Daniel S. Pine

What is an anxiety disorder

Initiated as part of the ongoing deliberation about the nosological structure of DSM, this review aims to evaluate whether the anxiety disorders share features of responding that define them and make them distinct from depressive disorders, and/or that differentiate fear disorders from anxious‐misery disorders. The review covers symptom self‐report as well as on‐line indices of behavioral, physiological, cognitive, and neural responding in the presence of aversive stimuli. The data indicate that the anxiety disorders share self‐reported symptoms of anxiety and fear; heightened anxiety and fear responding to cues that signal threat, cues that signal no threat, cues that formerly signaled threat, and contexts associated with threat; elevated stress reactivity to aversive stimuli; attentional biases to threat‐relevant stimuli and threat‐based appraisals of ambiguous stimuli; and elevated amygdala responses to threat‐relevant stimuli. Some differences exist among anxiety disorders, and between anxiety disorders and depressive disorders. However, the differences are not fully consistent with proposed subdivisions of fear disorders vs. anxious misery disorders, and comparative data in large part are lacking. Given the high rates of co‐morbidity, advances in our understanding of the features of responding that are shared across vs. unique to anxiety and depressive disorders will require dimensional approaches. In summary, the extant data help to define the features of responding that are shared across anxiety disorders, but are insufficient to justify revisions to the DSM nosology at this time. Depression and Anxiety, 2009.

Development of anxiety: the role of threat appraisal and fear learning

Anxious individuals exhibit threat biases at multiple levels of information processing. From a developmental perspective, abnormal safety learning in childhood may establish threat‐related appraisal biases early, which may contribute to chronic disorders in adulthood. This review illustrates how the interface among attention, threat appraisal, and fear learning can generate novel insights for outcome prediction. This review summarizes data on amygdala function, as it relates to learning and attention, highlights the importance of examining threat appraisal, and introduces a novel imaging paradigm to investigate the neural correlates of threat appraisal and threat‐sensitivity during extinction recall. This novel paradigm can be used to investigate key questions relevant to prognosis and treatment. Depression and Anxiety, 2011.© 2010 Wiley‐Liss, Inc.

ATTENTION BIASES, ANXIETY, AND DEVELOPMENT: TOWARD OR AWAY FROM THREATS OR REWARDS?

Research on attention provides a promising framework for studying anxiety pathophysiology and treatment. The study of attention biases appears particularly pertinent to developmental research, as attention affects learning and has down‐stream effects on behavior. This review summarizes recent findings about attention orienting in anxiety, drawing on findings in recent developmental psychopathology and affective neuroscience research. These findings generate specific insights about both development and therapeutics. The review goes beyond a traditional focus on biased processing of threats and considers biased processing of rewards. Building on this work, we then turn to the treatment of pediatric anxiety, where manipulation of attention to threat and/or reward may serve a therapeutic role as a component of Attention Bias Modification Therapy. Depression and Anxiety 0:1–13, 2011.u2003u2003© 2011 Wiley Periodicals, Inc.

THE EFFECTS OF LATENT VARIABLES IN THE DEVELOPMENT OF COMORBIDITY AMONG COMMON MENTAL DISORDERS

Background: Although numerous studies have examined the role of latent predispositions to internalizing and externalizing disorders in the structure of comorbidity among common mental disorders, none examined latent predispositions in predicting development of comorbidity. Methods: A novel method was used to study the role of latent variables in the development of comorbidity among lifetime DSM‐IV disorders in the National Comorbidity Surveys. Broad preliminary findings are briefly presented to describe the method. The method used survival analysis to estimate time‐lagged associations among 18 lifetime DSM‐IV anxiety, mood, behavior, and substance disorders. A novel estimation approach examined the extent to which these predictive associations could be explained by latent canonical variables representing internalizing and externalizing disorders. Results: Consistently significant positive associations were found between temporally primary and secondary disorders. Within‐domain time‐lagged associations were generally stronger than between‐domain associations. The vast majority of associations were explained by a model that assumed mediating effects of latent internalizing and externalizing variables, although the complexity of this model differed across samples. A number of intriguing residual associations emerged that warrant further investigation. Conclusions: The good fit of the canonical model suggests that common causal pathways account for most comorbidity among the disorders considered. These common pathways should be the focus of future research on the development of comorbidity. However, the existence of several important residual associations shows that more is involved than simple mediation. The method developed to carry out these analyses provides a unique way to pinpoint these significant residual associations for subsequent focused study. Depression and Anxiety, 2011.

ATTENTION BIAS TO THREAT FACES IN SEVERE MOOD DYSREGULATION

We used a dot‐probe paradigm to examine attention bias toward threat (i.e., angry) and happy face stimuli in severe mood dysregulation (SMD) versus healthy comparison (HC) youth. The tendency to allocate attention to threat is well established in anxiety and other disorders of negative affect. SMD is characterized by the negative affect of irritability, and longitudinal studies suggest childhood irritability predicts adult anxiety and depression. Therefore, it is important to study pathophysiologic connections between irritability and anxiety disorders.

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. Depression and Anxiety, 2010.

A preliminary study of the neural mechanisms of frustration in pediatric bipolar disorder using magnetoencephalography

Background: Irritability is prevalent and impairing in pediatric bipolar disorder (BD) but has been minimally studied using neuroimaging techniques. We used magnetoencephalography (MEG) to study theta band oscillations in the anterior cingulate cortex (ACC) during frustration in BD youth. ACC theta power is associated with attention to emotional stimuli, and the ACC may mediate responses to frustrating stimuli. Methods: We used the affective Posner task, an attention paradigm that uses rigged feedback to induce frustration, to compare 20 medicated BD youth (14.9±2.0 years; 45% male) and 20 healthy controls (14.7±1.7 years; 45% male). MEG measured neuronal activity after negative and positive feedback; we also compared groups on reaction time, response accuracy, and self‐reported affect. Patients met strict DSM‐IV BD criteria and were euthymic. Controls had no psychiatric history. Results: BD youth reported more negative affective responses than controls. After negative feedback, BD subjects, relative to controls, displayed greater theta power in the right ACC and bilateral parietal lobe. After positive feedback, BD subjects displayed lower theta power in the left ACC than did controls. Correlations between MEG, behavior, and affect were nonsignificant. Conclusion: In this first MEG study of BD youth, BD youth displayed patterns of theta oscillations in the ACC and parietal lobe in response to frustration‐inducing negative feedback that differed from healthy controls. These data suggest that BD youth may display heightened processing of negative feedback and exaggerated self‐monitoring after frustrating emotional stimuli. Future studies are needed with unmedicated bipolar youth, and comparison ADHD and anxiety groups. Depression and Anxiety, 2010.

Enduring influence of early temperament on neural mechanisms mediating attention-emotion conflict in adults.

Behavioral inhibition, a temperament identified in early childhood, is often associated with dysregulated attention and affective processing, particularly in response to threat. Longitudinal studies find that the manifestation of perturbed attention and affective processing often dissipates with age. Yet, childhood behavioral inhibition continues to predict perturbed brain function into adulthood. This suggests that adults with childhood behavioral inhibition may engage compensatory processes to effectively regulate emotion‐related attention. However, it is unknown whether perturbations in brain function reflect compensation for attention bias to emotional stimuli generally, or to threatening contexts more specifically. The present study tests these possibilities.

Fear conditioning and extinction in anxious and nonanxious youth and adults: examining a novel developmentally appropriate fear-conditioning task.

Fear conditioning and extinction have been implicated in the pathogenesis of anxiety disorders. However, due to ethical and methodological limitations, few studies have examined these learning processes across development, particularly among anxious individuals. The present study examined differences in fear conditioning and extinction in anxious and nonanxious youth and adults using a novel task designed to be more tolerable for children than existing paradigms.

Amygdala–Cortical Connectivity: Associations with Anxiety, Development, and Threat

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.