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Background Adolescent substance use, externalizing and attention problems, and early life stress (ELS) commonly co-occur. These psychopathologies show overlapping neural dysfunction in the form of reduced recruitment of reward processing neuro-circuitries. However, it is unclear to what extent these psychopathologies show common v. different neural dysfunctions as a function of symptom profiles, as no studies have directly compared neural dysfunctions associated with each of these psychopathologies to each other. Methods In study 1, a latent profile analysis (LPA) was conducted in a sample of 266 adolescents (aged 13–18, 41.7% female, 58.3% male) from a residential youth care facility and the surrounding community to investigate substance use, externalizing and attention problems, and ELS psychopathologies and their co-presentation. In study 2, we examined a subsample of 174 participants who completed the Passive Avoidance learning task during functional magnetic resonance imaging to examine differential and/or common reward processing neuro-circuitry dysfunctions associated with symptom profiles based on these co-presentations. Results In study 1, LPA identified profiles of substance use plus rule-breaking behaviors, attention-deficit hyperactivity disorder, and ELS. In study 2, the substance use/rule-breaking profile was associated with reduced recruitment of reward processing and attentional neuro-circuitries during the Passive Avoidance task (p < 0.05, corrected for multiple comparisons). Conclusions Findings indicate that there is reduced responsivity of striato-cortical regions when receiving outcomes on an instrumental learning task within a profile of adolescents with substance use and rule-breaking behaviors. Mitigating reward processing dysfunction specifically may represent a potential intervention target for substance-use psychopathologies accompanied by rule-breaking behaviors.

BackgroundConduct disorder (CD) has been associated with dysfunction in reinforcement-based decision-making. Two forms of affective traits that reflect the components of CD severity are callous-unemotional (CU; reduced guilt/empathy) traits and irritability. The form of the reinforcement-based decision-making dysfunction with respect to CD and CU traits remains debated and has not been examined with respect to irritability in cases with CD. The goals of the current study were to determine the extent of dysfunction in differential (reward v. punishment) responsiveness in CD, and CU traits and irritability in participants with CD.MethodsThe study involved 178 adolescents [typically developing (TD; N = 77) and cases with CD (N = 101)]. Participants were scanned with fMRI during a passive avoidance task that required participants to learn to respond to (i.e. approach) stimuli that engender reward and refrain from responding to (i.e. passively avoid) stimuli that engender punishment.ResultsAdolescents with CD showed reduced differential reward-punishment responsiveness within the striatum relative to TD adolescents. CU traits, but not irritability, were associated with reduced differential reward-punishment responsiveness within the striatum, rostromedial, and lateral frontal cortices.ConclusionsThe results suggest CD is associated with reduced differential reward-punishment responsiveness and the extent of this dysfunction in participants with CD is associated with the severity of CU traits but not irritability.

Previous studies examining structural brain correlates of irritability have taken a region-specific approach and have been relatively inconsistent. In a sample of adolescents with and without clinically impairing irritability, the current study examines: (i) cortical volume (CV) in canonical functional networks; (ii) the association between the CV of functional networks and severity of irritability; and (iii) the extent to which IQ mediates the association between structural abnormalities and severity of irritability. Structural MRI and IQ data were collected from 130 adolescents with high irritability (mean age = 15.54±1.83 years, 58 females, self-reported Affective Reactivity Index [ARI] ≥ 4) and 119 adolescents with low irritability (mean age = 15.10±1.93 years, 39 females, self-reported ARI < 4). Subject-specific network-wise CV was estimated after parcellating the whole brain into 17 previously reported functional networks. Our Multivariate Analysis of Covariance (MANCOVA) revealed that adolescents with high irritability had significantly reduced CV of the bilateral control and default-mode networks (p

While neuro-cognitive work examining aggression has examined patients with conditions at increased risk for aggression or individuals self-reporting past aggression, little work has attempted to identify neuro-cognitive markers associated with observed/recorded aggression. The goal of the current study was to determine the extent to which aggression by youth in the first three months of residential care was associated with atypical responsiveness to threat stimuli. This functional MRI study involved 98 (68 male; mean age = 15.96 [sd = 1.52]) adolescents in residential care performing a looming threat task involving images of threatening and neutral human faces or animals that appeared to be either loom or recede. Level of aggression was negatively associated with responding to looming stimuli (irrespective of whether these were threatening or neutral) within regions including bilateral inferior frontal gyrus, right inferior parietal lobule, right superior/middle temporal gyrus and a region of right uncus proximal to the amygdala. These data indicate that aggression level is associated with a decrease in responsiveness to a basic threat cue-looming stimuli. Reduced threat responsiveness likely results in the individual being less able to represent the negative consequences that may result from engaging in aggression, thereby increasing the risk for aggressive episodes.

Background It has been proposed that individuals with generalized anxiety disorder (GAD) show dysfunctional computations related to approach-avoidance decision-making. However, few studies have examined the neural basis of this impairment, particularly in adolescents with GAD. The goal of the current study was to address this gap in the literature. Method The study involved 51 adolescents with GAD and 51 typically developing (TD) comparison individuals matched on age (16.10 and 15.75 respective means), gender (30 F/21 M and 24 F/27 M), and IQ (103.20 and 103.18 respective means). Participants underwent functional magnetic resonance imaging during a passive avoidance task. Results We found a significant Group-by-Reinforcement interaction within reward-related brain regions including the caudate, putamen, mid cingulate/paracentral lobule, and superior and middle frontal gyrus. TD adolescents showed a greater differential response to reward versus punishment feedback within these regions relative to adolescents with GAD. In particular, this reflected reduced responses to rewards in the adolescents with GAD. There were no group differences in neural responses when making approach/avoidance responses. Conclusion The results of this study suggest reduced differential responsiveness to reinforcement as a component of the pathophysiology seen in adolescents with GAD. This dysfunction likely underpins decision-making impairments that may exacerbate the participants' worry.

Background: Widespread structural alterations have been shown to be implicated in individuals with generalized anxiety disorder (GAD). However, there have been inconsistent findings in cortical volume (CV) differences. Most structural neuroimaging studies looking at GAD used region-based approach with relatively small sample sizes, let alone be specific to adolescents with GAD. We believe this is the first study to look at CV measures using a network-based approach in a larger sample of adolescents with GAD. The goal of the current study was to focus on three different brain networks (i.e., Limbic, Frontoparietal, and Default Mode Network [DMN]) in adolescents with GAD. Method: The study involved 81 adolescents with GAD and 112 typically developing (TD) comparison individuals matched on age (15.98 and 15.63 respective means), sex (42F/39M and 45F/67M), and IQ (101.90 and 103.94 respective means). Participants underwent structural MRI. Freesurfer was used to estimate CV (both network-specific and region-specific within networks) and region-specific sub-cortical volume measures. Multivariate analysis of covariance (MANCOVA; with sex, age, IQ, and intracranial volume [ICV] as potential covariates) was used to estimate group differences. Results: We found significantly lower CV for the DMN in adolescents with GAD, compared with TD individuals. Adolescents with GAD also showed significantly lower hemispheric mean CV of the default-mode regions (particularly the prefrontal and temporal regions) and the hippocampus, compared with TD individuals. Conclusion: The current findings suggest structural alterations in adolescents with GAD. These structural alterations will need to be addressed when implementing and developing treatments for patients with GAD.

Background: The current study aimed to address two gaps in the literature on child maltreatment, reinforcement processing and psychopathology. First, the extent to which compromised reinforcement processing might be particularly associated with either neglect or abuse. Second, the extent to which maltreatment-related compromised reinforcement processing might be associated with particular symptom sets (depression, conduct problems, anxiety) or symptomatology more generally. Methods: A sample of adolescents (N = 142) aged between 14 and 18 years with varying levels of prior maltreatment participated in this fMRI study. They were scanned while performing a passive avoidance learning task, where the participant learns to respond to stimuli that engender reward and avoid responding to stimuli that engender punishment. Maltreatment (abuse and neglect) levels were assessed with the Childhood Trauma Questionnaire (CTQ). Results: We found that: (i) level of neglect, but not abuse, was negatively associated with differential BOLD responses to reward-punishment within the striatum and medial frontal cortex; and (ii) differential reward-punishment responses within these neglect-associated regions were particularly negatively associated with level of conduct problems. Conclusion: Our findings demonstrate the adverse neurodevelopmental impact of childhood maltreatment, particularly neglect, on reinforcement processing. Moreover, they suggest a neurodevelopmental route by which neglect might increase the risk for conduct problems.

Background: Irritability and callous-unemotional (CU; reduced guilt/empathy) traits vary dimensionally in the typically developing population but may be particularly marked in youth with conduct disorder (CD). While these dimensional traits are positively correlated, they have been associated with divergent forms of dysfunction, particularly with respect to threat processing (i.e., irritability with increased, and CU traits with decreased, threat responsiveness). This suggests that interactions between these two dimensions may be complex at the neurobiological level. However, this issue has received minimal empirical attention.Methods: The study included 105 adolescents (typically developing and cases with CD; N = 59). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding.Results: Significant irritability-by-CU traits-by-Direction-by-Emotion interactions were seen within right thalamus/PAG, left lingual gyrus and right fusiform gyrus; irritability was positively associated with the BOLD response for Looming Threatening vs. Receding Threatening trials, particularly for youth with low CU traits. In contrast, CU traits were negatively associated with the same differential BOLD response but particularly for youth showing higher levels of irritability. Similar findings were seen within left ventral anterior and posterior cingulate cortices, though the addition of the interaction with CU traits was only seen at slightly more lenient thresholds.Conclusions: The results support previous work linking irritability to increased, and CU traits to reduced, threat responsiveness. However, for adolescents with high irritability, if CU traits are also high, the underlying neuropathology appears to relate to reduced, rather than increased, threat responsiveness.

Background: Alcohol and cannabis are commonly used by adolescents in the United States. Both alcohol use disorder (AUD) and cannabis use disorder (CUD) have been associated with reduced emotion expression recognition ability. However, this work has primarily occurred in adults and has not considered neuro-cognitive risk factors associated with conduct problems that commonly co-occur with, and precede, substance use. Yet, conduct problems are also associated with reduced emotion expression recognition ability. The current study investigated the extent of negative association between AUD and CUD symptom severity and expression recognition ability over and above any association of expression recognition ability with conduct problems [conduct disorder (CD) diagnostic status].Methods: In this study, 152 youths aged 12.5–18 years (56 female; 60 diagnosed with CD) completed a rapid presentation morphed intensity facial expression task to investigate the association between relative severity of AUD/CUD and expression recognition ability.Results: Cannabis use disorder identification test (CUDIT) scores were negatively associated with recognition accuracy for higher intensity (particularly sad and fearful) expressions while CD diagnostic status was independently negatively associated with recognition of sad expressions. Alcohol use disorder identification test (AUDIT) scores were not significantly associated with expression recognition ability.Conclusions: These data indicate that relative severity of CUD and CD diagnostic status are statistically independently associated with reduced expression recognition ability. On the basis of these data, we speculate that increased cannabis use during adolescence may exacerbate a neuro-cognitive risk factor for the emergence of aggression and antisocial behavior.

Background Alcohol and cannabis are commonly used by adolescents in the United States. Both alcohol use disorder (AUD) and cannabis use disorder (CUD) have been associated with an increased risk of aggression. One form of aggression seen during retaliation is reactive aggression to social provocation. This study investigated the association between AUD and CUD symptom severity and recruitment of neural regions implicated in retaliation. Methods In this study, 102 youths aged 13–18 years (67 male; 84 in residential care) completed self-report measures of aggression-related constructs and participated in a retaliation task during functional magnetic resonance imaging to investigate the association between relative severity of AUD/CUD and atypical recruitment of regions implicated in retaliation. Results AUD Identification Test scores were positively associated with irritability and reactive aggression scores. CUD Identification Test scores were positively associated with callous-unemotional traits and both proactive and reactive aggression scores. In functional magnetic resonance imaging analyses, only AUD Identification Test (not CUD Identification Test) scores were associated with an exaggerated recruitment of regions implicated in retaliation (dorsomedial frontal, anterior insula cortices, caudate, and, to a lesser extent, periaqueductal gray). Conclusions These data suggest that relative severity of AUD is associated with a disinhibited, exaggerated retaliation response that relates to an increased risk for reactive aggression. Similar findings were not related to severity of CUD.

Childhood sexual abuse is associated with significant subsequent pathology and neurodevelopmental disruption. In particular, childhood sexual abuse has been associated with heightened threat sensitivity. However, little work has directly investigated this issue. In this study, we examine the association of childhood sexual abuse to neural and behavioral responses to looming, threatening face stimuli. The study involved 23 adolescents with significant past sexual abuse and 24 comparison individuals matched on IQ, age, and sex. Participants were scanned during a looming threat task that involved negative and neutral, human faces and animals that appeared to either loom toward or recede from the participant. We found that adolescents who had been previously subjected to sexual abuse, relative to comparison adolescents, showed increased neural responses to threatening looming stimuli in regions including rostral and superior frontal gyrus as well as posterior cingulate gyrus. In addition, they were significantly more slowed by looming stimuli, particularly if these were human faces, than adolescents who had not been exposed. These data demonstrate that prior sexual abuse was associated with heightened neural responsiveness to looming threats in a series of regions beyond the amygdala. These data are interpreted within models of rostromedial frontal and posterior cingulate cortices that stress their role in self-referential emotional processing and emotional maintenance.