Neural Responses to Intranasal Oxytocin in Youths With Severe Irritability.

OBJECTIVE: The authors investigated the neural impact of intranasal oxytocin on emotion processing areas in youths with severe irritability in the context of disruptive mood and behavior disorders. METHODS: Fifty-two participants with severe irritability, as measured by a score ≥4 on the Affective Reactivity Index (ARI), with diagnoses of disruptive behavior disorders (DBDs) and/or disruptive mood dysregulation disorder (DMDD) were randomly assigned to treatment with intranasal oxytocin or placebo daily for 3 weeks. Assessments were conducted at baseline and at the end of the trial; the primary outcomes were measures of irritability on the ARI and ratings on the Clinical Global Impressions severity scale (CGI-S) focusing on DBD and DMDD symptoms, and secondary outcomes included the CGI improvement scale (CGI-I) and ratings of proactive and reactive aggressive behavior on the Reactive-Proactive Aggression Questionnaire. Forty-three participants (22 in the oxytocin group and 21 in the placebo group) completed pre- and posttreatment functional MRI (fMRI) scans with the affective Stroop task. RESULTS: Youths who received oxytocin showed significant improvement in CGI-S and CGI-I ratings compared with those who received placebo. In the fMRI data, blood-oxygen-level-dependent (BOLD) responses to emotional stimuli in the dorsomedial prefrontal cortex and posterior cingulate cortex were significantly reduced after oxytocin compared with placebo. These BOLD response changes were correlated with improvement in clinical severity. CONCLUSIONS: This study provides initial and preliminary evidence that intranasal oxytocin may induce neural-level changes in emotion processing in youths with irritability in the context of DBDs and DMDD. This may lead to symptom and severity changes in irritability.

Psychopharmacological treatment of disruptive behavior in youths: systematic review and network meta-analysis.

To conduct a systematic review of the comparative efficacy of various psychotropic medications for the treatment of disruptive behavior (DBs) in youths. To this aim, we systematically reviewed randomized clinical trials (RCTs) of various psychotropic medications targeting symptoms of DBs and applied network meta-analysis to investigate their relative efficacy. Fifty-five RCTs meeting the inclusion criteria were selected. To predict and interpret relative treatment efficacy, we compared the efficacy of various psychotropic medications prescribed for DB symptoms based on their mechanism of action. Network meta-analysis revealed that for reducing DBs, second-generation antipsychotics, stimulants, and non-stimulant ADHD medications were more efficacious than placebo, and second-generation antipsychotics were the most efficacious. The dopaminergic modulation of top-down inhibitory process by these medications is discussed in this review. This study offers information on the relative efficacy of various psychotropic medications for the treatment of DB, and insight into a potential neurobiological underpinning for those symptoms. It also illustrates the potential utility of these neurobiological mechanisms as a target for future treatment studies.

Differential associations of conduct disorder, callous-unemotional traits and irritability with outcome expectations and values regarding the consequences of aggression.

BACKGROUND: Previous work has examined the association of aggression levels and callous-unemotional traits with outcome expectations and values regarding the consequences of aggression. Less work has examined the outcome expectations and values regarding the consequences of aggression of adolescents with Conduct Disorder (CD). Also, no studies have examined links between irritability (a second socio-affective trait associated with CD) and these social cognitive processes despite the core function of anger in retaliatory aggression and establishing dominance. METHOD: The current study, investigating these issues, involved 193 adolescents (typically developing [TD; N = 106], 87 cases with CD [N = 87]). Participants completed an adaptation of the Outcomes Expectations and Values Questionnaire and were assessed for CU traits and irritability via the Inventory of Callous-Unemotional traits and the Affective Reactivity Index. RESULTS: While CD was associated with atypical outcome expectations this was not seen within statistical models including CU traits and irritability. CU traits were associated with decreased expectation that aggression would result in feelings of remorse and victim suffering, as well as decreased concern that aggressive acts would result in punishment and victim suffering. Irritability was associated with increased expectations and concern that aggression would result in dominance and forced respect. CONCLUSIONS: The results suggest that CU traits and irritability, often present in youth with CD, are associated with different forms of maladaptive outcome expectations and values regarding the consequences of aggression. This suggests that the atypical social cognitive processes underlying aggressive behavior among youth exhibiting CU traits may differ from those exhibiting problems regulating anger.

Interaction of irritability and anxiety on emotional responding and emotion regulation: a functional MRI study.

BACKGROUND: Irritability and anxiety frequently co-occur in pediatric populations. Studies separately looking at the neural correlates of these symptoms have identified engagement of similar neural systems - particularly those implicated in emotional processing. Both irritability and anxiety can be considered negative valence emotional states that might relate to emotion dysregulation. However, previous work has not examined the neural responding during the performance of an emotion regulation task as a function of interaction between irritability and anxiety simultaneously. METHODS: This fMRI study involved 155 participants (90 with significant psychopathologies and 92 male) who performed the Affective Stroop Task, designed to engage emotion regulation as a function of task demands. The Affective Reactivity Index (ARI) was used to index irritability and the Screen for Child Anxiety Related Emotional Disorders (SCARED) was used to index anxiety. RESULTS: Levels of irritability, but not anxiety, was positively correlated with responses to visual images within the right rostro-medial prefrontal cortex and left anterior cingulate cortex during view trials. The second region of ventral anterior cingulate cortex showed a condition-by-emotion-by-ARI score-by-SCARED score interaction. Specifically, anxiety level was significantly correlated with a decreased differential BOLD response to negative relative to neutral view trials but only in the presence of relatively high irritability. CONCLUSIONS: Atypical maintenance of emotional stimuli within the rostro-medial prefrontal cortex may exacerbate the difficulties faced by adolescents with irritability. Moreover, increased anxiety combined with significant irritability may disrupt an automatic emotional conflict-based form of emotion regulation that is particularly associated with the ventral anterior cingulate cortex.

Segregating sustained attention from response inhibition in ADHD: An fMRI study.

BACKGROUND: The functional significance of the impairment shown by patients with ADHD on response inhibition tasks is unclear. Dysfunctional behavioral and BOLD responses to rare no-go cues might reflect disruption of response inhibition (mediating withholding the response) or selective attention (identifying the rare cue). However, a factorial go/no-go design (involving high and low frequency go and no-go stimuli) can disentangle these possibilities. METHODS: Eighty youths [22 female, mean age = 13.70 (SD = 2.21), mean IQ = 104.65 (SD = 13.00); 49 with diagnosed ADHD] completed the factorial go/no-go task while undergoing fMRI. RESULTS: There was a significant response type-by-ADHD symptom severity interaction within the left anterior insula cortex; increasing ADHD symptom severity was associated with decreased recruitment of this region to no-go cues irrespective of cue frequency. There was also a significant frequency-by-ADHD symptom severity interaction within the left superior frontal gyrus. ADHD symptom severity showed a quadratic relationship with responsiveness to low frequency cues (irrespective of whether these cues were go or no-go); within this region, at lower levels of symptom severity, increasing severity was associated with increased BOLD responses but at higher levels of symptom severity, decreasing BOLD responses. CONCLUSION: The current study reveals two separable forms of dysfunction that together probably contribute to the impairments shown by patients with ADHD on go/no-go tasks.

Applying a Cognitive Neuroscience Perspective to Disruptive Behavior Disorders: Implications for Schools.

A cognitive neuroscience perspective seeks to understand behavior, in this case disruptive behavior disorders (DBD), in terms of dysfunction in cognitive processes underpinned by neural processes. While this type of approach has clear implications for clinical mental health practice, it also has implications for school-based assessment and intervention with children and adolescents who have disruptive behavior and aggression. This review articulates a cognitive neuroscience account of DBD by discussing the neurocognitive dysfunction related to emotional empathy, threat sensitivity, reinforcement-based decision-making, and response inhibition. The potential implications for current and future classroom-based assessments and interventions for students with these deficits are discussed.

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.

Traits of empathy and anger: implications for psychopathy and other disorders associated with aggression.

Empathy and anger are two social emotions that modulate an individual's risk for aggression. Empathy is an emotional reaction to another individual's emotional state. Anger is an emotional reaction to threat, frustration or social provocation. Reduced empathy, seen in psychopathy, increases the risk for goal-directed aggression. Atypically increased anger (i.e. irritability), seen in conditions like disruptive mood dysregulation disorder and borderline personality disorder, increases the risk for reactive aggression. In this paper, I will outline core neurocognitive functions that correspond to empathy and which are compromised in individuals with psychopathic traits. In addition, I will outline neurocognitive functions involved in either the generation or regulation of anger and which are compromised in psychiatric conditions at increased risk for irritability/reactive aggression. It can be hoped that improved understanding of empathy and anger will lead to better assessment tools and improved interventions to reduce aggression risk.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.

Neuro-cognitive system dysfunction and symptom sets: A review of fMRI studies in youth with conduct problems.

In this paper, we review fMRI work on neuro-cognitive systems that are considered to be dysfunctional in individuals with conduct problems (i.e., individuals with Conduct Disorder (CD), Oppositional Defiant Disorder (ODD) or antisocial behavior without formal clinical diagnosis). These are: empathy, the acute threat response, reinforcement-based decision-making, response inhibition and the Default Mode Network. Evidence regarding the Default Mode Network is somewhat inconsistent and its functional role/the symptom sets consequent on its dysfunction remain underspecified. However, dysfunctions in the other four neuro-cognitive systems are associated with symptom sets seen in individuals with conduct problems.

Emotion-based learning systems and the development of morality.

In this paper it is proposed that important components of moral development and moral judgment rely on two forms of emotional learning: stimulus-reinforcement and response-outcome learning. Data in support of this position will be primarily drawn from work with individuals with the developmental condition of psychopathy as well as fMRI studies with healthy individuals. Individuals with psychopathy show impairment on moral judgment tasks and a pronounced increased risk for instrumental antisocial behavior. It will be argued that these impairments are developmental consequences of impaired stimulus-aversive conditioning on the basis of distress cue reinforcers and response-outcome learning in individuals with this disorder.

Reduced optimism and a heightened neural response to everyday worries are specific to generalized anxiety disorder, and not seen in social anxiety.

BACKGROUND: Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are co-morbid and associated with similar neural disruptions during emotion regulation. In contrast, the lack of optimism examined here may be specific to GAD and could prove an important biomarker for that disorder. METHOD: Unmedicated individuals with GAD (n = 18) and age-, intelligence quotient- and gender-matched SAD (n = 18) and healthy (n = 18) comparison individuals were scanned while contemplating likelihoods of high- and low-impact negative (e.g. heart attack; heartburn) or positive (e.g. winning lottery; hug) events occurring to themselves in the future. RESULTS: As expected, healthy subjects showed significant optimistic bias (OB); they considered themselves significantly less likely to experience future negative but significantly more likely to experience future positive events relative to others (p < 0.001). This was also seen in SAD, albeit at trend level for positive events (p < 0.001 and p < 0.10, respectively). However, GAD patients showed no OB for positive events (t 17 = 0.82, n.s.) and showed significantly reduced neural modulation relative to the two other groups of regions including the medial prefrontal cortex (mPFC) and caudate to these events (p < 0.001 for all). The GAD group further differed from the other groups by showing increased neural responses to low-impact events in regions including the rostral mPFC (p < 0.05 for both). CONCLUSIONS: The neural dysfunction identified here may represent a unique feature associated with reduced optimism and increased worry about everyday events in GAD. Consistent with this possibility, patients with SAD did not show such dysfunction. Future studies should consider if this dysfunction represents a biomarker for GAD.

Test-retest reliability of the facial expression labeling task.

Recognizing others' emotional expressions is vital for socioemotional development; impairments in this ability occur in several psychiatric disorders. Further study is needed to map the development of this ability and to evaluate its components as potential transdiagnostic endophenotypes. Before doing so, however, research is required to substantiate the test-retest reliability of scores of the face emotion identification tasks linked to developmental psychopathology. The current study estimated test-retest reliability of scores of one such task, the facial expression labeling task (FELT) among a sample of twin children (N = 157; ages 9-14). Participants completed the FELT at two visits two to five weeks apart. Participants discerned the emotion presented of faces depicting six emotions (i.e., happiness, anger, sadness, fear, surprise, and disgust) morphed with a neutral face to provide 10 levels of increasing emotional expressivity. The present study found strong test-retest reliability (Pearson r) of the FELT scores across all emotions. Results suggested that data from this task may be effectively analyzed using a latent growth curve model to estimate overall ability (i.e., intercept; r's = 0.76-0.85) and improvement as emotions become clearer (i.e., linear slope; r's = 0.69-0.83). Evidence of high test-retest reliability of this task's scores informs future developmental research and the potential identification of transdiagnostic endophenotypes for child psychopathology. (PsycINFO Database Record

Learning from other people's fear: amygdala-based social reference learning in social anxiety disorder.

BACKGROUND: Social anxiety disorder involves fear of social objects or situations. Social referencing may play an important role in the acquisition of this fear and could be a key determinant in future biomarkers and treatment pathways. However, the neural underpinnings mediating such learning in social anxiety are unknown. Using event-related functional magnetic resonance imaging, we examined social reference learning in social anxiety disorder. Specifically, would patients with the disorder show increased amygdala activity during social reference learning, and further, following social reference learning, show particularly increased response to objects associated with other people's negative reactions? METHOD: A total of 32 unmedicated patients with social anxiety disorder and 22 age-, intelligence quotient- and gender-matched healthy individuals responded to objects that had become associated with others' fearful, angry, happy or neutral reactions. RESULTS: During the social reference learning phase, a significant group × social context interaction revealed that, relative to the comparison group, the social anxiety group showed a significantly greater response in the amygdala, as well as rostral, dorsomedial and lateral frontal and parietal cortices during the social, relative to non-social, referencing trials. In addition, during the object test phase, relative to the comparison group, the social anxiety group showed increased bilateral amygdala activation to objects associated with others' fearful reactions, and a trend towards decreased amygdala activation to objects associated with others' happy and neutral reactions. CONCLUSIONS: These results suggest perturbed observational learning in social anxiety disorder. In addition, they further implicate the amygdala and dorsomedial prefrontal cortex in the disorder, and underscore their importance in future biomarker developments.

Dual neurocircuitry dysfunctions in disruptive behavior disorders: emotional responding and response inhibition.

BACKGROUND: To determine the functional integrity of the neural systems involved in emotional responding/regulation and response control/inhibition in youth (age 10-18 years) with disruptive behavioral disorders (DBDs: conduct disorder and/or oppositional defiant disorder) as a function of callous-unemotional (CU) traits. METHOD: Twenty-eight healthy youths and 35 youths with DBD [high CU (HCU), n = 18; low CU (LCU), n = 17] performed the fMRI Affective Stroop task. Participants viewed positive, neutral, and negative images under varying levels of cognitive load. A 3-way ANOVA (group×emotion by task) was conducted on the BOLD response data. RESULTS: Youth with DBD-HCU showed significantly less activation of ventromedial prefrontal cortex (vmPFC) and amygdala in response to negative stimuli, compared to healthy youth and youth with DBD-LCU. vmPFC responsiveness was inversely related to CU symptoms in DBD. Youth with DBD-LCU showed decreased functional connectivity between amygdala and regions including inferior frontal gyrus in response to emotional stimuli. Youth with DBD (LCU and HCU) additionally showed decreased insula responsiveness to high load (incongruent trials) compared to healthy youth. Insula responsiveness was inversely related to ADHD symptoms in DBD. CONCLUSIONS: These data reveal two forms of pathophysiology in DBD. One associated with reduced amygdala and vmPFC responses to negative stimuli and related to increased CU traits. Another associated with reduced insula responses during high load task trials and related to ADHD symptoms. Appropriate treatment will need to be individualized according to the patient's specific pathophysiology.

Abnormal decision-making in generalized anxiety disorder: Aversion of risk or stimulus-reinforcement impairment?

There is preliminary data indicating that patients with generalized anxiety disorder (GAD) show impairment on decision-making tasks requiring the appropriate representation of reinforcement value. The current study aimed to extend this literature using the passive avoidance (PA) learning task, where the participant has to learn to respond to stimuli that engender reward and avoid responding to stimuli that engender punishment. Six stimuli engendering reward and six engendering punishment are presented once per block for 10 blocks of trials. Thirty-nine medication-free patients with GAD and 29 age-, IQ and gender matched healthy comparison individuals performed the task. In addition, indexes of social functioning as assessed by the Global Assessment of Functioning (GAF) scale were obtained to allow for correlational analyzes of potential relations between cognitive and social impairments. The results revealed a Group-by-Error Type-by-Block interaction; patients with GAD committed significantly more commission (passive avoidance) errors than comparison individuals in the later blocks (blocks 7,8, and 9). In addition, the extent of impairment on these blocks was associated with their functional impairment as measured by the GAF scale. These results link GAD with anomalous decision-making and indicate that a potential problem in reinforcement representation may contribute to the severity of expression of their disorder.

Executive attention control and emotional responding in attention-deficit/hyperactivity disorder--A functional MRI study.

BACKGROUND: There are suggestions that patients with attention-deficit/hyperactivity disorder (ADHD) show impairment in executive attention control and emotion regulation. This study investigated emotion regulation as a function of the recruitment of executive attention in patients with ADHD. METHODS: Thirty-five healthy children/adolescents (mean age = 13.91) and twenty-six children/adolescents with ADHD (mean age = 14.53) participated in this fMRI study. They completed the affective Stroop paradigm viewing positive, neutral and negative images under varying cognitive loads. A 3-way ANOVA (diagnosis-by-condition-by-emotion) was conducted on the BOLD response data. Following this, 2 3-way ANOVAs (diagnosis-by-condition-by-emotion) were applied to context-dependent psychophysiological interaction (gPPI) analyses generated from a dorsomedial frontal cortex and an amygdala seed (identified from the BOLD response ANOVA main effects of condition and emotion respectively). RESULTS: A diagnosis-by-condition interaction within dorsomedial frontal cortex revealed reduced recruitment of dorsomedial frontal cortex as a function of increased task demands in the children/adolescents with ADHD relative to healthy children/adolescents. The level of reduction in recruitment of dorsomedial frontal cortex was significantly correlated with symptom severity (total and hyperactivity) measured by Conner's Parent Report Scale in the children/adolescents with ADHD. In addition, analysis of gPPI data from a dorsomedial frontal cortex seed revealed significant diagnosis-by-condition interactions within lateral frontal cortex; connectivity between dorsomedial frontal cortex and lateral frontal cortex was reduced in the patients with ADHD relative to comparison youth during congruent and incongruent task trials relative to view trials. There were no interactions of group, or main effect of group, within the amygdala in the BOLD response ANOVA (though children/adolescents with ADHD showed increased responses to positive images within temporal cortical regions during task trials; identified by the diagnosis-by-condition-by-emotion interaction). However, analysis of gPPI data from an amygdala seed revealed decreased connectivity between amygdala and lentiform nucleus in the presence of emotional stimuli in children/adolescents with ADHD (diagnosis-by-emotion interaction). CONCLUSION: The current study demonstrated disrupted recruitment of regions implicated in executive function and impaired connectivity within those regions in children/adolescents with ADHD. There were also indications of heightened representation of emotional stimuli in patients with ADHD. However, as the findings were specific for positive stimuli, the suggestion of a general failure in emotion regulation in ADHD was not supported.

Psychopathic traits from an RDoC perspective.

In this review an RDoC approach is applied to psychopathic traits. Two core neuro-cognitive systems relevant to the emergence of psychopathic traits are considered. These are the response to other individuals' emotional displays and reinforcement-based decision-making.

Neurodevelopmental changes in the responsiveness of systems involved in top down attention and emotional responding.

In this study, we aimed to investigate age related changes in systems implicated in top down attention and the implications of this for amygdala responses to emotional distracters. Fifty-one healthy subjects including 18 children (aged 10-14), 15 adolescents (aged 14-18), and 18 young adults (aged 18-25) completed the affective Stroop paradigm while undergoing functional MRI. While achieving comparable behavioral performance, children, relative to adolescents and adults, showed increased activation in areas including anterior cingulate gyrus and precentral gyrus in task relative to view trials. In addition, children showed increased activation within the amygdala and fusiform gyrus in response to emotional stimuli. Notably, the group difference within the amygdala was particularly pronounced during task trials. Also children showed increased connectivity between amygdala and superior frontal gyrus and bilateral postcentral gyrii in response to negative task trials. These data are consistent with previous work indicating less consolidated functional integrity in regions implicated in top down attention in children relative to older participants and extend this work by indicating that this less consolidated functional integrity leads to reduced automatic emotion regulation as a function of top down attention. Given that reduced automatic emotion regulation as a function of top down attention is considered a risk factor for the development of anxiety disorders, these data may contribute to an understanding of the increased risk for the development of these disorders at this age.

Disruptive behavior disorders: taking an RDoC(ish) approach.

The disruptive behavior disorders include Conduct Disorder (CD), Oppositional Defiant Disorder (ODD), and Attention Deficit Hyperactivity Disorder (ADHD). These disorders are highly comorbid with each other as well as with mood and anxiety disorders and personality disorders (particularly borderline personality disorder). The goal of this chapter is to consider these disorders from an RDoC(ish) approach. In other words, we will outline four functional processes and the behavioral implications of dysfunction within these processes. Moreover, we will briefly consider how dysfunction in one might increase the risk for the development of rather different behavioral problems that have been previously associated with rather different disorders. Our goal is to identify neurocognitive-based functional targets for treatment.