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. 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. Higher maternal support significantly moderated cortical fractional anisotropy values at term-equivalent age to predict higher Cognitive (interaction term β = 2.01, p = .05) and Language (interaction term β = 1.85, p = .04) scores. Findings suggest that supportive maternal behavior following early brain dysmaturation may provide an opportunity to promote optimal neurodevelopment in children born very preterm.

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.

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.

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. 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. 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.). PTSS, smaller amygdalar volume, and poorer cingulum structural connectivity were associated with headache frequency in youth, and may underlie headache chronicity.

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.

Introduction: Adolescence is a period of remarkable development as children’s brains change to resemble adult brains. Resting state fMRI measures fluctuations in blood-oxygen signal from which we can infer functional connectivity (FC). Graph theory is a branch of mathematics that can quantify the complex patterns of connectivity and network architecture inherent in the functional connectome. An ideal graph theory analysis explores edges that are weighted, directional, and heterogenous (can be positive or negative). Recent developmental studies have applied graph theory to the functional connectome, yet due to the considerable complexity added by each facet, most ignore one or more aspects of an ideal graph theory analysis (directionality and heterogeneity). Methods: The present cross-sectional study measured FC in typically developing children, adolescents, and young adults (age 6-24 years) using 150+ echo-planar volumes (3.6mm isotropic voxels, repetition/echo time=2000/30ms) acquired at rest. A standard pre-processing pipeline was used, and the functional connectome was quantified using a weighted, directed graph analysis, including both positive and negative connections. Five different graph theory metrics were utilized to quantify developmental trajectories: connection density, modularity, clustering coefficient, global efficiency, and betweenness centrality. Positive and negative connections were analyzed separately, and age and sex associations were explored. Results: The total sample comprised 219 participants (mean age (SD) [range] = 14.1 (3.3) [6.5-24.0] years, 50% female). For positive connections, modularity and betweenness centrality increased with age (both p<0.001), while connection density, clustering coefficient, and global efficiency decreased with age (all p<0.001). By contrast, for negative connections, modularity and betweenness centrality decreased with age (p=0.002, p=0.003), while connection density, clustering coefficient , and global efficiency increased with age (p<0.001, p<0.001, p=0.003). Effects of sex, hemisphere, and their interaction were minimal, though global efficiency for negative connections was higher in the right hemisphere than the left (p<0.001). Conclusion: Graph theory appears to be a useful tool for quantifying the complex development of the functional connectome. The developmental changes presented here may be driven by an intrinsic pressure to balance functionality with low metabolic cost to maintain the network. The positive connection network appears to shift towards a more efficient conformation resembling “small-world” architecture. In contrast, the negative connection network seems to shift away from such efficient architecture, possibly to prioritize improving functionality before later refinement.