Parsing neurodevelopmental features of irritability and anxiety: Replication and validation of a latent variable approach.

Irritability and anxiety are two common clinical phenotypes that involve high-arousal negative affect states (anger and fear), and that frequently co-occur. Elucidating how these two forms of emotion dysregulation relate to perturbed neurodevelopment may benefit from alternate phenotyping strategies. One such strategy applies a bifactor latent variable approach that can parse shared versus unique mechanisms of these two phenotypes. Here, we aim to replicate and extend this approach and examine associations with neural structure in a large transdiagnostic sample of youth (N = 331; M = 13.57, SD = 2.69 years old; 45.92% male). FreeSurfer was used to extract cortical thickness, cortical surface area, and subcortical volume. The current findings replicated the bifactor model and demonstrate measurement invariance as a function of youth age and sex. There were no associations of youth's factor scores with cortical thickness, surface area, or subcortical volume. However, we found strong convergent and divergent validity between parent-reported irritability and anxiety factors with clinician-rated symptoms and impairment. A general negative affectivity factor was robustly associated with overall functional impairment across symptom domains. Together, these results support the utility of the bifactor model as an alternative phenotyping strategy for irritability and anxiety, which may aid in the development of targeted treatments.

Anticipatory Effects on Perceived Pain: Associations With Development and Anxiety.

OBJECTIVE: Naturalistic studies suggest that expectation of adverse experiences such as pain exerts particularly strong effects on anxious youth. In healthy adults, expectation influences the experience of pain. The current study uses experimental methods to compare the effects of expectation on pain among adults, healthy youth, and youth with an anxiety disorder. METHODS: Twenty-three healthy adults, 20 healthy youth, and 20 youth with an anxiety disorder underwent procedures in which auditory cues were paired with noxious thermal stimulation. Through instructed conditioning, one cue predicted low-pain stimulation and the other predicted high-pain stimulation. At test, each cue was additionally followed by a single temperature calibrated to elicit medium pain ratings. We compared cue-based expectancy effects on pain across the three groups, based on cue effects on pain elicited on medium heat trials. RESULTS: Across all groups, as expected, participants reported greater pain with increasing heat intensity (ß = 2.29, t(41) = 29.94, p < .001). Across all groups, the critical medium temperature trials were rated as more painful in the high- relative to low-expectancy condition (ß = 1.72, t(41) = 10.48, p < .001). However, no evidence of between-group differences or continuous associations with age or anxiety was observed. CONCLUSIONS: All participants showed strong effects of expectancy on pain. No influences of development or anxiety arose. Complex factors may influence associations among anxiety, development, and pain reports in naturalistic studies. Such factors may be identified using experiments that employ more complex, yet controlled manipulations of expectancy or assess neural correlates of expectancy.

Childhood abuse and reduced cortical thickness in brain regions involved in emotional processing.

BACKGROUND: Alterations in gray matter development represent a potential pathway through which childhood abuse is associated with psychopathology. Several prior studies find reduced volume and thickness of prefrontal (PFC) and temporal cortex regions in abused compared with nonabused adolescents, although most prior research is based on adults and volume-based measures. This study tests the hypothesis that child abuse, independent of parental education, predicts reduced cortical thickness in prefrontal and temporal cortices as well as reduced gray mater volume (GMV) in subcortical regions during adolescence. METHODS: Structural MRI scans were obtained from 21 adolescents exposed to physical and/or sexual abuse and 37 nonabused adolescents (ages 13-20). Abuse was operationalized using dichotomous and continuous measures. We examined associations between abuse and brain structure in several a priori-defined regions, controlling for parental education, age, sex, race, and total brain volume for subcortical GMV. Significance was evaluated at p < .05 with a false discovery rate correction. RESULTS: Child abuse exposure and severity were associated with reduced thickness in ventromedial prefrontal cortex (PFC), right lateral orbitofrontal cortex, right inferior frontal gyrus, bilateral parahippocampal gyrus (PHG), left temporal pole, and bilateral inferior, right middle, and right superior temporal gyri. Neither abuse measure predicted cortical surface area or subcortical GMV. Bilateral PHG thickness was inversely related to externalizing symptoms. CONCLUSIONS: Child abuse, an experience characterized by a high degree of threat, is associated with reduced cortical thickness in ventromedial and ventrolateral PFC and medial and lateral temporal cortex in adolescence. Reduced PHG thickness may be a mediator linking abuse with externalizing psychopathology, although prospective research is needed to evaluate this possibility.

Amygdala-Cortical Connectivity: Associations with Anxiety, Development, and Threat.

BACKGROUND: Amygdala-prefrontal cortex (PFC) functional connectivity may be influenced by anxiety and development. A prior study on anxiety found age-specific dysfunction in the ventromedial PFC (vmPFC), but not amygdala, associated with threat-safety discrimination during extinction recall (Britton et al.). However, translational research suggests that amygdala-PFC circuitry mediates responses following learned extinction. Anxiety-related perturbations may emerge in functional connectivity within this circuit during extinction recall tasks. The current report uses data from the prior study to examine how anxiety and development relate to task-dependent amygdala-PFC connectivity. METHODS: Eighty-two subjects (14 anxious youths, 15 anxious adults, 25 healthy youths, 28 healthy adults) completed an extinction recall task, which directed attention to different aspects of stimuli. Generalized psychophysiological interaction analysis tested whether task-dependent functional connectivity with anatomically defined amygdala seed regions differed across anxiety and age groups. RESULTS: Whole-brain analyses showed significant interactions of anxiety, age, and attention task (i.e., threat appraisal, explicit threat memory, physical discrimination) on left amygdala functional connectivity with the vmPFC and ventral anterior cingulate cortex (Talairach XYZ coordinates: -16, 31, -6 and 1, 36, -4). During threat appraisal and explicit threat memory (vs. physical discrimination), anxious youth showed more negative amygdala-PFC coupling, whereas anxious adults showed more positive coupling. CONCLUSIONS: In the context of extinction recall, anxious youths and adults manifested opposite directions of amygdala-vmPFC coupling, specifically when appraising and explicitly remembering previously learned threat. Future research on anxiety should consider associations of both development and attention to threat with functional connectivity perturbations.

Cortico-limbic responses to masked affective faces across ptsd, panic disorder, and specific phobia.

BACKGROUND: Exaggerated amygdala and reduced ventromedial prefrontal cortex (vmPFC) responsiveness during emotional processing have been reported in studies examining individual anxiety disorders. Studies are needed, however, which directly compare activation of amygdalo-cortical circuitry across multiple anxiety disorders within the same study. Here we compared cortico-limbic neurocircuitry across three different anxiety disorders using a well-validated emotional probe task. METHODS: Sixty-five adult volunteers, including 22 healthy controls (HC) and participants meeting DSM-IV criteria for either posttraumatic stress disorder (14 PTSD), panic disorder (14 PD), or specific animal phobia (15 SP), underwent functional magnetic resonance imaging (fMRI) at 3 T while passively viewing backward-masked images of faces expressing fear, happy, and neutral emotions. RESULTS: A group comprising all three anxiety disorders showed greater activation within the left amygdala and reduced activation within the vmPFC compared to the HC group during the masked fear versus neutral condition. Pairwise group comparisons showed that amygdala activation only reached significance for the PTSD versus HCs, whereas decreased vmPFC was only evident for SP and PD groups versus the HC group. Furthermore, activation did not differ among the anxiety groups when contrasted directly with one another. A similar pattern was observed for masked happy versus neutral faces. CONCLUSIONS: Exclusive of specific diagnostic category, anxiety disorders were generally associated with increased activation of the amygdala and reduced activation within vmPFC. Categorical distinctions were generally weak or not observed and suggest that functional differences may reflect the magnitude of responses within a common neurocircuitry across disorders rather than activation of distinct systems.

Enteric alpha-synuclein expression is increased in Parkinson's disease but not Alzheimer's disease.

BACKGROUND AND OBJECTIVE: Alpha-synuclein (α-Syn) is immunohistochemically detectable in enteric neurons in some subjects. We determined its age distribution in the general autopsy population and in an age-matched subset investigated differences with Parkinson's (PD) and Alzheimer's diseases (AD). METHODS: Archival autopsy samples of colon from 95 cases (77 general population, 10 PD, and 8 AD) were immunostained with monoclonal antibody KM51. α-Syn detectability was semiquantitatively graded 1 to 3. RESULTS: α-Syn was detectable in 52% of the general population, and its level of expression did not change between ages 40 and 91. All PD subjects were α-Syn positive, with higher prevalence (P = 0.001) and grade (P = 0.003) than age-matched controls. AD subjects were no more likely to be α-Syn positive or have a higher grade than controls. CONCLUSIONS: Either PD develops selectively in the enterically α-Syn-positive population subset or PD induces this expression. Absence of increased α-Syn expression in AD points to differences in pathogenesis.

Fear-potentiated startle reveals diminished threat extinction in pathological anxiety.

BACKGROUND: Major theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes. METHODS: Youths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8-50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients. RESULTS: Patients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome. CONCLUSION: ITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

Computational modeling of threat learning reveals links with anxiety and neuroanatomy in humans.

Influential theories implicate variations in the mechanisms supporting threat learning in the severity of anxiety symptoms. We use computational models of associative learning in conjunction with structural imaging to explicate links among the mechanisms underlying threat learning, their neuroanatomical substrates, and anxiety severity in humans. We recorded skin-conductance data during a threat-learning task from individuals with and without anxiety disorders (N=251; 8-50 years; 116 females). Reinforcement-learning model variants quantified processes hypothesized to relate to anxiety: threat conditioning, threat generalization, safety learning, and threat extinction. We identified the best-fitting models for these processes and tested associations among latent learning parameters, whole-brain anatomy, and anxiety severity. Results indicate that greater anxiety severity related specifically to slower safety learning and slower extinction of response to safe stimuli. Nucleus accumbens gray-matter volume moderated learning-anxiety associations. Using a modeling approach, we identify computational mechanisms linking threat learning and anxiety severity and their neuroanatomical substrates.

Neural correlates of anxiety sensitivity during masked presentation of affective faces.

BACKGROUND: Anxiety Sensitivity (AS), the tendency to fear the thoughts, symptoms, and social consequences associated with the experience of anxiety, is associated with increased risk for developing anxiety disorders. Some evidence suggests that higher scores on the Anxiety Sensitivity Index (ASI), a measure of the AS construct, are associated with activation of the anterior insular cortex during overt emotion perception. Although the ASI provides subscale scores measuring Physical, Mental Incapacitation, and Social Concerns of AS, no study has examined the relationship between these factors and regional brain activation during affect processing. We hypothesized that insular responses to fear-related stimuli would be primarily related to the Physical Concerns subscale of the ASI, particularly for a sample of subjects with specific phobias. METHODS: Adult healthy controls (HC; n = 22) and individuals with specific phobia, small animal subtype (SAP; n = 17), completed the ASI and underwent functional magnetic resonance imaging while engaged in a backward-masked affect perception task that presents emotional facial stimuli below the threshold of conscious perception. RESULTS: Groups did not differ in ASI, state or trait anxiety scores, or insula activation. Total ASI scores were positively correlated with activation in the right middle/anterior insula for the combined sample and for the HC and SAP groups separately. Multiple regression analysis revealed that the relationship between AS and insular activation was primarily accounted for by Physical Concerns only. CONCLUSIONS: Findings support the hypothesized role of the right anterior insula in the visceral/interoceptive aspects of AS, even in response to masked affective stimuli.

Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder.

BACKGROUND: Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex (PFC) activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. METHODS: We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531) and several downstream single nucleotide polymorphisms (SNPs) modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22) and a trauma-exposed control group (n = 20) in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. RESULTS: In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression) modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. CONCLUSIONS: The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify intermediate phenotypes and dimensions of PTSD that clarify the functional link between genes and disease phenotype, and also highlight features of PTSD that show more proximal influence of susceptibility genes compared to current clinical categorizations.

Neural correlates of extinguished threat recall underlying the commonality between pediatric anxiety and irritability.

BACKGROUND: Anxiety and irritability frequently co-occur in youth and are mediated by aberrant threat responses. However, empirical evidence on neural mechanisms underlying this co-occurrence is limited. To address this, we apply data-driven latent phenotyping to data from a prior report of a well-validated threat extinction recall fMRI paradigm. METHODS: Participants included 59 youth (28 anxiety disorder, 31 healthy volunteers; Mage=13.15 yrs) drawn from a transdiagnostic sample of 331 youth, in which bifactor analysis was conducted to derive latent factors representing shared vs. unique variance of dimensionally-assessed anxiety and irritability. Participants underwent threat conditioning and extinction. Approximately three weeks later, during extinction recall fMRI, participants made threat-safety discriminations under two task conditions: current threat appraisal and explicit recall of threat contingencies. Linear mixed-effects analyses examined associations of a "negative affectivity" factor reflecting shared anxiety and irritability variance with whole-brain activation and task-dependent amygdala connectivity. RESULTS: During recall of threat-safety contingencies, higher negative affectivity was associated with greater prefrontal (ventrolateral/ventromedial, dorsolateral, orbitofrontal), motor, temporal, parietal, and occipital activation. During threat appraisal, higher negative affectivity was associated with greater amygdala-inferior parietal lobule connectivity to threat/safety ambiguity. LIMITATIONS: Sample included only healthy youth and youth with anxiety disorders. Results may not generalize to other diagnoses for which anxiety and irritability are also common, and our negative affectivity factor should be interpreted as anxiety disorders with elevated irritability. Reliability of some subfactors was poor. CONCLUSIONS: Aberrant amygdala-prefrontal-parietal circuitry during extinction recall of threat-safety stimuli may be a mechanism underlying the co-occurrence of pediatric anxiety and irritability.

Across-subjects multiple baseline trial of exposure-based cognitive-behavioral therapy for severe irritability: a study protocol.

INTRODUCTION: Irritability is defined as a tendency towards anger in response to frustration. Clinically, impairing irritability is a significant public health problem. There is a need for mechanism-based psychotherapies targeting severe irritability as it manifests in the context of disruptive mood dysregulation disorder (DMDD). This study protocol describes a randomised multiple baseline design testing the preliminary efficacy of a new treatment, exposure-based cognitive-behavioral therapy for severe irritability in youth, which also integrates components of parent management training. We will investigate associations of this intervention with primary clinical measures, as well as ecological momentary assessment measures. METHODS AND ANALYSIS: Forty youth will be enrolled. Participants, aged 8-17 years, must present at least one of two core symptoms of DMDD: abnormal mood or increased reactivity to negative emotional stimuli, with severe impairment in one domain (home, school, peers) and moderate in another, or moderate impairment in at least two domains. Each participant is randomised to a 2-week, 4-week or 6-week baseline observation period, followed by 12 active treatment sessions. Clinical ratings are conducted at baseline, biweekly (clinician), weekly (parent/child) throughout treatment, post-treatment, and 3-month and 6-month follow-up (clinician). Clinician ratings on the Affective Reactivity Index and Clinical Global Impressions-Improvement scale for DMDD are our primary outcome measures. Secondary outcome measures include parent and child reports of irritability. Post hoc additional symptom measures include clinician, parent and self-ratings of depression, anxiety and overall functional impairment. Prospective, digitally based event sampling of symptoms is acquired for a week pre-treatment, mid-treatment and post-treatment. Based on our pathophysiological model of irritability implicating frustrative non-reward, aberrant threat processing and instrumental learning, we probe these three brain-based targets using functional MRI paradigms to assess target engagement. ETHICS AND DISSEMINATION: The research project and all related materials were submitted and approved by the appropriate Institutional Review Board (IRB) of the National Institute of Mental Health (NIMH). TRIAL REGISTRATION NUMBERS: NCT02531893 and NCT00025935.

Anxiety sensitivity correlates with two indices of right anterior insula structure in specific animal phobia.

BACKGROUND: Anxiety sensitivity (AS) is a dispositional trait involving fear of anxiety-related symptoms. Functional imaging research suggests that the activity of the anterior insular cortex, particularly the right insula, may both mediate AS and play a role in the pathophysiology of phobias. However, no imaging studies have examined whether AS relates to insula morphology. We examined whether AS was significantly correlated with right anterior insula volume and thickness among adults with specific animal phobia (SAP) and healthy comparison (HC) subjects. METHODS: Nineteen adults with SAP and 20 demographically group-matched HC subjects underwent magnetic resonance imaging at 3 Tesla. Subjects also completed the Anxiety Sensitivity Index (ASI). Regression and correlation analyses examined ASI scores in relation to anterior and posterior insular cortex volume and thickness within and across subject groups. RESULTS: SAP subjects had significantly higher ASI scores than HC, but did not differ in terms of insula volumes or thickness. ASI scores predicted right anterior insula thickness in SAP but not HC subjects, and right anterior insula volume in the sample as a whole. Correlations of ASI scores with the anterior and posterior insula volume and thickness were not significant in either group. CONCLUSIONS: These findings suggest that the right anterior insular cortex size is a neural substrate of AS within specific phobia, rather than an independent diagnostic marker of the disorder. Future investigations should examine whether heightened AS represents a shared intermediate phenotype across anxiety disorders, manifesting functionally as increased insular reactivity and clinically as a fear of anxiety symptoms.

Amygdala activation in response to facial expressions in pediatric obsessive-compulsive disorder.

BACKGROUND: Exaggerated amygdala activation to threatening faces has been detected in adults and children with anxiety disorders, compared to healthy comparison (HC) subjects. However, the profile of amygdala activation in response to facial expressions in obsessive-compulsive disorder (OCD) may be a distinguishing feature; a prior study found that compared with healthy adults, adults with OCD exhibited less amygdala activation to emotional and neutral faces, relative to fixation [Cannistraro et al. (2004). Biological Psychiatry 56:916-920]. METHODS: In the current event-related functional magnetic resonance imaging (fMRI) study, a pediatric OCD sample (N=12) and a HC sample (N=17) performed a gender discrimination task while viewing emotional faces (happy, fearful, disgusted) and neutral faces. RESULTS: Compared to the HC group, the OCD group showed less amygdala/hippocampus activation in all emotion and neutral conditions relative to fixation. CONCLUSIONS: Like previous reports in adult OCD, pediatric OCD may have a distinct neural profile from other anxiety disorders, with respect to amygdala activation in response to emotional stimuli that are not disorder specific.

Exposure-Based Cognitive-Behavioral Therapy for Disruptive Mood Dysregulation Disorder: An Evidence-Based Case Study.

Severe, chronic irritability is one of the most frequently reported problems in youth referred for psychiatric care. Irritability predicts adult depressive and anxiety disorders, and long-term impairment. Reflecting this pressing public health need, severe, chronic, and impairing irritability is now codified by the DSM-5 diagnosis of disruptive mood dysregulation disorder (DMDD). Since DMDD has only recently been added as its own nosological class, efficacious treatments that specifically target severe irritability as it presents in DMDD are still being developed. In a recent pilot study, we described the general concept of exposure-based cognitive-behavioral therapy (CBT) for irritability. This mechanism-driven treatment is based on our pathophysiological model of irritability that postulates two underlying mechanisms, which potentiate each other: (1) heightened reactivity to frustrative nonreward, and (2) aberrant approach responses to threat. In this case report, we describe and illustrate the specific therapeutic techniques used to address severe irritability in an 11-year-old boy with a primary diagnosis of DMDD. Specific techniques within this CBT include motivational interviewing to build commitment and target oppositionality; creation of an anger hierarchy; in-session controlled, gradual exposure; and parent training focusing on contingency management to counteract the instrumental learning deficits in irritable youth. Parents learn to tolerate their own emotional responses to their youth's irritability (e.g., parents engage in their own exposure) and increase their adaptive contingencies for their youth's behavior (e.g., withdraw attention during unwanted behavior, praise desirable behavior). Future directions in the context of this CBT, such as leveraging technology, computational modeling, and pathophysiological targets, are discussed.

Age Differences in the Neural Correlates of Anxiety Disorders: An fMRI Study of Response to Learned Threat.

OBJECTIVE: Although both pediatric and adult patients with anxiety disorders exhibit similar neural responding to threats, age-related differences have been found in some functional MRI (fMRI) studies. To reconcile disparate findings, the authors compared brain function in youths and adults with and without anxiety disorders while rating fear and memory of ambiguous threats. METHODS: Two hundred medication-free individuals ages 8-50 were assessed, including 93 participants with an anxiety disorder. Participants underwent discriminative threat conditioning and extinction in the clinic. Approximately 3 weeks later, they completed an fMRI paradigm involving extinction recall, in which they rated their levels of fear evoked by, and their explicit memory for, morph stimuli with varying degrees of similarity to the extinguished threat cues. RESULTS: Age moderated two sets of anxiety disorder findings. First, as age increased, healthy subjects compared with participants with anxiety disorders exhibited greater amygdala-ventromedial prefrontal cortex (vmPFC) connectivity when processing threat-related cues. Second, age moderated diagnostic differences in activation in ways that varied with attention and brain regions. When rating fear, activation in the vmPFC differed between the anxiety and healthy groups at relatively older ages. In contrast, when rating memory for task stimuli, activation in the inferior temporal cortex differed between the anxiety and healthy groups at relatively younger ages. CONCLUSIONS: In contrast to previous studies that demonstrated age-related similarities in the biological correlates of anxiety disorders, this study identified age differences. These findings may reflect this study's focus on relatively late-maturing psychological processes, particularly the appraisal and explicit memory of ambiguous threat, and inform neurodevelopmental perspectives on anxiety.

Infant behavioral reactivity predicts change in amygdala volume 12 years later.

The current study examined the link between temperamental reactivity in infancy and amygdala development in middle childhood. A sample (n = 291) of four-month-old infants was assessed for infant temperament, and two groups were identified: those exhibiting negative reactivity (n = 116) and those exhibiting positive reactivity (n = 106). At 10 and 12 years of age structural imaging was completed on a subset of these participants (n = 75). Results indicate that, between 10 and 12 years of age, left amygdala volume increased more slowly in those with negative compared to positive reactive temperament. These results provide novel evidence linking early temperament to distinct patterns of brain development over middle childhood.

Self-Efficacy As a Target for Neuroscience Research on Moderators of Treatment Outcomes in Pediatric Anxiety.

Objective: Despite the advances in the field of neuroscience, many questions remain regarding the mechanisms of anxiety, as well as moderators of treatment outcome. Long-term adverse outcomes for anxious youth may relate to pathophysiologically based information processing patterns and self-referential beliefs, such as self-efficacy. In fact, there are no studies highlighting the relationship between self-efficacy and neurocircuitry in youth. The purpose of this study was to explore the relationships between self-efficacy, brain morphometry, and youth anxiety. Methods: Parent, child, and clinician ratings of anxiety symptoms and child-reported self-efficacy were analyzed in a sample of 8- to 17-year-old youth (n = 51). Measures were collected from all youth at baseline and during and after treatment for the patients. Anxious patients (n = 26) received 12 sessions of cognitive behavioral therapy (CBT). Moreover, imaging data obtained from all participants before treatment were utilized in analyses. Results: Patients reported lower self-efficacy than healthy volunteers. Across the entire sample, anxiety was negatively related to total, social, and emotional efficacy. Both social and emotional efficacy predicted anxiety posttreatment. In addition, social efficacy predicted social anxiety symptoms posttreatment and social efficacy increased across treatment. There were no significant relations between self-efficacy and neurocircuitry. Conclusions: Self-efficacy is an important treatment target for anxious youth. Although self-efficacy was not related to brain morphometry, self-efficacy beliefs may constitute an important mechanism through which CBT and psychopharmacological interventions decrease fear and anxiety symptoms in youth.

Threat-induced anxiety during goal pursuit disrupts amygdala-prefrontal cortex connectivity in posttraumatic stress disorder.

To investigate how unpredictable threat during goal pursuit impacts fronto-limbic activity and functional connectivity in posttraumatic stress disorder (PTSD), we compared military veterans with PTSD (n = 25) vs. trauma-exposed control (n = 25). Participants underwent functional magnetic resonance imaging (fMRI) while engaged in a computerized chase-and-capture game task that involved optimizing monetary rewards obtained from capturing virtual prey while simultaneously avoiding capture by virtual predators. The game was played under two alternating contexts-one involving exposure to unpredictable task-irrelevant threat from randomly occurring electrical shocks, and a nonthreat control condition. Activation in and functional connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) was tested across threat and nonthreat task contexts with generalized psychophysiological interaction (gPPI) analyses. PTSD patients reported higher anxiety than controls across contexts. Better task performance represented by successfully avoiding capture by predators under threat compared with nonthreat contexts was associated with stronger left amygdala-vmPFC functional connectivity in controls and greater vmPFC activation in PTSD patients. PTSD symptom severity was negatively correlated with vmPFC activation in trauma-exposed controls and with right amygdala-vmPFC functional connectivity across all participants in the threat relative to nonthreat contexts. The findings showed that veterans with PTSD have disrupted amygdala-vmPFC functional connectivity and greater localized vmPFC processing under threat modulation of goal-directed behavior, specifically related to successfully avoiding loss of monetary rewards. In contrast, trauma survivors without PTSD relied on stronger threat-modulated left amygdala-vmPFC functional connectivity during goal-directed behavior, which may represent a resilience-related functional adaptation.

Anticipatory Threat Responding: Associations With Anxiety, Development, and Brain Structure.

BACKGROUND: While translational theories link neurodevelopmental changes in threat learning to pathological anxiety, findings from studies in patients inconsistently support these theories. This inconsistency may reflect difficulties in studying large patient samples with wide age ranges using consistent methods. A dearth of imaging data in patients further limits translational advances. We address these gaps through a psychophysiology and structural brain imaging study in a large sample of patients across the lifespan. METHODS: A total of 351 participants (8-50 years of age; 209 female subjects; 195 healthy participants and 156 medication-free, treatment-seeking patients with anxiety) completed a differential threat conditioning and extinction paradigm that has been validated in pediatric and adult populations. Skin conductance response indexed psychophysiological response to conditioned (CS+, CS-) and unconditioned threat stimuli. Structural magnetic resonance imaging data were available for 250 participants. Analyses tested anxiety and age associations with psychophysiological response in addition to associations between psychophysiology and brain structure. RESULTS: Regardless of age, patients and healthy comparison subjects demonstrated comparable differential threat conditioning and extinction. The magnitude of skin conductance response to both conditioned stimulus types differentiated patients from comparison subjects and covaried with dorsal prefrontal cortical thickness; structure-response associations were moderated by anxiety and age in several regions. Unconditioned responding was unrelated to anxiety and brain structure. CONCLUSIONS: Rather than impaired threat learning, pathological anxiety involves heightened skin conductance response to potential but not immediately present threats; this anxiety-related potentiation of anticipatory responding also relates to variation in brain structure. These findings inform theoretical considerations by highlighting anticipatory response to potential threat in anxiety.