in 17 patients with FMS and 17 sex- and age-matched healthy control participants. Each participant viewed pleasant (erotica), neutral, and unpleasant (attack related) pictures, and abrupt white noises were delivered during two-thirds of the pictures to evoke startle eyeblinks. Appetitive and defensive responding was assessed from subjective (valence/pleasure and arousal ratings) and physiological (corrugator EMG, heart rate, skin-conductance response, startle-reflex modulation) reactions to pictures. Results suggested FMS was associated with greater defensive activation (displeasure, subjective arousal, corrugator EMG) to the unpleasant, threat-related pictures, but not deficits in appetitive activation to erotic pictures. Although preliminary, these data suggest individuals with FMS have deficits in affective processing, but this dysregulation may be limited to defensive activation. Implications for treatment and future research are discussed. Perspective Fibromyalgia is a debilitating disease associated with affective distress. Results from the present study suggest that FMS is associated with enhanced defensive activation to nonpainful threat-related stimuli, but not deficits in appetitive reactions to erotic stimuli. These findings have implications for the treatment and study of FMS.

Physiological reactions to noxious stimuli are often used to make inferences about pain, but few studies have thoroughly examined the intra- and interindividual relationships between them. In the present study (N=104), multilevel analyses was used to assess relations between physiological (nociceptive flexion reflex magnitude [NFR], blink reflex magnitude, skin conductance response [SCR], heart rate [HR]) and subjective reactions to electrocutaneous stimuli. All physiological reactions were significant predictors of ratings when entered alone, explaining 1% (SCR) to 29% (NFR) of the variance; but only NFR, blink, and HR were significant in a multivariate predictor model. Significant interindividual variability in slopes was found for blink and HR, but not NFR. A final trimmed model that included NFR, blink, and the blink random slope explained 35% of the variance in ratings.

The nociceptive flexion reflex (NFR) is a polysynaptic withdrawal reflex typically assessed from biceps femoris electromyogram (EMG) following noxious stimulation of the ipsilateral sural nerve. Electrophysiological evidence suggests the reflex is elicited following the activation of small diameter A-delta afferents. As a result, the NFR is assumed to be a categorically distinct construct that emerges from EMG activity only following nociceptor activation. Despite the widespread use of the NFR in pain research, there has been little attempt to verify the latent structure of the NFR. The present study used "coherent cut kinetics" taxometric analyses to examine whether the latent structure of biceps femoris EMG reflects the taxonic structure that would be predicted from electrophysiological evidence. To achieve this end, preliminary analyses first compared different methods of scoring NFR magnitude. Results suggested the presence of a taxon in the covariance of biceps femoris EMG and stimulus intensity that is likely to be the NFR. Furthermore, preliminary analyses suggested the best method of scoring NFR magnitude was using Cohen's d. Implications of these results are discussed.

Prior research suggests emotional picture-viewing modulates motoric (nociceptive flexion reflex), autonomic (skin conductance response, heart rate acceleration), and subjective (pain rating) reactions to noxious electrodermal stimulation. The present study sought to determine whether emotional valence and arousal contribute to nociception modulation. To do so, pictures varying in emotional content (erotica, food, neutral, loss, attack) were chosen to manipulate emotional valence (pleasant = erotic and food; unpleasant = loss and attack) and arousal (low = food and loss; moderate = erotica and attack). Pictures were presented in pseudorandom order to elicit emotional processing while noxious electric stimulations were delivered to the sural nerve. Nociceptive flexion reflex (NFR) magnitude, skin conductance response (SCR), heart rate (HR) acceleration, and subjective pain ratings to each stimulation were measured, standardized, averaged by picture content, and analyzed. Results suggested that picture-viewing explained 52% of the variance in the multivariate combination of the nociceptive reactions and modulated them in parallel. Pleasant pictures inhibited reactions, whereas unpleasant pictures enhanced them. However, only erotica and attack pictures elicited significant modulation relative to neutral pictures, suggesting arousal also contributed. An exploratory multilevel analysis also supported this conclusion. Together, these data suggest emotional control of nociceptive reactions (ECON) is associated with a valence-byarousal interaction. Implications of these findings for how emotional picture-viewing can be used to study supraspinal modulation are discussed. � 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Emotionally charged facial expressions (happy, fear) served as conditioned stimuli in a differential fear conditioning procedure. Expressions were presented in pseudo-random order on a computer monitor. For half of the participants, the fear expression was paired with an aversive electric stimulation (UCS), whereas the happy expression was unpaired. The other participants had the opposite pairing. To assess the influence of conditioned fear on pain, expressions were shown again in the absence of the UCS and pain threshold was assessed during each expression. The latency of finger withdrawal from a radiant heat device was used to index pain threshold. Skin conductance response (SCR) and self-reported emotion were measured to assess fear conditioning. Consistent with preparedness theory, differential fear conditioning was only present when the fear expression was paired with the UCS. Moreover, pain threshold was only influenced by fear conditioning in persons for whom the fear expression was paired with the UCS. Specifically, finger withdrawal latencies were lower (suggesting hyperalgesia) during the fear expression than during the happy expression; an effect that was not present before CSUCS pairing. This work suggests that some stimuli are more readily associated with an aversive event and can lead to pain enhancement. Perspective: Although preliminary, these results suggest that fear-relevant environmental stimuli (including facial expressions) may provide important environmental cues during aversive events that influence the level of pain experienced.

Despite the widespread use of the nociceptive flexion reflex (NFR) paradigm in clinical and experimental pain research, there is currently no consensus on how best to define NFR threshold. Accordingly, the present studies were designed to assess the accuracy and reliability of different NFR threshold scoring criteria. Study 1 compared 13 scoring criteria in their accuracy for identifying the presence of the NFR, then generated empirically derived cut-points for the best criteria, and examined the test-retest reliability of NFR thresholds derived from these cut-points. Study 2 evaluated the replicability of these findings in an independent sample. Results from the two studies suggested that standardized peak (NFR Interval Peak z score) and mean (NFR Interval z score) biceps femoris electromyogram (EMG) activity were accurate and reliable criteria for defining NFR threshold. Acknowledging that cut-points may need to be adjusted for different research designs, graphs depicting sensitivity and specificity across a range of cut-points have been provided to facilitate researcher’s decision-making. It is hoped that the results of these studies will promote a standard NFR threshold assessment methodology, and further encourage the application of the NFR paradigm in the investigation of mechanisms and characteristics of both painful and non-painful diseases.

Prior research has found that pain catastrophizing measured before pain testing is not correlated with the nociceptive flexion reflex (NFR) threshold (a measure of spinal nociception), suggesting that catastrophizing does not alter pain through descending modulatory mechanisms. However, recent evidence suggests that in vivo catastrophizing (measured during or after pain testing) is a better predictor of pain outcomes. In the present study, NFR threshold and pain sensation ratings were assessed in 78 healthy participants by delivering electric stimulations to the sural nerve. After pain testing, participants were asked to rate their affective reaction (displeasure, arousal) to electric stimuli and to report on their pain catastrophizing. Hierarchical regression analyses controlling for participant sex, pre-experiment affect, depressive symptoms, and self-efficacy were used to predict pain-related outcomes (NFR threshold, pain sensation, displeasure ratings, arousal ratings) from in vivo catastrophizing scores. Results indicated that in vivo catastrophizing was related to pain sensation but not to NFR thresholds or arousal reactions. The relation between in vivo catastrophizing and displeasure ratings was not significant after other variables were controlled. These data support prior research suggesting that catastrophizing does not alter pain by engaging descending modulatory mechanisms. Perspective Pain catastrophizing is an important psychological predictor of pain and pain-related functioning. The present study confirms prior reports suggesting that catastrophizing does not work by engaging mechanisms that alter pain transmission in the spinal cord before the signal travels to the brain.

This study tested the prospective effects of hope on depression and anxiety using a longitudinal design. A sample of 522 college students completed self-report measures of hope, depression, and anxiety at three time points, with 1-month delays between administrations. Structural equation modeling was employed to test two cross-lagged panel models of the reciprocal effects of the Agency and Pathways components of hope on depression and anxiety. Results indicated statistically significant negative effects for the Agency component of hope on later depression but no unique effect of the Pathways component of hope on depression. Likewise, Agency showed a statistically significant negative effect on later anxiety, but again Pathways had no significant influence on anxiety. In both cases, neither depression nor anxiety demonstrated any longitudinal effects on either the Agency or Pathways components of hope. Implications of these findings are discussed, along with potential directions for future research.

Individuals with high-trait anxiety frequently report decreased perceived control. However, it is unclear how these processes are instantiated at a neural level. Prior research suggests that individuals prone to anxiety may have exaggerated activity in the anterior insula and altered activity in the cingulate cortex during anticipation of aversive events. Thus, we hypothesized that anxiety proneness influences anterior insula activation during anticipation of unpredictable threat through decreased perceived control. Forty physically healthy adults underwent neuroimaging while they explored computer-simulated contexts associated either with or without the threat of an unpredictable shock. Skin conductance, anxiety ratings and blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging were used to assess responses to threat versus no threat. Perceived control was measured using the Anxiety Control Questionnaire-Revised. Mediation analysis examined how anxiety proneness influenced BOLD activity. Anticipation of unpredictable threat resulted in increased skin conductance responses, anxiety ratings and enhanced activation in bilateral insula, anterior midcingulate cortex (aMCC) and bed nucleus of the stria terminalis. Individuals with greater anxiety proneness and less perceived control showed greater activity in dorsal anterior insula (dAI). Perceived control mediated the relationship between anxiety proneness and dAI activity. Increased dAI activity was associated with increased activity in aMCC, which correlated with increased exploratory behavior. Results provide evidence that exaggerated insula activation during the threat of unpredictable shock is directly related to low perceived control in anxiety-prone individuals. Perceived control thus may constitute an important treatment target to modulate insula activity during anxious anticipation in anxiety-disordered individuals.

Research has shown that individuals who have sustained mild head injury demonstrate a slowed speed of processing that is exacerbated by fatigue/stress. We administered the Paced Auditory Serial Addition Test (PASAT) at the beginning and at the end of a 4-h experimental protocol to determine whether fatigue or a stressor would result in poorer scores for individuals who had previously sustained mild head injury. A significant improvement was found between the first and second administration for both head-injured and control subjects, but difference scores revealed a significant between-groups difference for the first of the four trials, with the head-injured participants performing worse than controls. Apparently, head-injured participants were slower to develop, as well as slower to regain, a means of efficiently processing rapidly presented information.