Adverse childhood experiences, brain efficiency, and the development of pain symptoms in youth.

BACKGROUND: Adverse childhood experiences (ACEs) are often reported by youths with chronic pain, and both ACEs and chronic pain disrupt how information is processed. However, it is unknown whether changes to shared neural networks underlie the relationship between ACEs and the development of pain symptoms. This study explored the relationships between ACEs, brain efficiency, and pain symptomology in youth. METHODS: A community sample of youths aged 14-18 years underwent MRIs, answered trauma and pain questionnaires, and underwent pain sensory testing, twice, 3 months apart (Nbaseline = 44; Nfollow-up = 42). Sensory testing determined thresholds for mechanical and thermal stimuli. Global and local network efficiencies were evaluated using graph theory. Generalized estimating equations were applied to examine whether brain efficiency moderated the relationships between ACEs, pain intensity, and pain sensitivity (i.e., mechanical detection, heat pain, and temperature change thresholds). RESULTS: There was a significant interaction between ACEs and global brain efficiency in association with pain intensity (ß = -0.31, p = 0.02) and heat pain (ß = -0.29, p = 0.004). Lower global brain efficiency exacerbated the relationship between ACEs and pain intensity (θX → Y|W = -1.16 = 0.37, p = 0.05), and heat pain sensitivity (θX → Y|W = -1.30 = 0.44, p = 0.05). Higher global brain efficiency ameliorated the relationship between ACEs and pain intensity (θX → Y|W = 1.75 = -0.53, p = 0.05). CONCLUSIONS: The relationship between ACEs and pain symptomology was comparable to chronic pain phenotypes (i.e., higher pain intensity and pain thresholds) and may vary as a function of brain efficiency in youth. This stresses the importance of assessing for pain symptoms in trauma-exposed youth, as earlier identification and intervention are critical in preventing the chronification of pain. SIGNIFICANCE: This article explores the relationship between ACEs, pain symptomology, and brain efficiency in youth. ACEs may affect how the brain processes information, including pain. Youths with lower brain efficiencies that were exposed to more ACEs have pain symptomology comparable to youths with chronic pain. Understanding this relationship is important for the earlier identification of pain symptoms, particularly in vulnerable populations such as youths exposed to trauma, and is critical for preventing the chronification of pain.

Macrostructural Brain Morphology as Moderator of the Relationship Between Pandemic-Related Stress and Internalizing Symptomology During COVID-19 in High-Risk Adolescents.

BACKGROUND: According to person-by-environment models, individual differences in traits may moderate the association between stressors and the development of psychopathology; however, findings in the literature have been inconsistent and little literature has examined adolescent brain structure as a moderator of the effects of stress on adolescent internalizing symptoms. The COVID-19 pandemic presented a unique opportunity to examine the associations between stress, brain structure, and psychopathology. Given links of cortical morphology with adolescent depression and anxiety, the current study investigated whether cortical morphology moderated the relationship between stress from the COVID-19 pandemic and the development of internalizing symptoms in familial high-risk adolescents. METHODS: Prior to the COVID-19 pandemic, 72 adolescents (27 male) completed a measure of depressive and anxiety symptoms and underwent magnetic resonance imaging. T1-weighted images were acquired to assess cortical thickness and surface area. Approximately 6 to 8 months after COVID-19 was declared a global pandemic, adolescents reported their depressive and anxiety symptoms and pandemic-related stress. RESULTS: Adjusting for pre-pandemic depressive and anxiety symptoms and stress, increased pandemic-related stress was associated with increased depressive but not anxiety symptoms. This relationship was moderated by cortical thickness and surface area in the anterior cingulate and cortical thickness in the medial orbitofrontal cortex such that increased stress was only associated with increased depressive and anxiety symptoms among adolescents with lower cortical surface area and higher cortical thickness in these regions. CONCLUSIONS: Results further our understanding of neural vulnerabilities to the associations between stress and internalizing symptoms in general and during the COVID-19 pandemic in particular.

Brain Function and Pain Interference After Pediatric Intensive Interdisciplinary Pain Treatment.

OBJECTIVES: Intensive interdisciplinary pain treatments (IIPTs) are programs that aim to improve functioning in youth with severe chronic pain. Little is known about how the brain changes after IIPT; however, decreased brain responses to emotional stimuli have been identified previously in pediatric chronic pain relative to healthy controls. We examined whether IIPT increased brain responses to emotional stimuli, and whether this change was associated with a reduction in pain interference. PATIENTS AND METHODS: Twenty youths with chronic pain aged 14 to 18 years were scanned using functional magnetic resonance imaging, pre and post-IIPT. During the functional magnetic resonance imaging, patients were presented with emotional stimuli (ie, faces expressing happiness/fear), neutral expressions, and control (ie, scrambled) images. Patients completed a measure of pain interference pre and post-IIPT. Paired t tests were used to examine differences in brain activation in response to emotional versus neutral stimuli, pre to post-IIPT. Data from significant brain clusters were entered into linear mixed models to examine the relationships between brain activation and impairment pre and post-IIPT. RESULTS: Patients demonstrated a decrease in middle frontal gyrus (MFG) activation in response to emotional stimuli (happy + fear) relative to scrambled images, between pre and post-IIPT ( P < 0.05). Lower MFG activation was associated with lower pain interference, pre and post-IIPT ( P < 0.05). CONCLUSION: Contrary to our hypothesis, IIPT was associated with a reduction in MFG activation to emotional stimuli, and this change was associated with reduced pain interference. The MFG is a highly interconnected brain area involved in both pain chronification and antinociception. With further validation of these results, the MFG may represent an important biomarker for evaluating patient treatment response and target for future pain interventions.

Sleep disturbances, altered brain microstructure and chronic headache in youth.

Chronic headache (persistent or recurrent headache for 3-months or longer) is highly prevalent among youth. While sleep disturbances have been associated with headache, their inter-relationship with brain connectivity remains unknown. This observational study examined whether self-report and actigraphy measures of sleep were associated with alterations to white matter tracts (i.e., uncinate fasciculus and cingulum) in youth with chronic headache versus healthy controls. Thirty youth aged 10-18 years with chronic headache and thirty controls underwent an MRI. Diffusion tensor images were obtained and mean fractional anisotropy values of the cingulum and uncinate were extracted. One-week prior to their MRI, youth wore an actigraph to obtain sleep duration, wake after sleep onset and sleep efficiency measures. Moreover, they completed questionnaires regarding their sleep quality and pain symptomatology. Linear regression was applied to examine the relationships between sleep (self-report and actigraphy), fractional anisotropy, and number of headache days per month. Self-report and actigraphy measures of sleep did not differ between patients and controls. However, poorer self-reported sleep quality was associated with lower fractional anisotropy values in the left uncinate (P = 0.05). Lower left uncinate fractional anisotropy was related to increased headache frequency (P = 0.002) in youth with chronic headache. Therefore, alterations to connectivity may be associated with the relationship between altered perceptions of sleep and headache chronicity.

Trajectories of pain intensity, pain catastrophizing, and pain interference in the perinatal and postpartum period.

Introduction: Chronic pain (pain >3 months) is a growing epidemic. Normal pregnancy may give rise to recurrent and sometimes constant pain for women. Women with worse pain symptoms are more likely to report symptoms of anxiety, depression, and/or insomnia during the perinatal period, which may impact labor and delivery outcomes. We examined the relationship between demographic and psychological predictors of pain throughout pregnancy and into the postpartum. Objectives: To examine trajectories of pain intensity, pain catastrophizing, and pain interference during pregnancy and the early postpartum, and associated sociodemographic predictors of trajectory membership. Methods: One hundred forty-two pregnant women were assessed at 4 time points for measures of pain intensity, pain catastrophizing, pain interference, and symptoms of insomnia, depression, and generalized anxiety. Women completed the first survey before 20 weeks' gestation and were reassessed every 10 weeks. Surveys were completed on average at 15 weeks', 25 weeks', and 35 weeks' gestation, and at 6-week postpartum. Using latent class mixed models, trajectory analysis was used to determine trajectories of pain intensity, pain catastrophizing, and pain interference. Results: A 1-class pain intensity model, 2-class pain catastrophizing model, and 3-class pain interference model were identified. Adaptive lasso and imputation demonstrated model robustness. Individual associations with trajectories included baseline symptoms of anxiety, depression, and insomnia, and pain symptomology. Conclusion: These findings may help to identify women who are at high risk for experiencing pain symptoms during pregnancy and could aid in developing targeted management strategies to prevent mothers from developing chronic pain during their pregnancy and into the postpartum period.

Baseline Factors Associated with Pain Intensity, Pain Catastrophizing, and Pain Interference in Intensive Interdisciplinary Pain Treatment for Youth.

Background: More could be known about baseline factors related to desirable Intensive Interdisciplinary Pain Treatment (IIPT) outcomes. This study examined how baseline characteristics (age, gender, child pain catastrophizing (PCS-C), pain interference, pain intensity, anxiety, depression, paediatric health-related quality of life (PedsQLTM), and parent catastrophizing (PCS-P)) were associated with discharge and 3-month follow-up scores of PCS-C, pain intensity, and pain interference. Methods: PCS-C, pain intensity, and pain interference T-scores were acquired in 45 IIPT patients aged 12-18 at intake (baseline), discharge, and 3-month follow-up. Using available and imputed data, linear mixed models were developed to explore associations between PCS-C, pain intensity, and pain interference aggregated scores at discharge and follow-up with baseline demographics and a priori selected baseline measures of pain, depression, anxiety, and PCS-C/P. Results: PCS-C and pain interference scores decreased over time compared to baseline. Pain intensity did not change significantly. Baseline PCS-C, pain interference, anxiety, depression, and PedsQLTM were associated with discharge/follow-up PCS-C (available and imputed data) and pain interference scores (available data). Only baseline pain intensity was significantly associated with itself at discharge/follow-up. Conclusions: Participants who completed the IIPT program presented with reduced PCS-C and pain interference over time. Interventions that target pre-treatment anxiety and depression may optimize IIPT outcomes.

Changes in Brain GABA and Glutamate and Improvements in Physical Functioning Following Intensive Pain Rehabilitation in Youth With Chronic Pain.

Intensive interdisciplinary pain treatments (IIPT) have been developed to treat youth with unmanaged chronic pain and functional disability. Dysregulation of metabolites gamma-aminobutyric acid (GABA) and glutamate are thought to play a role in the chronification of pain due to imbalances in inhibition and excitation in adults. Using magnetic resonance spectroscopy (MRS), we investigated the effect of IIPT on GABA and Glx (glutamate + glutamine) in 2 pain-related brain regions: the left posterior insula (LPI) and the anterior cingulate cortex (ACC). Data were collected in 23 youth (mean age = 16.09 ± 1.40, 19 female) at entry and discharge from a hospital-based outpatient IIPT. GABA and Glx were measured using GABA-edited MEGA-PRESS and analyzed using Gannet. Physical measures including a 6-minute walk test were recorded, and patients completed the PLAYSelf Physical Literacy Questionnaire, PROMIS Pain Interference Questionnaire, and Functional Disability Inventory. LPI GABA (P < .05) significantly decreased, but not ACC GABA (P > .05), following IIPT. There were no significant Glx changes (P > .05). The decrease in LPI GABA was associated with increased distance in the 6-minute walk test (P < .001). IIPT may decrease GABAergic inhibitory tone within the LPI, thereby promoting plasticity and contributing to improvements in physical outcomes with IIPT. PERSPECTIVE: Regional GABA changes are associated with a reduction in pain interference and improvement in physical function in youth following intensive pain rehabilitation. GABA may serve as a possible biomarker for IIPT; and may also further aid in the development of IIPT, and other treatments for chronic pain in youth.

The waiting game: investigating the neurobiological transition from acute to persistent pain in adolescent rats.

Persistent postsurgical pain affects 20% of youth undergoing a surgical procedure, with females exhibiting increased prevalence of chronic pain compared with males. This study sought to examine the sexually-dimorphic neurobiological changes underlying the transition from acute to persistent pain following surgery in adolescence. Male and female Sprague Dawley rats were randomly allocated to a sham or injury (plantar-incision surgery) condition and assessed for pain sensitivity while also undergoing magnetic resonance imaging at both an acute and chronic timepoint within adolescence. We found that injury resulted in persistent pain in both sexes, with females displaying most significant sensitivity. Injury resulted in significant gray matter density increases in brain areas including the cerebellum, caudate putamen/insula, and amygdala and decreases in the hippocampus, hypothalamus, nucleus accumbens, and lateral septal nucleus. Gray matter density changes in the hippocampus and lateral septal nucleus were driven by male rats whereas changes in the amygdala and caudate putamen/insula were driven by female rats. Overall, our results indicate persistent behavioral and neurobiological changes following surgery in adolescence, with sexually-dimorphic and age-specific outcomes, highlighting the importance of studying both sexes and adolescents, rather than extrapolating from male adult literature.

Brain Development and Maternal Behavior in Relation to Cognitive and Language Outcomes in Preterm-Born Children.

BACKGROUND: Children born very preterm (≤32 weeks gestational age) show poorer cognitive and language development compared with their term-born peers. The importance of supportive maternal responses to the child's cues for promoting neurodevelopment is well established. However, little is known about whether supportive maternal behavior can buffer the association of early brain dysmaturation with cognitive and language performance. METHODS: Infants born very preterm (N = 226) were recruited from the neonatal intensive care unit for a prospective, observational cohort study. Chart review (e.g., size at birth, postnatal infection) was conducted from birth to discharge. Magnetic resonance imaging, including diffusion tensor imaging, was acquired at approximately 32 weeks postmenstrual age and again at term-equivalent age. Fractional anisotropy, a quantitative measure of brain maturation, was obtained from 11 bilateral regions of interest in the cortical gray matter. At 3 years (n = 187), neurodevelopmental testing (Bayley Scales of Infant and Toddler Development-III) was administered, and parent-child interaction was filmed. Maternal behavior was scored using the Emotional Availability Scale-IV. A total of 146 infants with neonatal brain imaging and follow-up data were included for analysis. Generalized estimating equations were used to examine whether maternal support interacted with mean fractional anisotropy values to predict Cognitive and Language scores at 3 years, accounting for confounding neonatal and maternal factors. RESULTS: Higher maternal support significantly moderated cortical fractional anisotropy values at term-equivalent age to predict higher Cognitive (interaction term ß = 2.01, p = .05) and Language (interaction term ß = 1.85, p = .04) scores. CONCLUSIONS: Findings suggest that supportive maternal behavior following early brain dysmaturation may provide an opportunity to promote optimal neurodevelopment in children born very preterm.

Trauma and pain sensitization in youth with chronic pain.

Introduction: Chronic pain (pain lasting ≥3 months) co-occurs with internalizing mental health issues, such as posttraumatic stress symptoms (PTSS), at high rates in youth. The mechanisms underlying these relationships remain unclear. Posttraumatic stress symptoms, including re-experiencing (eg, intrusive memories), alterations in cognition and mood, hyperarousal, and avoidance could lead to altered neuronal processing, pain sensitization, and greater reports of pain. However, the relationships between PTSS and pain sensitization in youth with chronic pain are not known. Methods: Youth (n = 165) aged 10 to 18 years were recruited from outpatient multidisciplinary chronic pain programs. Symptoms of PTSS were assessed using psychometrically sound questionnaires. Youth also underwent a cold-pressor task, the most commonly used experimental pain induction technique. During this task, they reported on their expected pain, actual pain intensity, and pre- and post-state pain catastrophizing. Their pain threshold was recorded. A multivariate general linear model was used to examine the relationships between PTSS, ratings of pain intensity, state pain catastrophizing, and pain threshold, controlling for age, gender, ethnicity, anxiety, and depressive symptoms. Results: Higher PTSS were associated with greater pain thresholds (P = 0.03) and higher pre- and post-state pain catastrophizing (P ≤ 0.05). Conclusions: Individuals with higher PTSS may avoid or dissociate from pain-inducing stimuli, thus leading to higher pain thresholds. However, individuals with higher PTSS also tend to catastrophize prior to and following exposure to pain. Avoidant and pain catastrophizing behaviors may serve to perpetuate chronic pain conditions. Future research is needed to determine how PTSS are related to pain sensitization prior to the development of chronic pain in at-risk youth.

Subclinical post-traumatic stress symptomology and brain structure in youth with chronic headaches.

BACKGROUND/AIMS: Post-traumatic stress symptoms (PTSS) and chronic pain often co-occur at high rates in youth. PTSS may alter brain structure thereby contributing to headache chronicity. This study examined whether PTSS and altered limbic circuitry were associated with headache frequency in youth. METHODS: Thirty youth aged 10-18 years with chronic headaches and 30 age- and sex-matched controls underwent a 3T MRI scan. Volumes of the hippocampus and amygdala were obtained from T1-weighted images. Mean fractional anisotropy (FA, an index of white matter structure) axial and radial diffusivity values of the cingulum and uncinate fasciculus were extracted from diffusion-weighted images. Youth reported on their headaches daily, for one-month, and self-reported pubertal status, emotion regulation, adverse childhood experiences (ACEs) and PTSS using validated measures. Volumes of the hippocampus and amygdala and diffusivity values of the cingulum and uncinate were compared between patients and controls. Hierarchical linear regressions were used to examine the association between PTSS, subcortical volumes and/or diffusivity values and headache frequency. RESULTS: Mean FA values of the cingulum were higher in patients compared to controls (P = 0.02, Cohen's d = 0.69). Greater PTSS (P = 0.04), smaller amygdala volumes (P = 0.01) and lower FA of the cingulum (P = 0.04) were associated with greater headache frequency, after accounting for age, puberty, pain duration, emotion regulation, and ACEs (Adjusted R2 ≥ 0.15). Headache frequency was associated with increases in radial diffusivity (P = 0.002, Adjusted R2 = 0.59), as opposed to axial diffusivity (n.s.). CONCLUSIONS: PTSS, smaller amygdalar volume, and poorer cingulum structural connectivity were associated with headache frequency in youth, and may underlie headache chronicity.