Community and household-level socioeconomic disadvantage and functional organization of the salience and emotion network in children and adolescents.

Socioeconomic disadvantage (SED) during childhood has been linked to disparities in physical and mental health. A growing body of research has focused on identifying neurodevelopmental consequences of SED, commonly measured using within-household factors (e.g., household income), to better understand the processes underlying SED-related disparities. These studies suggest that childhood SED has a widespread impact on brain development, altering development of multiple brain regions simultaneously. These findings also raise the possibility that childhood SED impacts development of key brain systems, such as the salience and emotion network (SEN), which is positioned at the intersection of brain systems involved in cognitive and emotion-related functioning and is thought to mediate information flow within and between these networks. The present study tests for associations between household- and community-level SED, as well as their interaction, and measures of SEN-based functional neural organization in 57 children and adolescents (ages 6-17). We applied graph theoretical analyses to resting-state functional magnetic resonance imaging (fMRI) data to examine SEN-based functional network topology. Results showed that youth residing in more distressed communities demonstrate lower hub-like properties (i.e., less efficient global information transfer and fewer connections) of two core SEN nodes - the anterior cingulate cortex and the left supramarginal gyrus. Similarly, lower household income was associated with lower efficiency of the anterior cingulate, but had no effect on the supramarginal gyrus. There was, however, an interaction between income and community SED in the rostral prefrontal cortex, such that higher income was associated with higher clustering coefficient and lower betweenness centrality, suggesting greater local processing and lower influence of this region on information flow across the network. These effects were significant only among youth living in low (but not high) SED communities, suggesting that within-household SED factors may not protect against the detrimental effects of a disadvantaged community context. Similarly, the age-related increase in average path length of the left rostral prefrontal cortex was only significant among youth living in low (but not high) SED communities. Given that maturation of the SEN is considered to be a critical functional backbone supporting the development of more flexible cognitive and emotional processes into adulthood, we tested for links between SEN graph metrics and measures of cognitive and emotion-related functioning. We found that higher community SED and lower income were both associated with lower IQ. Lower IQ, in turn, was associated with global efficiency of the left supramarginal gyrus. Observed effects of SED on SEN-based functional neural organization may help to explain the strong and pervasive link between childhood SED and disparities in cognitive and emotional outcomes.

Emotion-related brain organization and behavioral responses to socioemotional stimuli in pediatric cancer survivors with posttraumatic stress symptoms.

BACKGROUND: Pediatric cancer is a life-changing, stressful experience for children and their families. Although most children adjust well, psychologically, a significant subset report posttraumatic stress symptoms (PTSS), with nearly 75% reexperiencing traumatic parts of cancer and/or its treatment. However, little research has examined the effects of pediatric cancer and related PTSS on emotional processing, and on functional properties of key emotional centers in the brain (e.g., amygdala). PROCEDURE: We examined cancer-related PTSS, behavioral responses during an emotion-processing task, and resting-state functional connectivity of the amygdala in 17 pediatric cancer survivors (ages 6-11) and 17 age- and sex-matched controls. RESULTS: Cancer survivors, relative to controls, were more likely to rate ambiguous (i.e., neutral) faces as negative (i.e., "negativity bias"). Higher reexperiencing PTSS was associated with faster responses to neutral faces. Although there were no group differences in amygdala centrality, within survivors, both higher reexperiencing PTSS and faster reaction times were associated with increased centrality of the amygdala-a functional property associated with hubs of information processing in the brain. In an exploratory mediation analysis, we found that amygdala centrality mediated the link between reaction time and PTSS, suggesting that changes in the brain may be a proximal marker of the expression of emotion-related symptomology. CONCLUSIONS: Negativity bias in cancer survivors may reflect their stressful experiences with cancer and/or its treatment. This negativity bias may represent a susceptibility to changes in emotion-related brain functioning, which may, in turn, lead to PTSS.

Poor between-session recall of extinction learning and hippocampal activation and connectivity in children.

BACKGROUND: In healthy adults, successful between-session recall of extinction learning depends on the hippocampus and ventromedial prefrontal cortex (vmPFC), especially when tested in the extinction context. Poor extinction recall and dysfunction within hippocampal-vmPFC circuitry are associated with fear-based disorders (e.g., anxiety, posttraumatic stress disorder). Despite the early age of onset of virtually all fear-based disorders and the protracted development of the hippocampus and vmPFC across the first two decades of life, little is known about extinction recall and the underlying neural correlates in children. METHODS: Here, we tested extinction recall in 43 pre-adolescent children (ages 6-11 yrs) by coupling functional magnetic resonance imaging and virtual reality with a novel interpersonal threat-related two-day (ABBA) fear-extinction paradigm. Conditioned fear responding was assessed at behavioral, subjective, physiological, and neural levels. RESULTS: Although children demonstrated intact within-session extinction, there was poor between-session recall of extinction learning (retention index: 13.56%), evidenced by elevations in skin conductance, avoidant behavioral responses, and subjective ratings. Elevations in conditioning fear responding were accompanied by activation in the hippocampus and insula, and increased connectivity of the hippocampus with the insula and dorsal anterior cingulate cortex - regions implicated in the return of fear in adult studies. Children who kept more distance from the extinguished cue during extinction subsequently demonstrated heightened hippocampal-cingulate coupling during recall, suggesting that avoidant behavior interferes with extinction retention. CONCLUSIONS: Poor extinction recall in children may have implications for developmental vulnerability to fear-based disorders, and for the application of therapeutic strategies that rely on principles of extinction (e.g., exposure therapy) to pediatric samples.

Neurodevelopmental consequences of pediatric cancer and its treatment: applying an early adversity framework to understanding cognitive, behavioral, and emotional outcomes.

Today, children are surviving pediatric cancer at unprecedented rates, making it one of modern medicine's true success stories. However, we are increasingly becoming aware of several deleterious effects of cancer and the subsequent "cure" that extend beyond physical sequelae. Indeed, survivors of childhood cancer commonly report cognitive, emotional, and psychological difficulties, including attentional difficulties, anxiety, and posttraumatic stress symptoms (PTSS). Cognitive late- and long-term effects have been largely attributed to neurotoxic effects of cancer treatments (e.g., chemotherapy, cranial irradiation, surgery) on brain development. The role of childhood adversity in pediatric cancer - namely, the presence of a life-threatening disease and endurance of invasive medical procedures - has been largely ignored in the existing neuroscientific literature, despite compelling research by our group and others showing that exposure to more commonly studied adverse childhood experiences (i.e., domestic and community violence, physical, sexual, and emotional abuse) strongly imprints on neural development. While these adverse childhood experiences are different in many ways from the experience of childhood cancer (e.g., context, nature, source), they do share a common element of exposure to threat (i.e., threat to life or physical integrity). Therefore, we argue that the double hit of early threat and cancer treatments likely alters neural development, and ultimately, cognitive, behavioral, and emotional outcomes. In this paper, we (1) review the existing neuroimaging research on child, adolescent, and adult survivors of childhood cancer, (2) summarize gaps in our current understanding, (3) propose a novel neurobiological framework that characterizes childhood cancer as a type of childhood adversity, particularly a form of early threat, focusing on development of the hippocampus and the salience and emotion network (SEN), and (4) outline future directions for research.

Trustworthiness and electrocortical processing of emotionally ambiguous faces in student police officers.

Perceptions of emotional facial expressions and trustworthiness of others guides behavior and has considerable implications for individuals who work in fields that require rapid decision making, such as law enforcement. This is particularly complicated for more ambiguous expressions, such as 'neutral' faces. We examined behavioral and electrocortical responses to facial expressions in 22 student police officers (18 males; 23.2 ± 3.63 years). Participants completed an emotional face appraisal task that involved viewing three expressions (fearful, neutral, happy) and were asked to identify the emotion and rate the trustworthiness of each face. The late positive potential (LPP), an event-related potential that tracks emotional intensity and/or salience of a stimulus, was measured during the task. Overall, participants rated neutral faces similarly to fearful faces and responded fastest to these expressions. Neutral faces also elicited a robust late LPP response that did not differ from LPP to fearful or happy faces, and there was substantial individual variation in trustworthiness ratings for neutral faces. Together, 'neutral' facial expressions elicited similar trustworthiness ratings to negatively-valenced stimuli. Brain and behavioral responses to neutral faces also varied across student officers; thus, encounters with ambiguous faces in the field may promote increased perceived threat in some officers, which may have real-world consequences (e.g., decision to shoot, risk of psychopathology).

Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study.

RATIONALE: Excessive fear and anxiety, coupled with corticolimbic dysfunction, are core features of stress- and trauma-related psychopathology, such as posttraumatic stress disorder (PTSD). Interestingly, low doses of ∆9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults. Together, these findings suggest the cannabinoid system as a potential pharmacological target in the treatment of excess fear and anxiety. However, the effects of THC on corticolimbic functioning in response to threat have not be investigated in adults with trauma-related psychopathology. OBJECTIVE: To address this gap, the present study tests the effects of an acute low dose of THC on corticolimbic responses to threat in three groups of adults: (1) non-trauma-exposed healthy controls (HC; n = 25), (2) trauma-exposed adults without PTSD (TEC; n = 27), and (3) trauma-exposed adults with PTSD (n = 19). METHODS: Using a randomized, double-blind, placebo-controlled, between-subjects design, 71 participants were randomly assigned to receive either THC or placebo (PBO) and subsequently completed a well-established threat processing paradigm during functional magnetic resonance imaging. RESULTS: In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling. CONCLUSIONS: These preliminary data suggest that THC modulates threat-related processing in trauma-exposed individuals with PTSD, which may prove advantageous as a pharmacological approach to treating stress- and trauma-related psychopathology.

Mindfulness and dynamic functional neural connectivity in children and adolescents.

BACKGROUND: Interventions that promote mindfulness consistently show salutary effects on cognition and emotional wellbeing in adults, and more recently, in children and adolescents. However, we lack understanding of the neurobiological mechanisms underlying mindfulness in youth that should allow for more judicious application of these interventions in clinical and educational settings. METHODS: Using multi-echo multi-band fMRI, we examined dynamic (i.e., time-varying) and conventional static resting-state connectivity between core neurocognitive networks (i.e., salience/emotion, default mode, central executive) in 42 children and adolescents (ages 6-17). RESULTS: We found that trait mindfulness in youth relates to dynamic but not static resting-state connectivity. Specifically, more mindful youth transitioned more between brain states over the course of the scan, spent overall less time in a certain connectivity state, and showed a state-specific reduction in connectivity between salience/emotion and central executive networks. The number of state transitions mediated the link between higher mindfulness and lower anxiety, providing new insights into potential neural mechanisms underlying benefits of mindfulness on psychological health in youth. CONCLUSIONS: Our results provide new evidence that mindfulness in youth relates to functional neural dynamics and interactions between neurocognitive networks, over time.

Distinct neural correlates of trait resilience within core neurocognitive networks in at-risk children and adolescents.

Background: Most children who are exposed to threat-related adversity (e.g., violence, abuse, neglect) are resilient - that is, they show stable trajectories of healthy psychological development. Despite this, most research on neurodevelopmental changes following adversity has focused on the neural correlates of negative outcomes, such as psychopathology. The neural correlates of trait resilience in pediatric populations are unknown, and it is unclear whether they are distinct from those related to adversity exposure and the absence of negative outcomes (e.g., depressive symptomology). Methods: This functional magnetic resonance imaging (fMRI) study reports on a diverse sample of 55 children and adolescents (ages 6-17 years) recruited from a range of stressful environments (e.g., lower income, threat-related adversity exposure). Participants completed a multi-echo multi-band resting-state fMRI scan and self-report measures of trait resilience and emotion-related symptomology (e.g., depressive symptoms). Resting-state data were submitted to an independent component analysis (ICA) to identify core neurocognitive networks (salience and emotion network [SEN], default mode network [DMN], central executive network [CEN]). We tested for links among trait resilience and dynamic (i.e., time-varying) as well as conventional static (i.e., averaged across the entire session) resting-state functional connectivity (rsFC) of core neurocognitive networks. Results: Youth with higher trait resilience spent a lower fraction of time in a particular dynamic rsFC state, characterized by heightened rsFC between the anterior DMN and right CEN. Within this state, trait resilience was associated with lower rsFC of the SEN with the right CEN and anterior DMN. There were no associations among trait resilience and conventional static rsFC. Importantly, although more resilient youth reported lower depressive symptoms, the effects of resilience on rsFC were independent of depressive symptoms and adversity exposure. Conclusions: The present study is the first to report on the neural correlates of trait resilience in youth, and offers initial insight into potential adaptive patterns of brain organization in the context of environmental stressors. Understanding the neural dynamics underlying positive adaptation to early adversity will aid in the development of interventions that focus on strengthening resilience rather than mitigating already-present psychological problems.

A novel paradigm to study interpersonal threat-related learning and extinction in children using virtual reality.

Disruptions in fear-extinction learning are centrally implicated in a range of stress-related disorders, including anxiety and posttraumatic stress disorder. Given that these disorders frequently begin in childhood/adolescence, an understanding of fear-extinction learning in children is essential for (1) detecting the source of developmental susceptibility, (2) identifying mechanisms leading to pathology, and (3) informing the development and/or more judicious application of treatments for youth. Here, we offer and validate a novel virtual reality paradigm to study threat-related learning and extinction in children that models real-world cues, environments, and fear-inducing events that children are likely to experience, and are linked to the development of fear- and stress-related pathologies. We found that our paradigm is well tolerated in children as young as 6 years, that children show intact fear and extinction learning, and show evidence of divergence in subjective, physiological, and behavioral measures of conditioned fear. The paradigm is available for use in 3-D and in 2-D (e.g., for the MRI scanner) upon request at www.tnp2lab.org .