The effects of parental presence on amygdala and mPFC activation during fear conditioning: An exploratory study.

Learning safe versus dangerous cues is crucial for survival. During development, parents can influence fear learning by buffering their children's stress response and increasing exploration of potentially aversive stimuli. Rodent findings suggest that these behavioral effects are mediated through parental presence modulation of the amygdala and medial prefrontal cortex (mPFC). Here, we investigated whether similar parental modulation of amygdala and mPFC during fear learning occurs in humans. Using a within-subjects design, behavioral (final N = 48, 6-17 years, mean = 11.61, SD = 2.84, 60% females/40% males) and neuroimaging data (final N = 39, 6-17 years, mean = 12.03, SD = 2.98, 59% females/41% males) were acquired during a classical fear conditioning task, which included a CS+ followed by an aversive noise (US; 75% reinforcement rate) and a CS-. Conditioning occurred once in physical contact with the participant's parent and once alone (order counterbalanced). Region of interest analyses examined the unconditioned stress response by BOLD activation to the US (vs. implicit baseline) and learning by activation to the CS+ (vs. CS-). Results showed that during US presentation, parental presence reduced the centromedial amygdala activity, suggesting buffering of the unconditioned stress response. In response to learned stimuli, parental presence reduced mPFC activity to the CS+ (relative to the CS-), although this result did not survive multiple comparisons' correction. These preliminary findings indicate that parents modulate amygdala and mPFC activity during exposure to unconditioned and conditioned fear stimuli, potentially providing insight into the neural mechanisms by which parents act as a social buffer during fear learning. RESEARCH HIGHLIGHTS: This study used a within-participant experimental design to investigate how parental presence (vs. absence) affects youth's neural responses in a classical fear conditioning task. Parental presence reduced the youth's centromedial amygdala activation to the unconditioned stimulus (US), suggesting parental buffering of the neural unconditioned response (UR). Parental presence reduced the youth's mPFC activation to a conditioned threat cue (CS+) compared to a safety cue (CS-), suggesting possible parental modulation of fear learning.

Probing the content of affective semantic memory following caregiving-related early adversity.

Cognitive science has demonstrated that we construct knowledge about the world by abstracting patterns from routinely encountered experiences and storing them as semantic memories. This preregistered study tested the hypothesis that caregiving-related early adversities (crEAs) shape affective semantic memories to reflect the content of those adverse interpersonal-affective experiences. We also tested the hypothesis that because affective semantic memories may continue to evolve in response to later-occurring positive experiences, child-perceived attachment security will inform their content. The sample comprised 160 children (ages 6-12 at Visit 1; 87F/73 M), 66% of whom experienced crEAs (n = 105). At Visit 1, crEA exposure prior to study enrollment was operationalized as parental-reports endorsing a history of crEAs (abuse/neglect, permanent/significant parent-child separation); while child-reports assessed concurrent attachment security. A false memory task was administered online ∼2.5 years later (Visit 2) to probe the content of affective semantic memories-specifically attachment schemas. Results showed that crEA exposure (vs. no exposure) was associated with a higher likelihood of falsely endorsing insecure (vs. secure) schema scenes. Attachment security moderated the association between crEA exposure and insecure schema-based false recognition. Findings suggest that interpersonal-affective semantic schemas include representations of parent-child interactions that may capture the quality of one's own attachment experiences and that these representations shape how children remember attachment-relevant narrative events. Findings are also consistent with the hypothesis that these affective semantic memories can be modified by later experiences. Moving forward, the approach taken in this study provides a means of operationalizing Bowlby's notion of internal working models within a cognitive neuroscience framework. RESEARCH HIGHLIGHTS: Affective semantic memories representing insecure schema knowledge (child needs + needs-not-met) may be more salient, elaborated, and persistent among youths exposed to early caregiving adversity. All youths, irrespective of early caregiving adversity exposure, may possess affective semantic memories that represent knowledge of secure schemas (child needs + needs-met). Establishing secure relationships with parents following early-occurring caregiving adversity may attenuate the expression of insecure semantic memories, suggesting potential malleability. Affective semantic memories include schema representations of parent-child interactions that may capture the quality of one's own attachment experiences and shape how youths remember attachment-relevant events.

Age-Related Increases in Posterior Hippocampal Granularity Are Associated with Remote Detailed Episodic Memory in Development.

Episodic memory is critical to human functioning. In adults, episodic memory involves a distributed neural circuit in which the hippocampus plays a central role. As episodic memory abilities continue to develop across childhood and into adolescence, studying episodic memory maturation can provide insight into the development and construction of these hippocampal networks, and ultimately clues to their function in adulthood. While past developmental studies have shown that the hippocampus helps to support memory in middle childhood and adolescence, the extent to which ongoing maturation within the hippocampus contributes to developmental change in episodic memory abilities remains unclear. In contrast, slower maturing regions, such as the PFC, have been suggested to be the neurobiological locus of memory improvements into adolescence. However, it is also possible that the methods used to detect hippocampal development during middle childhood and adolescence are not sensitive enough. Here, we examine how temporal covariance (or differentiation) in voxel representations within anterior and posterior hippocampus change with age to support the development of detailed recollection in male and female developing humans. We find age-related increases in the distinctiveness of temporal activation profiles in the posterior, but not anterior, hippocampus. Second, we show that this measure of granularity, when present during postencoding rest periods, correlates with the recall of detailed memories of preceding stimuli several weeks postencoding, suggesting that granularity may promote memory stabilization.SIGNIFICANCE STATEMENT Studying hippocampal maturation can provide insight into episodic memory development, as well as clues to episodic functioning in adulthood. Past work has shown evidence both for and against hippocampal contributions to age-related improvements in memory performance, but has relied heavily on univariate approaches (averaging activity across hippocampal voxels), which may not be sensitive to nuanced developmental change. Here we use a novel approach, examining time signatures in individual hippocampal voxels to reveal regionally specific (anterior vs posterior hippocampus) differences in the distinctiveness (granularity) of temporal activation profiles across development. Importantly, posterior hippocampus granularity during windows of putative memory stabilization was associated with long-term memory specificity. This suggests that the posterior hippocampus gradually builds the capacity to support detailed episodic recall.

Age-related change in task-evoked amygdala-prefrontal circuitry: A multiverse approach with an accelerated longitudinal cohort aged 4-22 years.

The amygdala and its connections with medial prefrontal cortex (mPFC) play central roles in the development of emotional processes. While several studies have suggested that this circuitry exhibits functional changes across the first two decades of life, findings have been mixed - perhaps resulting from differences in analytic choices across studies. Here we used multiverse analyses to examine the robustness of task-based amygdala-mPFC function findings to analytic choices within the context of an accelerated longitudinal design (4-22 years-old; N = 98; 183 scans; 1-3 scans/participant). Participants recruited from the greater Los Angeles area completed an event-related emotional face (fear, neutral) task. Parallel analyses varying in preprocessing and modeling choices found that age-related change estimates for amygdala reactivity were more robust than task-evoked amygdala-mPFC functional connectivity to varied analytical choices. Specification curves indicated evidence for age-related decreases in amygdala reactivity to faces, though within-participant changes in amygdala reactivity could not be differentiated from between-participant differences. In contrast, amygdala-mPFC functional connectivity results varied across methods much more, and evidence for age-related change in amygdala-mPFC connectivity was not consistent. Generalized psychophysiological interaction (gPPI) measurements of connectivity were especially sensitive to whether a deconvolution step was applied. Our findings demonstrate the importance of assessing the robustness of findings to analysis choices, although the age-related changes in our current work cannot be overinterpreted given low test-retest reliability. Together, these findings highlight both the challenges in estimating developmental change in longitudinal cohorts and the value of multiverse approaches in developmental neuroimaging for assessing robustness of results.

Heterogeneity in caregiving-related early adversity: Creating stable dimensions and subtypes.

Early psychosocial adversities exist at many levels, including caregiving-related, extrafamilial, and sociodemographic, which despite their high interrelatedness may have unique impacts on development. In this paper, we focus on caregiving-related early adversities (crEAs) and parse the heterogeneity of crEAs via data reduction techniques that identify experiential cooccurrences. Using network science, we characterized crEA cooccurrences to represent the comorbidity of crEA experiences across a sample of school-age children (n = 258; 6-12 years old) with a history of crEAs. crEA dimensions (variable level) and crEA subtypes (subject level) were identified using parallel factor analysis/principal component analysis and graph-based Louvain community detection. Bagging enhancement with cross-validation provided estimates of robustness. These data-driven dimensions/subtypes showed evidence of stability, transcended traditional sociolegally defined groups, were more homogenous than sociolegally defined groups, and reduced statistical correlations with sociodemographic factors. Finally, random forests showed both unique and common predictive importance of the crEA dimensions/subtypes for childhood mental health symptoms and academic skills. These data-driven outcomes provide additional tools and recommendations for crEA data reduction to inform precision medicine efforts in this area.

Fear modulates parental orienting during childhood and adolescence.

Adults quickly orient toward sources of danger and deploy fight-or-flight tactics to manage threatening situations. In contrast, infants who cannot implement the safety strategies available to adults and depend heavily on caregivers for survival are more likely to turn toward familiar adults, such as their parents, to help them navigate threatening circumstances. However, work has yet to investigate how readily children and adolescents orient toward their parents in threatening or fearful contexts. The current work addressed this question using a visual search paradigm that included arrays of parents' and strangers' faces as target and distractor stimuli, preceded by a fear or neutral emotional priming procedure. Linear mixed-effects models showed that children and adolescents (N = 88, age range = 4-17 years; 42M/46F) were faster to search for the face of their parent than of a stranger. However, fear priming attenuated this effect of the parent on search times, such that children and adolescents were significantly slower to orient toward their parent in an array of strangers' faces if they were first primed with fear as opposed to a neutral video. This work indicates that fear priming may phasically interfere with parental orienting during childhood and adolescence, possibly because fear reallocates attention away from parents and toward (potentially threatening) unfamiliar people in the environment to facilitate the development of independent threat learning and coping systems.

An exploration of amygdala-prefrontal mechanisms in the intergenerational transmission of learned fear.

Humans learn about their environments by observing others, including what to fear and what to trust. Observational fear learning may be especially important early in life when children turn to their parents to gather information about their world. Yet, the vast majority of empirical research on fear learning in youth has thus far focused on firsthand classical conditioning, which may fail to capture one of the primary means by which fears are acquired during development. To address this gap in the literature, the present study examined observational fear learning in youth (n = 33; age range: 6-17 years) as they watched videos of their parent and an "unfamiliar parent" (i.e., another participant's parent) undergo fear conditioning. Youth demonstrated stronger fear learning when observing their parent compared to an unfamiliar parent, as indicated by changes in their self-reported liking of the stimuli to which their parents were conditioned (CS+, a geometric shape paired with an aversive noise; CS-, a geometric shape never paired with an aversive noise) and amygdala responses. Parent trait anxiety was associated with youth learning better (i.e., reporting a stronger preference for the CS- relative to CS+), and exhibiting stronger medial prefrontal-amygdala connectivity. Neuroimaging data were additionally acquired from a subset of parents during firsthand conditioning, and parental amygdala and mPFC activation were associated with youth's neural recruitment. Together, these results suggest that youth preferentially learn fears via observation of their parents, and this learning is associated with emotional traits and neural recruitment in parents.

Adaptation in the face of adversity: Decrements and enhancements in children's cognitive control behavior following early caregiving instability.

Cognitive control is typically described as disrupted following exposure to early caregiving instability. While much of the work within this field has approached cognitive control broadly, evidence from adults retrospectively reporting early-life instability has shown more nuanced effects on cognitive control, even demonstrating enhancements in certain subdomains. That is, exposure to unstable caregiving may disrupt some areas of cognitive control, yet promote adaptation in others. Here, we investigated three domains of cognitive control in a sample of school-age children (N = 275, Age = 6-12 years) as a function of early caregiving instability, defined as the total number of caregiving switches. Results demonstrated that caregiving instability was associated with reduced response inhibition (Go/No-Go) and attentional control (Flanker), but enhanced cognitive flexibility (Dimensional Change Card Sort Task Switching). Conversely, there were no statistically significant associations with group (i.e., institutional care versus foster care) or maltreatment exposure and these patterns. These findings build on the specialization framework, suggesting that caregiving instability results in both decrements and enhancements in children's cognitive control, consistent with the hypothesis that cognitive control development is scaffolded by early environmental pressures.

Using gastrointestinal distress reports to predict youth anxiety risk: Implications for mental health literacy and community care.

This study investigates the generalizability and predictive validity of associations between gastrointestinal (GI) symptoms and youth anxiety to establish their utility in community mental health decision-making. We analyzed data from youth ages 3 to 21 years in volunteer cohorts collected in Los Angeles (N = 327) and New York City (N = 102), as well as the Healthy Brain Network cohort (N = 1957). Youth GI distress was measured through items taken from the parent-reported Child Behavior Checklist (CBCL). We examined generalizability of GI-anxiety associations across cohorts and anxiety reporters, then evaluated the performance of these models in predicting youth anxiety in holdout data. Consistent with previous work, higher levels of gastrointestinal distress were associated with more parent-reported youth anxiety behaviors in all three cohorts. Models trained on data from the Healthy Brain Network cohort predicted parent-reported and child-reported anxiety behaviors, as well as clinician-evaluated anxiety diagnoses, at above chance levels in holdout data. Models which included GI symptoms often, but not always, outperformed models based on age and sex alone in predicting youth anxiety. Based on the generalizability and predictive validity of GI-anxiety associations investigated here, GI symptoms may be an effective tool for child-facing professionals for identifying children at risk for anxiety (Preprint: https://psyarxiv.com/zgavu/).

Positive valence bias and parent-child relationship security moderate the association between early institutional caregiving and internalizing symptoms.

Institutional caregiving is associated with significant deviations from species-expected caregiving, altering the normative sequence of attachment formation and placing children at risk for long-term emotional difficulties. However, little is known about factors that can promote resilience following early institutional caregiving. In the current study, we investigated how adaptations in affective processing (i.e., positive valence bias) and family-level protective factors (i.e., secure parent-child relationships) moderate risk for internalizing symptoms in previously institutionalized (PI) youth. Children and adolescents with and without a history of institutional care performed a laboratory-based affective processing task and self-reported measures of parent-child relationship security. PI youth were more likely than comparison youth to show positive valence biases when interpreting ambiguous facial expressions. Both positive valence bias and parent-child relationship security moderated the association between institutional care and parent-reported internalizing symptoms, such that greater positive valence bias and more secure parent-child relationships predicted fewer symptoms in PI youth. However, when both factors were tested concurrently, parent-child relationship security more strongly moderated the link between PI status and internalizing symptoms. These findings suggest that both individual-level adaptations in affective processing and family-level factors of secure parent-child relationships may ameliorate risk for internalizing psychopathology following early institutional caregiving.

Impact of the COVID-19 Pandemic on the Effectiveness of a Metabolic Health Telemedicine Intervention for Weight Loss: A Propensity Score Matching Analysis.

Background: Coronavirus disease 2019 (COVID-19) pandemic public health measures such as stay-at-home and mandatory work-from-home orders have been associated with obesogenic lifestyle changes, increased risk of weight gain, and their metabolic sequelae. We sought to assess the impact of this pandemic on weight loss from a telemedicine-delivered very-low-carbohydrate intervention targeting nutritional ketosis (NKI). Methods: A total of 746 patients with a BMI ≥25kg/m2, enrolled between January and March 2020 and treated for at least 1 year with the NKI, were classified as pandemic cohort (PC). A separate cohort of 699 patients who received 1 year of the NKI in the preceding years, enrolled between January and March 2018, were identified as pre-pandemic cohort (Pre-PC). Demographic and clinical data were obtained from medical records to compare the cohorts and assess the outcomes. Using propensity score matching (PSM), balanced and matched groups of 407 patients in the Pre-PC and 407 patients in the PC were generated. Longitudinal change in absolute weight and percentage weight change from baseline to 1 year were assessed. Results: Weight significantly decreased in both PC and Pre-PC at 3, 6, 9, and 12 months. The weight loss trajectory was similar in both PC and Pre-PC with no significant weight differences between the two cohorts at 3, 6, 9, and 12 months. On an average, the PC lost 7.5% body weight while the Pre-PC lost 7.9% over 1 year, and the percent weight loss did not differ between the two cohorts (p = 0.50). Conclusion: A very-low-carbohydrate telemedicine intervention delivered comparable and medically significant weight loss independent of pandemic stress and lifestyle limitations.

Reduced COVID-19 severity elicited by weight loss from a medically supervised ketogenic diet in a geographically diverse ambulatory population with type 2 diabetes and obesity.

Objective: To investigate factors associated with COVID-19 severity in ambulatory individuals with type 2 diabetes mellitus (T2DM) and obesity treated with a medically supervised ketogenic diet (MSKD). Research design and methods: In this real-world, retrospective, exploratory analysis, multivariate modelling was used to assess clinical factors associated with hospitalisation for COVID-19 in a geographically diverse outpatient population with T2DM treated virtually. Results: Leading up to COVID-19 onset, non-hospitalised patients had higher average ketones (0.64 vs 0.52 mmol/L; p=0.016) and greater weight loss (6.8% vs 4.2%; p=0.009) compared with those hospitalised. Greater weight loss was significantly associated with lower likelihood of hospitalisation (adjusted OR=0.91, p=0.005), controlling for enrolment demographics and medical characteristics. Conclusions: Therapies such as MSKD, which elicit rapid, significant weight loss, may favourably impact COVID-19 hospitalisation rate and severity in individuals with T2DM and obesity.

Shifting children's attentional focus to emotions during art museum experiences.

Art exposure can influence children's emotional growth, but little is known about tools that aid emotional development in art museums. We implemented attentional and social manipulations to test whether (1) modifications to unscripted instructions and (2) caregiver prompts shape children's attentional focus towards either the emotional or elemental content (e.g., colour and medium) of paintings. These manipulations occurred within an on-going art museum education programme. Afterwards, children's (N = 60; ages 3-13 years) attentional focus towards emotions or elements was assessed by asking them to select words that best described the art. Children focused on emotion more, but the instructional manipulation successfully influenced word choices towards the targeted focus. Caregiver prompts also influenced focus towards the elements and away from emotions. These findings highlight that children's attention to art's emotional content can be altered by social context, which here was demonstrated within a museum programme.

Longitudinal changes in amygdala, hippocampus and cortisol development following early caregiving adversity.

Although decades of research have shown associations between early caregiving adversity, stress physiology and limbic brain volume (e.g., amygdala, hippocampus), the developmental trajectories of these phenotypes are not well characterized. In the current study, we used an accelerated longitudinal design to assess the development of stress physiology, amygdala, and hippocampal volume following early institutional care. Previously Institutionalized (PI; N = 93) and comparison (COMP; N = 161) youth (ages 4-20 years old) completed 1-3 waves of data collection, each spaced approximately 2 years apart, for diurnal cortisol (N = 239) and structural MRI (N = 156). We observed a developmental shift in morning cortisol in the PI group, with blunted levels in childhood and heightened levels in late adolescence. PI history was associated with reduced hippocampal volume and reduced growth rate of the amygdala, resulting in smaller volumes by adolescence. Amygdala and hippocampal volumes were also prospectively associated with future morning cortisol in both groups. These results indicate that adversity-related physiological and neural phenotypes are not stationary during development but instead exhibit dynamic and interdependent changes from early childhood to early adulthood.

Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for Stress-Related Psychopathology.

Early adverse experiences are associated with heighted vulnerability for stress-related psychopathology across the lifespan. While extensive work has investigated the effects of early adversity on neurobiology in adulthood, developmental approaches can provide further insight on the neurobiological mechanisms that link early experiences and long-term mental health outcomes. In the current review, we discuss the role of emotion regulation circuitry implicated in stress-related psychopathology from a developmental and transdiagnostic perspective. We highlight converging evidence suggesting that multiple forms of early adverse experiences impact the functional development of amygdala-prefrontal circuitry. Next, we discuss how adversity-induced alterations in amygdala-prefrontal development are associated with symptoms of emotion dysregulation and psychopathology. Additionally, we discuss potential mechanisms through which protective factors may buffer the effects of early adversity on amygdala-prefrontal development to confer more adaptive long-term outcomes. Finally, we consider limitations of the existing literature and make suggestions for future longitudinal and translational research that can better elucidate the mechanisms linking early adversity, neurobiology, and emotional phenotypes. Together, these findings may provide further insight into the neuro-developmental mechanisms underlying the emergence of adversity-related emotional disorders and facilitate the development of targeted interventions that can ameliorate risk for psychopathology in youth exposed to early life stress.

Dysfunctional Social Reinforcement Processing in Disruptive Behavior Disorders: An Functional Magnetic Resonance Imaging Study.

OBJECTIVE: Prior functional magnetic resonance imaging (fMRI) work has revealed that children/adolescents with disruptive behavior disorders (DBDs) show dysfunctional reward/non-reward processing of non-social reinforcements in the context of instrumental learning tasks. Neural responsiveness to social reinforcements during instrumental learning, despite the importance of this for socialization, has not yet been previously investigated. METHODS: Twenty-nine healthy children/adolescents and 19 children/adolescents with DBDs performed the fMRI social/non-social reinforcement learning task. Participants responded to random fractal image stimuli and received social and non-social rewards/non-rewards according to their accuracy. RESULTS: Children/adolescents with DBDs showed significantly reduced responses within the caudate and posterior cingulate cortex (PCC) to non-social (financial) rewards and social non-rewards (the distress of others). Connectivity analyses revealed that children/adolescents with DBDs have decreased positive functional connectivity between the ventral striatum (VST) and the ventromedial prefrontal cortex (vmPFC) seeds and the lateral frontal cortex in response to reward relative to non-reward, irrespective of its sociality. In addition, they showed decreased positive connectivity between the vmPFC seed and the amygdala in response to non-reward relative to reward. CONCLUSION: These data indicate compromised reinforcement processing of both non-social rewards and social non-rewards in children/adolescents with DBDs within core regions for instrumental learning and reinforcement-based decision- making (caudate and PCC). In addition, children/adolescents with DBDs show dysfunctional interactions between the VST, vmPFC, and lateral frontal cortex in response to rewarded instrumental actions potentially reflecting disruptions in attention to rewarded stimuli.

The role of ventral striatum in reward-based attentional bias.

INTRODUCTION: Models of attention suggest that endogenous and exogenous factors can bias attention. However, recent data suggest that reward can also enhance attention towards relevant stimulus features as a function of involuntary biases. In this study, we utilized the additional singleton task to determine the neural circuitry that biases perceptual processing as a function of reward history. METHODS: Participants searched for a unique shape amongst an array of differently shaped objects. All shapes, including the target shape, had the same color except one distractor shape. Participants randomly received a low or high reward after correct trials. From one trial to the next, target colors could stay the same or swap with the distractor color. Interestingly, and despite the irrelevancy of reward magnitude for task accuracy, the difference in reaction time between swap and non-swap trials usually is more pronounced following a high compared to a low reward. RESULTS: In the current study, we showed that reward modulated attention is larger for individuals with enhanced reward magnitude sensitivity in the ventral striatum. In addition, connectivity data shows that ventral striatum was more positively connected with visual cortex during high reward non-swap trials compared to high reward swap trials for participants showing stronger reward modulated attention. CONCLUSIONS: This suggests that involuntary reward modulated attention might be implemented by direct influences of the ventral striatum on visual cortex.

Neurodevelopmental Changes in Social Reinforcement Processing: A Functional Magnetic Resonance Imaging Study.

OBJECTIVE: In the current study we investigated neurodevelopmental changes in response to social and non-social reinforcement. METHODS: Fifty-three healthy participants including 16 early adolescents (age, 10-15 years), 16 late adolescents (age, 15-18 years), and 21 young adults (age, 21-25 years) completed a social/non-social reward learning task while undergoing functional magnetic resonance imaging. Participants responded to fractal image stimuli and received social or non-social reward/non-rewards according to their accuracy. ANOVAs were conducted on both the blood oxygen level dependent response data and the product of a context-dependent psychophysiological interaction (gPPI) analysis involving ventromedial prefrontal cortex (vmPFC) and bilateral insula cortices as seed regions. RESULTS: Early adolescents showed significantly increased activation in the amygdala and anterior insula cortex in response to non-social monetary rewards relative to both social reward/non-reward and monetary non-rewards compared to late adolescents and young adults. In addition, early adolescents showed significantly more positive connectivity between the vmPFC/bilateral insula cortices seeds and other regions implicated in reinforcement processing (the amygdala, posterior cingulate cortex, insula cortex, and lentiform nucleus) in response to non-reward and especially social non-reward, compared to late adolescents and young adults. CONCLUSION: It appears that early adolescence may be marked by: (i) a selective increase in responsiveness to non-social, relative to social, rewards; and (ii) enhanced, integrated functioning of reinforcement circuitry for non-reward, and in particular, with respect to posterior cingulate and insula cortices, for social non-reward.

Neural Correlates of the Propensity for Retaliatory Behavior in Youths With Disruptive Behavior Disorders.

OBJECTIVE: Youths with disruptive behavior disorders (DBD) (conduct disorder and oppositional defiant disorder) have an elevated risk for maladaptive reactive aggression. Theory suggests that this is due to an elevated sensitivity of basic threat circuitry implicated in retaliation (amygdala/periaqueductal gray) in youths with DBD and low levels of callous-unemotional traits and dysfunctional regulatory activity in the ventromedial prefrontal cortex in youths with DBD irrespective of callous-unemotional traits. METHOD: A total of 56 youths 10-18 years of age (23 of them female) participated in the study: 30 youths with DBD, divided by median split into groups with high and low levels of callous-unemotional traits, and 26 healthy youths. All participants completed an ultimatum game task during functional MRI. RESULTS: Relative to the other groups, youths with DBD and low levels of callous-unemotional traits showed greater increases in activation of basic threat circuitry when punishing others and dysfunctional down-regulation of the ventromedial prefrontal cortex during retaliation. Relative to healthy youths, all youths with DBD showed reduced amygdala-ventromedial prefrontal cortex connectivity during high provocation. Ventromedial prefrontal cortex responsiveness and ventromedial prefrontal cortex-amygdala connectivity were related to patients' retaliatory propensity (behavioral responses during the task) and parent-reported reactive aggression. CONCLUSIONS: These data suggest differences in the underlying neurobiology of maladaptive reactive aggression in youths with DBD who have relatively low levels of callous-unemotional traits. Youths with DBD and low callous-unemotional traits alone showed significantly greater threat responses during retaliation relative to comparison subjects. These data also suggest that ventromedial prefrontal cortex-amygdala connectivity is critical for regulating retaliation/reactive aggression and, when dysfunctional, contributes to reactive aggression, independent of level of callous-unemotional traits.