Anxiety Disorders: Fox NA

Pine DS, Helfinstein SM, Bar-Haim Y, Nelson E, Fox NA. · Mood and Anxiety Disorders Program, Intramural Research Program, The National Institute of Mental Health, Bethesda, MD 20892-2670, USA. · Neuropsychopharmacology. · Pubmed #18754004 No free full text.

Abstract: Alterations in brain development may contribute to chronic mental disorders. Novel treatments targeted toward the early-childhood manifestations of such chronic disorders may provide unique therapeutic opportunities. However, attempts to develop and deliver novel treatments face many challenges. Work on pediatric anxiety disorders illustrates both the inherent challenges as well as the unusual opportunities for therapeutic advances. The present review summarizes three aspects of translational research on pediatric anxiety disorders as the work informs efforts to develop novel interventions. First, the review summarizes data on developmental conceptualizations of anxiety from both basic neuroscience and clinical perspectives. This summary is integrated with a discussion of the two best-established treatments, cognitive behavioral therapy and selective serotonin reuptake inhibitors. Second, the review summarizes work on attention bias to threat, considering implications for both novel treatments and translational research on neural circuitry functional development. This illustrates the manner in which clinical findings inform basic systems neuroscience research. Finally, the review summarizes work in basic science on fear learning, as studied in fear conditioning, consolidation, and extinction paradigms. This summary ends by describing potential novel treatments, illustrating the manner in which basic neuroscience informs therapeutics.

Pérez-Edgar K, Fox NA. · University of Maryland, College Park, MD 20742, USA. · Child Adolesc Psychiatr Clin N Am. · Pubmed #16171698 No free full text.

Abstract: Recently, multidisciplinary research teams have come together to assess the emergence, course, and treatment of anxiety disorders in young children and adolescents. A number of researchers have suggested that early temperament traits may play a significant role in the causes and maintenance of early anxiety. This article reviews the current understanding of temperament and anxiety as separate constructs and then attempts to examine the developmental links between the two constructs. The authors examine the outstanding issues that must be addressed before the benefits of bridging these traditionally independent fields of study can be fully exploited.

Fox NA, Henderson HA, Marshall PJ, Nichols KE, Ghera MM. · Department of Human Development, University of Maryland, College Park, MD 20742, USA. · Annu Rev Psychol. · Pubmed #15709935 No free full text.

Abstract: Behavioral inhibition refers to a temperament or style of reacting that some infants and young children exhibit when confronted with novel situations or unfamiliar adults or peers. Research on behavioral inhibition has examined the link between this set of behaviors to the neural systems involved in the experience and expression of fear. There are strong parallels between the physiology of behaviorally inhibited children and the activation of physiological systems associated with conditioned and unconditioned fear. Research has examined which caregiving behaviors support the frequency of behavioral inhibition across development, and work on the interface of cognitive processes and behavioral inhibition reveal both how certain cognitive processes moderate behavioral inhibition and how this temperament affects the development of cognition. This research has taken place within a context of the possibility that stable behavioral inhibition may be a risk factor for psychopathology, particularly anxiety disorders in older children. The current chapter reviews these areas of research and provides an integrative account of the broad impact of behavioral inhibition research.

Reeb-Sutherland BC, Helfinstein SM, Degnan KA, Pérez-Edgar K, Henderson HA, Lissek S, Chronis-Tuscano A, Grillon C, Pine DS, Fox NA. · Department of Human Development, University of Maryland, 3304 Benjamin Building, College Park, MD 20742, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #19454917 No free full text.

Abstract: OBJECTIVE: Behaviorally inhibited children face increased risk for anxiety disorders, although factors that predict which children develop a disorder remain poorly specified. The current study examines whether the startle reflex response may be used to differentiate between behaviorally inhibited adolescents with and without a history of anxiety. METHOD: Participants were assessed for behavioral inhibition during toddlerhood and early childhood. They returned to the laboratory as adolescents and completed a fear-potentiated startle paradigm and a clinical diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version). Magnitude of the startle reflex was examined at baseline and during cues associated with safety and threat. RESULTS: Only adolescents who showed high levels of behavioral inhibition and had a lifetime occurrence of anxiety disorders showed increased startle reactivity in the presence of safety cues. Neither behavioral inhibition nor diagnosis was related to startle reactivity during threat cues. CONCLUSIONS: These results suggest that neurobiological measures, such as the startle reflex, may be a potential risk marker for the development of anxiety disorders among behaviorally inhibited adolescents. These methods may enhance our ability to identify vulnerable individuals before the development of anxious psychopathology.

McDermott JM, Perez-Edgar K, Henderson HA, Chronis-Tuscano A, Pine DS, Fox NA. · University of Wisconsin, Madison, Wisconsin, USA. · Biol Psychiatry. · Pubmed #19108817 No free full text.

Abstract: BACKGROUND: Behaviorally inhibited (BI) children who also exhibit enhanced response monitoring might be at particularly high risk for anxiety disorders. The current study tests the hypothesis that response monitoring, as manifest in the error-related negativity (ERN), moderates the association between BI and anxiety. METHODS: Participants (n=113; 73 male) assessed for early-childhood BI were re-assessed as adolescents with a clinical interview and a flanker paradigm that generated behavioral data and event-related potentials (ERPs). Risk for anxiety disorders in adolescents was examined as a function of childhood-BI status and adolescent performance on the flanker paradigm. RESULTS: Adolescents with childhood BI displayed ERP evidence of enhanced response monitoring, manifest as large ERNs. The ERN moderated the relationship between early BI and later clinically significant disorders. CONCLUSIONS: Physiological measures of response monitoring might moderate associations between early-childhood BI and risk for psychopathology. The subset of children with BI and enhanced response monitoring might face greater risk for later-life clinical anxiety than children with either BI or enhanced response monitoring alone.

Guyer AE, Lau JY, McClure-Tone EB, Parrish J, Shiffrin ND, Reynolds RC, Chen G, Blair RJ, Leibenluft E, Fox NA, Ernst M, Pine DS, Nelson EE. · Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, 15K North Dr, Room 208, Bethesda, MD 20892-2670, USA. · Arch Gen Psychiatry. · Pubmed #18981342 links to  free full text

Abstract: CONTEXT: Amygdala and ventrolateral prefrontal cortex (vlPFC) dysfunction manifests in adolescents with anxiety disorders when they view negatively valenced stimuli in threatening contexts. Such fear-circuitry dysfunction may also manifest when anticipated social evaluation leads socially anxious adolescents to misperceive peers as threatening. OBJECTIVE: To determine whether photographs of negatively evaluated smiling peers viewed during anticipated social evaluation engage the amygdala and vlPFC differentially in adolescents with and without social anxiety. DESIGN: Case-control study. SETTING: Government clinical research institute. PARTICIPANTS: Fourteen adolescents with anxiety disorders associated with marked concerns of social evaluation and 14 adolescents without a psychiatric diagnosis matched on sex, age, intelligence quotient, and socioeconomic status. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal measured with event-related functional magnetic resonance imaging. Before and during neuroimaging scans, participants anticipating social evaluation completed peer- and self-appraisals. Event-related analyses were tailored to participants' ratings of specific peers. RESULTS: Participants classified 40 pictures of same-age peers as ones with whom they did or did not want to engage in a social interaction. Anxious adolescents showed greater amygdala activation than healthy adolescents when anticipating evaluation from peers previously rated as undesired for an interaction. Psychophysiological interaction connectivity analyses also revealed a significant positive association between amygdala and vlPFC activation in anxious vs healthy adolescents in response to these stimuli. CONCLUSIONS: Anticipating social evaluation from negatively perceived peers modulates amygdala and vlPFC engagement differentially in anxious and healthy adolescents. Amygdala and vlPFC dysfunction manifests in adolescent anxiety disorders in specific contexts of anticipated peer evaluation.

Helfinstein SM, White LK, Bar-Haim Y, Fox NA. · Child Development Laboratory, Department of Human Development, University of Maryland, College Park, MD 20742, USA. · Behav Res Ther. · Pubmed #18472088 links to  free full text

Abstract: Anxious individuals show an attention bias towards threatening information. However, under conditions of sustained environmental threat this otherwise-present attention bias disappears. It remains unclear whether this suppression of attention bias can be caused by a transient activation of the fear system. In the present experiment, high socially anxious and low socially anxious individuals (HSA group, n=12; LSA group, n=12) performed a modified dot-probe task in which they were shown either a neutral or socially threatening prime word prior to each trial. EEG was collected and ERP components to the prime and faces displays were computed. HSA individuals showed an attention bias to threat after a neutral prime, but no attention bias after a threatening prime, demonstrating that suppression of attention bias can occur after a transient activation of the fear system. LSA individuals showed an opposite pattern: no evidence of a bias to threat with neutral primes but induction of an attention bias to threat following threatening primes. ERP results suggested differential processing of the prime and faces displays by HSA and LSA individuals. However, no group by prime interaction was found for any of ERP components.

Schmidt LA, Fox NA, Hamer DH. · Department of Psychology, Neuroscience and Behaviour, 1280 Main Street West, McMaster University, Hamilton, Ontario L8S 4K1, Canada. · Dev Psychopathol. · Pubmed #17931437 No free full text.

Abstract: Recent work on the molecular genetics of complex traits in typical and atypical human development has focused primarily on associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts internalizing- and externalizing-related behaviors, respectively. Apparently for the first time in the extant literature, we report a gene-gene statistical interaction on behavior problems in a group of typically developing children at age 7. DNA was extracted from buccal cells collected from 108 children and genotyped for short and long alleles of the 5-HTT gene and the short (2-5 repeats) versus long (6-8 repeats) allele of the DRD4 gene. Mothers completed the Child Behavior Checklist. As predicted, children with one or two copies of the short allele of the 5-HTT gene and the long allele version of the DRD4 gene exhibited significantly more internalizing and externalizing behaviors at age 7 than children with other combinations of the 5-HTT and DRD4 short and long genotypes. As well, children with the 5-HTT long and DRD4 long genotypes had the lowest reported scores on internalizing and externalizing behaviors at age 7, suggesting that the presence of the 5-HTT long genotype may serve as a protective factor against these behaviors in children with the long DRD4 genotype. Implications of these findings for understanding cumulative biological risk and protective factors in childhood behavior problems and psychopathology are discussed.

Degnan KA, Fox NA. · University of Maryland, College Park, MD 20742, USA. · Dev Psychopathol. · Pubmed #17705900 No free full text.

Abstract: Behavioral inhibition is reported to be one of the most stable temperamental characteristics in childhood. However, there is also evidence for discontinuity of this trait, with infants and toddlers who were extremely inhibited displaying less withdrawn social behavior as school-age children or adolescents. There are many possible explanations for the discontinuity in this temperament over time. They include the development of adaptive attention and regulatory skills, the influence of particular styles of parenting or caregiving contexts, and individual characteristics of the child such as their level of approach-withdrawal motivation or their gender. These discontinuous trajectories of behaviorally inhibited children and the factors that form them are discussed as examples of the resilience process.

Pérez-Edgar K, Roberson-Nay R, Hardin MG, Poeth K, Guyer AE, Nelson EE, McClure EB, Henderson HA, Fox NA, Pine DS, Ernst M. · Department of Psychology, George Mason University, USA. · Neuroimage. · Pubmed #17376704 links to  free full text

Abstract: Behavioral inhibition (BI) is a risk factor for anxiety disorders. While the two constructs bear behavioral similarities, previous work has not extended these parallels to the neural level. This study examined amygdala reactivity during a task previously used with clinically anxious adolescents. Adolescents were selected for enduring patterns of BI or non-inhibition (BN). We examined amygdala response to evocative emotion faces in BI (N=10, mean 12.8 years) and BN (N=17, mean 12.5 years) adolescents while systematically manipulating attention. Analyses focused on amygdala response during subjective ratings of internal fear (constrained attention) and passive viewing (unconstrained attention) during the presentation of emotion faces (Happy, Angry, Fearful, and Neutral). BI adolescents, relative to BN adolescents, showed exaggerated amygdala response during subjective fear ratings and deactivation during passive viewing, across all emotion faces. In addition, the BI group showed an abnormally high amygdala response to a task condition marked by novelty and uncertainty (i.e., rating fear state to a Happy face). Perturbations in amygdala function are evident in adolescents temperamentally at risk for anxiety. Attention state alters the underlying pattern of neural processing, potentially mediating the observed behavioral patterns across development. BI adolescents also show a heightened sensitivity to novelty and uncertainty, which has been linked to anxiety. These patterns of reactivity may help sustain early temperamental biases over time and contribute to the observed relation between BI and anxiety.

Rich BA, Schmajuk M, Perez-Edgar KE, Fox NA, Pine DS, Leibenluft E. · Pediatrics and Developmental Neuropsychiatry Branch, Section on Development and Affective Neuroscience, NIMH Mood and Anxiety Program, Bethesda, MD 20892, USA. · Am J Psychiatry. · Pubmed #17267795 links to  free full text

Abstract: OBJECTIVE: Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children). METHOD: Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. RESULTS: The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. CONCLUSIONS: Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.

Rich BA, Schmajuk M, Perez-Edgar KE, Pine DS, Fox NA, Leibenluft E. · Pediatrics and Developmental Neuropsychiatry Branch, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1255, USA. · Biol Psychiatry. · Pubmed #15953589 No free full text.

Abstract: BACKGROUND: Theories in affective neuroscience suggest that mood disorders involve perturbations in attention-emotion interactions. We tested the hypothesis that frustration adversely impacts attention and behavior in children with bipolar disorder (BPD). METHODS: Thirty-five children with BPD and 26 normal control subjects completed: 1) a Posner attention task with feedback but no contingencies; 2) an affective Posner with contingencies; and 3) an affective Posner that used rigged feedback to induce frustration. Reaction time (RT) and event-related potential (ERP) data were collected. RESULTS: At baseline (task 1), there were no between-group differences in behavior or ERPs. Children with BPD exhibited reduced parietal P3 amplitude on task 3 only. On trials occurring after negative feedback, control subjects showed decreased RT when contingencies were introduced (task 2), whereas BPD subjects did not. CONCLUSIONS: The introduction of contingencies was associated with impaired performance of children with BPD, suggesting deficits in their ability to adapt to changing contingencies. In addition, frustration was associated with disrupted attention allocation in children with BPD. We hypothesize that children with BPD inappropriately deployed attention to their internal frustration rather than to the task, causing impaired performance.

Fox NA. · Institute for Child Study, Department of Human Development, University of Maryland, 3304 Benjamin Building, College Park, MD 20742-1131, USA. · Ann N Y Acad Sci. · Pubmed #15838111 No free full text.

Abstract: Individual differences in the way persons respond to stimulation can have important consequences for their ability to learn and their choice of vocation. Temperament is the study of such individual differences, being thought of as the behavioral style of an individual. Common to all approaches in the study of temperament are the notions that it can be identified in infancy, is fairly stable across development, and influences adult personality. We have identified a specific temperament type in infancy that involves heightened distress to novel and unfamiliar stimuli. Infants who exhibit this temperament are likely, as they get older, to display behavioral inhibition-wariness and heightened vigilance of the unfamiliar-particularly in social situations. Our work has also described the underlying biology of this temperament and has linked it to neural systems supporting fear responses in animals. Children displaying behavioral inhibition are at-risk for behavioral problems related to anxiety and social withdrawal.

Stein BD, Zima BT, Elliott MN, Burnam MA, Shahinfar A, Fox NA, Leavitt LA. · RAND, Santa Monica, CA 90401, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #11349704 No free full text.

Abstract: OBJECTIVE: To describe the amount and nature of violence exposure and examine the relationship between violence exposure and distress symptoms among children in foster care. METHOD: Violence exposure and distress symptoms were evaluated in interviews, conducted between July 1996 and March 1998, of 300 children from Los Angeles County living in out-of-home placement. RESULTS: Interviews were successfully completed in 91% of eligible children. The majority of children (85%) reported having been a witness to violence, and 51% had been a victim of violence during their lifetime. Of these youths, 54% and 41%, respectively, reported having been exposed to such violence in the past 6 months. Girls, victims of assaultive violence and weapon related violence, and those reporting exposure to mild violence were more likely (p < .05) to have higher levels of distress symptoms than those without such characteristics, after age was controlled for. CONCLUSIONS: Children in foster care continue to have high levels of violence exposure, even after removal from their biological parents' home. The relationship between violence exposure and distress symptoms underscores the need for clinicians to inquire about multiple forms of violence exposure among children living in out-of-home placement.