Christine A. Rabinak

Convergence of fMRI and ERP measures of emotional face processing in combat-exposed U. S. military veterans

The late positive potential (LPP) and fMRI blood-oxygen-level dependent (BOLD) activity can provide complementary measures of the processing of affective and social stimuli. Separate lines of research using these measures have often employed the same stimuli, paradigms, and samples; however, there remains relatively little understanding of the way in which individual differences in one of these measures relates to the other, and all prior research has been conducted in psychiatrically healthy samples and using emotional scenes (not faces). Here, 32 combat-exposed U. S. military veterans with varying levels of posttraumatic stress symptomatology viewed affective social stimuli (angry, fearful, and happy faces) and geometric shapes during separate EEG and fMRI BOLD recordings. Temporospatial principal component analysis was used to quantify the face-elicited LPP in a data-driven manner, prior to conducting whole-brain correlations between resulting positivities and fMRI BOLD elicited by faces. Participants with larger positivities to fearful faces (> shapes) showed increased activation in the amygdala; larger positivities to angry and happy faces (> shapes) were associated with increased BOLD activation in the posterior fusiform gyrus and inferior temporal gyrus, respectively. Across all face types, larger positivities were associated with increased activation in the fusiform face area. Correlations using mean area amplitude LPPs showed an association with increased activation in the anterior insula for angry faces (> shapes). LPP-BOLD associations were not moderated by PTSD. Findings provide the first evidence of correspondence between face-elicited LPP and BOLD activation across a range of (normal to disordered) psychiatric health.

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.

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

&NA; 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. HighlightsChildhood socioeconomic disadvantage (SED) is linked to a range of poor outcomesNeuroimaging studies suggest that childhood SED has widespread impact on the brainMost studies have examined household SED (e.g., income) but not community SEDCommunity SED had unique effects on the salience and emotion brain networkSED‐related changes in the brain were also associated with lower IQ

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

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).

Effects of acute Δ9-tetrahydrocannabinol on next-day extinction recall is mediated by post-extinction resting-state brain dynamics

ABSTRACT We have previously demonstrated that an acute dose of &Dgr;9‐tetrahydrocanninbinol (THC), administered prior to extinction learning, facilitates later recall of extinction learning and modulates the underlying neural circuitry, including the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), and amygdala (AMYG). It remains unknown whether THC‐induced changes in fear‐extinction neural circuitry can be detected following extinction learning, which may reflect ongoing processes involved consolidation of the extinction memory. To address this gap, we used a randomized, double‐blind, placebo‐controlled, between‐subjects design to compare acute pharmacological effects of THC (7.5mg) vs. placebo (PBO) on post‐extinction resting‐state functional connectivity (RS‐FC) within fear‐extinction circuitry in 77 healthy adults (THC=40; PBO=37). RS‐FC was examined between vmPFC, HPC, and AMYG using two complementary approaches: 1) static RS‐FC (average correlation in ROI‐ROI pairs across the entire scan); and 2) dynamic (i.e., time‐varying) RS‐FC (sliding window correlation time series variance). RS‐FC was then linked to behavioral and brain measures of extinction recall. Compared to PBO, THC administration was associated with lower AMYG‐HPC static RS‐FC, but higher AMYG‐vmPFC dynamic RS‐FC. Lower AMYG‐HPC static RS‐FC was associated with higher HPC activation, as well as, better extinction recall. Moreover, lower AMYG‐HPC static RS‐FC following extinction learning mediated the link between THC administration and extinction recall. Post‐extinction RS‐FC patterns may reflect sustained effects of THC on fear‐extinction circuitry even in the absence of an overt task, and/or effects of ongoing processes that serve to strengthen the neural connections supporting the consolidation of the memory and better extinction recall. HIGHLIGHTSPre‐extinction THC administration has been shown to enhance extinction recall.THC altered static and dynamic RS‐FC during a post‐extinction rest period.RS‐FC mediated the link between pre‐extinction THC and next‐day recall.RS‐FC effects may reflect processes supporting consolidation of extinction learning.

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.

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 6–17u202fyears) 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.

Socioeconomic disadvantage and altered corticostriatal circuitry in urban youth

Socioeconomic disadvantage (SED) experienced in early life is linked to a range of risk behaviors and diseases. Neuroimaging research indicates that this association is mediated by functional changes in corticostriatal reward systems that modulate goal‐directed behavior, reward evaluation, and affective processing. Existing research has focused largely on adults and within‐household measures as an index of SED, despite evidence that broader community‐level SED (e.g., neighborhood poverty levels) has significant and sometimes distinct effects on development and health outcomes. Here, we test effects of both household‐ and community‐level SED on resting‐state functional connectivity (rsFC) of the ventral striatum (VS) in 100 racially and economically diverse children and adolescents (ages 6–17). We observed unique effects of household income and community SED on VS circuitry such that higher community SED was associated with reduced rsFC between the VS and an anterior region of the medial prefrontal cortex (mPFC), whereas lower household income was associated with increased rsFC between the VS and the cerebellum, inferior temporal lobe, and lateral prefrontal cortex. Lower VS‐mPFC rsFC was also associated with higher self‐reported anxiety symptomology, and rsFC mediated the link between community SED and anxiety. These results indicate unique effects of community‐level SED on corticostriatal reward circuitry that can be detected in early life, which carries implications for future interventions and targeted therapies. In addition, our findings raise intriguing questions about the distinct pathways through which specific sources of SED can affect brain and emotional development.

What's parenting got to do with it: emotional autonomy and brain and behavioral responses to emotional conflict in children and adolescents

Healthy parenting may be protective against the development of emotional psychopathology, particularly for children reared in stressful environments. Little is known, however, about the brain and behavioral mechanisms underlying this association, particularly during childhood and adolescence, when emotional disorders frequently emerge. Here, we demonstrate that psychological control, a parenting strategy known to limit socioemotional development in children, is associated with altered brain and behavioral responses to emotional conflict in 27 at-risk (urban, lower income) youth, ages 9-16. In particular, youth reporting higher parental psychological control demonstrated lower activity in the left anterior insula, a brain area involved in emotion conflict processing, and submitted faster but less accurate behavioral responses-possibly reflecting an avoidant pattern. Effects were not replicated for parental care, and did not generalize to an analogous nonemotional conflict task. We also find evidence that behavioral responses to emotional conflict bridge the previously reported link between parental overcontrol and anxiety in children. Effects of psychological control may reflect a parenting style that limits opportunities to practice self-regulation when faced with emotionally charged situations. Results support the notion that parenting strategies that facilitate appropriate amounts of socioemotional competence and autonomy in children may be protective against social and emotional difficulties.

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 learningxa0and 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.