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.

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.

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.

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.

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.

Dissociable roles of ventromedial prefrontal cortex (vmPFC) and rostral anterior cingulate cortex (rACC) in value representation and optimistic bias.

Optimistic bias (OB) is seen when individuals underestimate their probability of experiencing negative life events and overestimate their probability of experiencing positive life events. A reduced OB has been linked with increased depression symptoms. However, given the relevance of this information to mood and anxiety disorders, little is currently known regarding the neurobiology of OB. In the current study, we examine the neural basis of OB in healthy individuals (n=33) during probability estimation of future positive and negative events occurring to themselves relative to other, comparable individuals. In line with previous work, subjects showed significant OB; they considered themselves significantly more likely to experience future positive and significantly less likely to experience future negative events relative to comparable others. Positive, relative to negative events, un-modulated by subjects' probability estimates, were associated with significantly greater activity within the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Moreover, responses within both regions to positive events negatively related to the healthy subjects' self reports of depression symptoms. However, there was no significant modulation of activity in either region by the subject's OB, objectified as the level to which they thought the event was more likely [positive events] or less likely [negative events] to occur to them relative to comparable others. In contrast, activity within the rostral anterior cingulate cortex (rACC) was positively modulated by OB for positive events and activity within the anterior insula and dorsomedial prefrontal cortex (dmPFC) was negatively modulated by OB for negative events. However, there was no significant relationship between responsiveness within these regions and self reports of depression symptoms. The data are discussed with reference to current models of vmPFC, rACC and anterior insula functioning.

Cognitive control of attention is differentially affected in trauma-exposed individuals with and without post-traumatic stress disorder.

BACKGROUND: This study aimed to determine whether patients with post-traumatic stress disorder (PTSD) show difficulty in recruitment of the regions of the frontal and parietal cortex implicated in top-down attentional control in the presence and absence of emotional distracters. METHOD: Unmedicated individuals with PTSD (n = 14), and age-, IQ- and gender-matched individuals exposed to trauma (n = 15) and healthy controls (n = 19) were tested on the affective number Stroop task. In addition, blood oxygen level-dependent responses, as measured via functional magnetic resonance imaging, were recorded. RESULTS: Patients with PTSD showed disrupted recruitment of lateral regions of the superior and inferior frontal cortex as well as the parietal cortex in the presence of negative distracters. Trauma-comparison individuals showed indications of a heightened ability to recruit fronto-parietal regions implicated in top-down attentional control across distracter conditions. CONCLUSIONS: These results are consistent with suggestions that emotional responsiveness can interfere with the recruitment of regions implicated in top-down attentional control; the heightened emotional responding of patients with PTSD may lead to the heightened interference in the recruitment of these regions.

Empathic responsiveness in amygdala and anterior cingulate cortex in youths with psychopathic traits.

BACKGROUND: Psychopathic traits are associated with increases in antisocial behaviors such as aggression and are characterized by reduced empathy for others' distress. This suggests that psychopathic traits may also impair empathic pain sensitivity. However, whether psychopathic traits affect responses to the pain of others versus the self has not been previously assessed. METHOD: We used whole-brain functional magnetic resonance imaging to measure neural activation in 14 adolescents with oppositional defiant disorder or conduct disorder and psychopathic traits, as well as 21 healthy controls matched on age, gender, and intelligence. Activation in structures associated with empathic pain perception was assessed as adolescents viewed photographs of pain-inducing injuries. Adolescents imagined either that the body in each photograph was their own or that it belonged to another person. Behavioral and neuroimaging data were analyzed using random-effects analysis of variance. RESULTS: Youths with psychopathic traits showed reduced activity within regions associated with empathic pain as the depicted pain increased. These regions included rostral anterior cingulate cortex, ventral striatum (putamen), and amygdala. Reductions in amygdala activity particularly occurred when the injury was perceived as occurring to another. Empathic pain responses within both amygdala and rostral anterior cingulate cortex were negatively correlated with the severity of psychopathic traits as indexed by PCL:YV scores. CONCLUSIONS: Youths with psychopathic traits show less responsiveness in regions implicated in the affective response to another's pain as the perceived intensity of this pain increases. Moreover, this reduced responsiveness appears to predict symptom severity.

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 prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior.

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene x exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene x exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene-environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene x exposure interactions may shape behavior through associated changes in brain function.

Adolescents with psychopathic traits report reductions in physiological responses to fear.

BACKGROUND: Psychopathy is characterized by profound affective deficits, including shallow affect and reduced empathy. Recent research suggests that these deficits may apply particularly to negative emotions, or to certain negative emotions such as fear. Despite increased focus on the cognitive and neural underpinnings of psychopathy, little is known about how psychopathy is associated with emotional deficits across a range of emotions. In addition, the relationship between psychopathy and the subjective experience of emotion has not yet been assessed. METHODS: Eighteen 10-17-year-olds with psychopathic traits and 24 comparison children and adolescents reported on their subjective experiences of emotion during five recent emotionally evocative life events, following a paradigm developed by Scherer and colleagues (Scherer & Wallbott, 1994). Group comparisons were then performed to assess variations in subjective experiences across emotions. RESULTS: As predicted, psychopathy was associated with reductions in the subjective experience of fear relative to other emotions. Children and adolescents with psychopathic traits reported fewer symptoms associated with sympathetic nervous system arousal during fear-evoking experiences. CONCLUSIONS: Rather than being related to uniformly impoverished emotional experience, psychopathic traits appear to be associated with greater deficits in subjective experiences of fear. This pattern of responding supports and extends previous observations that psychopathy engenders deficits in fear learning, physiological responses to threats, and the recognition of fear in others.

Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia.

Generalized social phobia (GSP) involves the fear of being negatively evaluated. Previous work suggests that self-referentiality, mediated by the medial prefrontal cortex (MFPC), plays an important role in the disorder. However, it is not clear whether this anomalous MPFC response to self-related information in patients with GSP concerns an increased representation of their own or others' opinions. In this article, we examine whether GSP is associated with increased response to own (1st person) or other individuals' (2nd person) opinions relative to healthy individuals. Unmedicated individuals with GSP (n=15) and age-, IQ-, and gender-matched comparison individuals (n=15) read 1st (e.g., I'm ugly), and 2nd (e.g., You're ugly) person viewpoint comments during functional magnetic resonance imaging. We observed significant group-by-viewpoint interactions within the ventral MPFC. Whereas the healthy comparison individuals showed significantly increased (or less decreased) BOLD responses to 1st relative to 2nd person viewpoints, the patients showed significantly increased responses to 2nd relative to 1st person viewpoints. The reduced BOLD responses to 1st person viewpoint comments shown by the patients correlated significantly with severity of social anxiety symptom severity. These results underscore the importance of dysfunctional self-referential processing and MPFC in GSP. We believe that these data reflect a reorganization of self-referential reasoning in the disorder with a self-concept perhaps atypically related to the view of others.

Reduced amygdala-orbitofrontal connectivity during moral judgments in youths with disruptive behavior disorders and psychopathic traits.

We used functional magnetic resonance imaging (fMRI) to investigate dysfunction in the amygdala and orbitofrontal cortex in adolescents with disruptive behavior disorders and psychopathic traits during a moral judgment task. Fourteen adolescents with psychopathic traits and 14 healthy controls were assessed using fMRI while they categorized illegal and legal behaviors in a moral judgment implicit association task. fMRI data were then analyzed using random-effects analysis of variance and functional connectivity. Youths with psychopathic traits showed reduced amygdala activity when making judgments about legal actions and reduced functional connectivity between the amygdala and orbitofrontal cortex during task performance. These results suggest that psychopathic traits are associated with amygdala and orbitofrontal cortex dysfunction. This dysfunction may relate to previous findings of disrupted moral judgment in this population.

Neuroimaging of psychopathy and antisocial behavior: a targeted review.

The goal of this article is to provide a selective and targeted review of the neuroimaging literature on psychopathic tendencies and antisocial behavior and to explore the extent to which this literature supports recent cognitive neuroscientific models of psychopathy and antisocial behavior. The literature reveals that individuals who present with an increased risk for reactive, but not instrumental, aggression show increased amygdala responses to emotionally evocative stimuli. This is consistent with suggestions that such individuals are primed to respond strongly to an inappropriate extent to threatening or frustrating events. In contrast, individuals with psychopathic tendencies show decreased amygdala and orbitofrontal cortex responses to emotionally provocative stimuli or during emotional learning paradigms. This is consistent with suggestions that such individuals face difficulties with basic forms of emotional learning and decision making.

Stimulus-reinforcement-based decision making and anxiety: impairment in generalized anxiety disorder (GAD) but not in generalized social phobia (GSP).

BACKGROUND: Generalized social phobia (GSP) involves the fear/avoidance of social situations whereas generalized anxiety disorder (GAD) involves an intrusive worry about everyday life circumstances. It remains unclear whether these, highly co-morbid, conditions represent distinct disorders or alternative presentations of a single underlying pathology. In this study, we examined stimulus-reinforcement-based decision making in GSP and GAD. METHOD: Twenty unmedicated patients with GSP, 16 unmedicated patients with GAD and 19 age-, IQ- and gender-matched healthy comparison (HC) individuals completed the Differential Reward/Punishment Learning Task (DRPLT). In this task, the subject chooses between two objects associated with different levels of reward or punishment. Thus, response choice indexes not only reward/punishment sensitivity but also sensitivity to reward/punishment level according to between-object reinforcement distance. RESULTS: We found that patients with GAD committed a significantly greater number of errors than both the patients with GSP and the HC individuals. By contrast, the patients with GSP and the HC individuals did not differ in performance on this task. CONCLUSIONS: These results link GAD with anomalous non-affective-based decision making. They also indicate that GSP and GAD are associated with distinct pathophysiologies.

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.

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.

Deficits in facial affect recognition among antisocial populations: a meta-analysis.

Individuals with disorders marked by antisocial behavior frequently show deficits in recognizing displays of facial affect. Antisociality may be associated with specific deficits in identifying fearful expressions, which would implicate dysfunction in neural structures that subserve fearful expression processing. A meta-analysis of 20 studies was conducted to assess: (a) if antisocial populations show any consistent deficits in recognizing six emotional expressions; (b) beyond any generalized impairment, whether specific fear recognition deficits are apparent; and (c) if deficits in fear recognition are a function of task difficulty. Results show a robust link between antisocial behavior and specific deficits in recognizing fearful expressions. This impairment cannot be attributed solely to task difficulty. These results suggest dysfunction among antisocial individuals in specified neural substrates, namely the amygdala, involved in processing fearful facial affect.