Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence.

Maltreatment during childhood is a major risk factor for anxiety and depression, which are major public health problems. However, the underlying brain mechanism linking maltreatment and internalizing disorders remains poorly understood. Maltreatment may alter the activation of fear circuitry, but little is known about its impact on the connectivity of this circuitry in adolescence and whether such brain changes actually lead to internalizing symptoms. We examined the associations between experiences of maltreatment during childhood, resting-state functional brain connectivity (rs-FC) of the amygdala and hippocampus, and internalizing symptoms in 64 adolescents participating in a longitudinal community study. Childhood experiences of maltreatment were associated with lower hippocampus-subgenual cingulate rs-FC in both adolescent females and males and lower amygdala-subgenual cingulate rs-FC in females only. Furthermore, rs-FC mediated the association of maltreatment during childhood with adolescent internalizing symptoms. Thus, maltreatment in childhood, even at the lower severity levels found in a community sample, may alter the regulatory capacity of the brain's fear circuit, leading to increased internalizing symptoms by late adolescence. These findings highlight the importance of fronto-hippocampal connectivity for both sexes in internalizing symptoms following maltreatment in childhood. Furthermore, the impact of maltreatment during childhood on both fronto-amygdala and -hippocampal connectivity in females may help explain their higher risk for internalizing disorders such as anxiety and depression.

Compassion training alters altruism and neural responses to suffering.

Compassion is a key motivator of altruistic behavior, but little is known about individuals' capacity to cultivate compassion through training. We examined whether compassion may be systematically trained by testing whether (a) short-term compassion training increases altruistic behavior and (b) individual differences in altruism are associated with training-induced changes in neural responses to suffering. In healthy adults, we found that compassion training increased altruistic redistribution of funds to a victim encountered outside of the training context. Furthermore, increased altruistic behavior after compassion training was associated with altered activation in brain regions implicated in social cognition and emotion regulation, including the inferior parietal cortex and dorsolateral prefrontal cortex (DLPFC), and in DLPFC connectivity with the nucleus accumbens. These results suggest that compassion can be cultivated with training and that greater altruistic behavior may emerge from increased engagement of neural systems implicated in understanding the suffering of other people, executive and emotional control, and reward processing.

Evidence for coordinated functional activity within the extended amygdala of non-human and human primates.

Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala.

Mindfulness video game improves connectivity of the fronto-parietal attentional network in adolescents: A multi-modal imaging study.

Mindfulness training has been shown to improve attention and change the underlying brain substrates in adults. Most mindfulness training programs involve a myriad of techniques, and it is difficult to attribute changes to any particular aspect of the program. Here, we created a video game, Tenacity, which models a specific mindfulness technique - focused attention on one's breathing - and assessed its potential to train an attentional network in adolescents. A combined analysis of resting state functional connectivity (rs-FC) and diffusion tensor imaging (DTI) yielded convergent results - change in communication within the left fronto-parietal network after two weeks of playing Tenacity compared to a control game. Rs-FC analysis showed greater connectivity between left dorsolateral prefrontal cortex (dlPFC) and left inferior parietal cortex (IPC) in the Tenacity group. Importantly, changes in left dlPFC - IPC rs-FC and changes in structural connectivity of the white matter tract that connects these regions -left superior longitudinal fasiculus (SLF) - were associated with changes in performance on an attention task. Finally, changes in left dlPFC - IPC rs-FC correlated with the change in left SLF structural connectivity as measured by fractional anisotropy (FA) in the Tenacity group only.

Visual Attention to Suffering After Compassion Training Is Associated With Decreased Amygdala Responses.

Compassion meditation training is hypothesized to increase the motivational salience of cues of suffering, while also enhancing equanimous attention and decreasing emotional reactivity to suffering. However, it is currently unknown how compassion meditation impacts visual attention to suffering, and how this impacts neural activation in regions associated with motivational salience as well as aversive responses, such as the amygdala. Healthy adults were randomized to 2 weeks of compassion or reappraisal training. We measured BOLD fMRI responses before and after training while participants actively engaged in their assigned training to images depicting human suffering or non-suffering. Eye-tracking data were recorded concurrently, and we computed looking time for socially and emotionally evocative areas of the images, and calculated visual preference for suffering vs. non-suffering. Increases in visual preference for suffering due to compassion training were associated with decreases in the amygdala, a brain region involved in negative valence, arousal, and physiological responses typical of fear and anxiety states. This pattern was specifically in the compassion group, and was not found in the reappraisal group. In addition, compassion training-related increases in visual preference for suffering were also associated with decreases in regions sensitive to valence and empathic distress, spanning the anterior insula and orbitofrontal cortex (while the reappraisal group showed the opposite effect). Examining visual attention alone demonstrated that engaging in compassion in general (across both time points) resulted in visual attention preference for suffering compared to engaging in reappraisal. Collectively, these findings suggest that compassion meditation may cultivate visual preference for suffering while attenuating neural responses in regions typically associated with aversive processing of negative stimuli, which may cultivate a more equanimous and nonreactive form of attention to stimuli of suffering.

Neural correlates of video game empathy training in adolescents: a randomized trial.

The ability to understand emotional experiences of others, empathy, is a valuable skill for effective social interactions. Various types of training increase empathy in adolescents, but their impact on brain circuits underlying empathy has not been examined. Video games provide a unique medium familiar and engaging to adolescents and can be used to deliver training at scale. We developed an empathy training video game, Crystals of Kaydor (Crystals), and investigated whether playing Crystals increases empathic accuracy (EA) and related brain activation in adolescents (N = 74; 27 female; mean age(sd) = 12.8(0.7) years; age range 11-14 years). Participants completed a resting state functional MRI (rs-fMRI) scan and an EA task during an fMRI scan before and after 2 weeks of daily gameplay with either the empathy training game, Crystals (N = 34), or the commercial video game Bastion (N = 40), an active control condition. There were no group differences in EA improvement following gameplay, however, engagement with training aspects of Crystals was associated with a higher increase in EA-related activation in right temporoparietal junction following gameplay. Moreover, rs-fMRI connectivity in empathy-related brain circuits (posterior cingulate-medial prefrontal cortex; MPFC) was stronger after Crystals gameplay compared to Bastion. The more individuals' EA increased following Crystals versus Bastion, the stronger their rs-fMRI connectivity in brain circuits relevant for emotion regulation (amygdala-MPFC). These findings suggest that a video game designed to increase empathic accuracy produces behaviorally-relevant, functional neural changes in fewer than 6 h of gameplay in adolescents.

Enhanced prefrontal-amygdala connectivity following childhood adversity as a protective mechanism against internalizing in adolescence.

BACKGROUND: Much research has focused on the deleterious neurobiological effects of childhood adversity that may underlie internalizing disorders. While most youth show emotional adaptation following adversity, the corresponding neural mechanisms remain poorly understood. METHODS: In this longitudinal community study, we examined the associations among childhood family adversity, adolescent internalizing symptoms, and their interaction on regional brain activation and amygdala/hippocampus functional connectivity during emotion processing in 132 adolescents. RESULTS: Consistent with prior work, childhood adversity predicted heightened amygdala reactivity to negative, but not positive, images in adolescence. However, amygdala reactivity was not related to internalizing symptoms. Furthermore, childhood adversity predicted increased fronto-amygdala connectivity to negative, but not positive, images, yet only in lower internalizing adolescents. Childhood adversity also predicted increased fronto-hippocampal connectivity to negative images, but was not moderated by internalizing. These findings were unrelated to adolescence adversity or externalizing symptoms, suggesting specificity to childhood adversity and adolescent internalizing. CONCLUSIONS: Together, these findings suggest that adaptation to childhood adversity is associated with augmentation of fronto-subcortical circuits specifically for negative emotional stimuli. Conversely, insufficient enhancement of fronto-amygdala connectivity, with increasing amygdala reactivity, may represent a neural signature of vulnerability for internalizing by late adolescence. These findings implicate early childhood as a critical period in determining the brain's adaptation to adversity, and suggest that even normative adverse experiences can have significant impact on neurodevelopment and functioning. These results offer potential neural mechanisms of adaptation and vulnerability which could be used in the prediction of risk for psychopathology following childhood adversity.

Experience-Driven Differences in Childhood Cortisol Predict Affect-Relevant Brain Function and Coping in Adolescent Monozygotic Twins.

Stress and emotion involve diverse developmental and individual differences. Partially attributed to the development of the prefrontal cortex (PFC), the amygdala, and hypothalamic-pituitary-adrenal axis, the precise genetic and experiential contributions remain unknown. In previous work, childhood basal cortisol function predicted adolescent resting-state functional connectivity (rs-FC) and psychopathology. To parse experience-driven (non-genetic) contributions, we investigated these relations with a monozygotic (MZ) twin design. Specifically, we examined whether intrapair differences in childhood afternoon cortisol levels predicted cotwin differences in adolescent brain function and coping. As expected, intrapair differences in childhood cortisol forecast amygdala-perigenual PFC rs-FC (R2 = 0.84, FWE-corrected p = 0.01), and amygdala recovery following unpleasant images (R2 = 0.40, FWE-corrected p < 0.05), such that the cotwin with higher childhood cortisol evinced relatively lower rs-FC and poorer amygdala recovery in adolescence. Cotwin differences in amygdala recovery also predicted coping styles. These data highlight experience-dependent change in childhood and adolescence.

The Role of Compassion in Altruistic Helping and Punishment Behavior.

Compassion, the emotional response of caring for another who is suffering and that results in motivation to relieve suffering, is thought to be an emotional antecedent to altruistic behavior. However, it remains unclear whether compassion enhances altruistic behavior in a uniform way or is specific to sub-types of behavior such as altruistic helping of a victim or altruistic punishment of a transgressor. We investigated the relationship between compassion and subtypes of altruistic behavior using third-party paradigms where participants (1) witnessed an unfair economic exchange between a transgressor and a victim, and (2) had the opportunity to either spend personal funds to either economically (a) help the victim or (b) punish the transgressor. In Study 1, we examined whether individual differences in self-reported empathic concern (the emotional component of compassion) was associated with greater altruistic helping or punishment behavior in two independent samples. For participants who witnessed an unfair transaction, trait empathic concern was associated with greater helping of a victim and had no relationship to punishment. However, in those who decided to punish the transgressor, participants who reported greater empathic concern decided to punish less. In Study 2, we directly enhanced compassion using short-term online compassion meditation training to examine whether altruistic helping and punishment were increased after two weeks of training. Compared to an active reappraisal training control group, the compassion training group gave more to help the victim and did not differ in punishment of the transgressor. Together, these two studies suggest that compassion is related to greater altruistic helping of victims and is not associated with or may mitigate altruistic punishment of transgressors.

Preschool externalizing behavior predicts gender-specific variation in adolescent neural structure.

Dysfunction in the prefrontal cortex, amygdala, and hippocampus is believed to underlie the development of much psychopathology. However, to date only limited longitudinal data relate early behavior with neural structure later in life. Our objective was to examine the relationship of early life externalizing behavior with adolescent brain structure. We report here the first longitudinal study linking externalizing behavior during preschool to brain structure during adolescence. We examined the relationship of preschool externalizing behavior with amygdala, hippocampus, and prefrontal cortex volumes at age 15 years in a community sample of 76 adolescents followed longitudinally since their mothers' pregnancy. A significant gender by externalizing behavior interaction revealed that males-but not females-with greater early childhood externalizing behavior had smaller amygdala volumes at adolescence (t = 2.33, p = .023). No significant results were found for the hippocampus or the prefrontal cortex. Greater early externalizing behavior also related to smaller volume of a cluster including the angular gyrus and tempoparietal junction across genders. Results were not attributable to the impact of preschool anxiety, preschool maternal stress, school-age internalizing or externalizing behaviors, or adolescent substance use. These findings demonstrate a novel, gender-specific relationship between early-childhood externalizing behavior and adolescent amygdala volume, as well as a cross-gender result for the angular gyrus and tempoparietal junction.

Robust Automated Amygdala Segmentation via Multi-Atlas Diffeomorphic Registration.

Here, we describe a novel method for volumetric segmentation of the amygdala from MRI images collected from 35 human subjects. This approach is adapted from open-source techniques employed previously with the hippocampus (Suh et al., 2011; Wang et al., 2011a,b). Using multi-atlas segmentation and machine learning-based correction, we were able to produce automated amygdala segments with high Dice (Mean = 0.918 for the left amygdala; 0.916 for the right amygdala) and Jaccard coefficients (Mean = 0.850 for the left; 0.846 for the right) compared to rigorously hand-traced volumes. This automated routine also produced amygdala segments with high intra-class correlations (consistency = 0.830, absolute agreement = 0.819 for the left; consistency = 0.786, absolute agreement = 0.783 for the right) and bivariate (r = 0.831 for the left; r = 0.797 for the right) compared to hand-drawn amygdala. Our results are discussed in relation to other cutting-edge segmentation techniques, as well as commonly available approaches to amygdala segmentation (e.g., Freesurfer). We believe this new technique has broad application to research with large sample sizes for which amygdala quantification might be needed.

Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence.

Early life stress (ELS) and function of the hypothalamic-pituitary-adrenal axis predict later psychopathology. Animal studies and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortex (vmPFC) circuitry implicated in the regulation of emotion. Here we prospectively investigated the roles of ELS and childhood basal cortisol amounts in the development of adolescent resting-state functional connectivity (rs-FC), assessed by functional connectivity magnetic resonance imaging (fcMRI), in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which predicted decreased amygdala-vmPFC rs-FC 14 years later. For females, adolescent amygdala-vmPFC functional connectivity was inversely correlated with concurrent anxiety symptoms but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol levels function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.