Abnormal Attention Modulation of Fear Circuit Function in Pediatric Generalized Anxiety Disorder

Emotional Development and Affective Neuroscience Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH/DHHS, Bethesda, MD 20892, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 02/2007; 64(1):97-106. DOI: 10.1001/archpsyc.64.1.97
Source: PubMed


Considerable work implicates abnormal neural activation and disrupted attention to facial-threat cues in adult anxiety disorders. However, in pediatric anxiety, no research has examined attention modulation of neural response to threat cues.
To determine whether attention modulates amygdala and cortical responses to facial-threat cues differentially in adolescents with generalized anxiety disorder and in healthy adolescents.
Case-control study.
Government clinical research institute.
Fifteen adolescents with generalized anxiety disorder and 20 controls.
Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging. During imaging, participants completed a face-emotion rating task that systematically manipulated attention.
While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful faces than to happy faces in a distributed network including the amygdala, ventral prefrontal cortex, and anterior cingulate cortex (P<.05, small-volume corrected, for all). Right amygdala findings appeared particularly strong. Functional connectivity analyses demonstrated positive correlations among the amygdala, ventral prefrontal cortex, and anterior cingulate cortex.
This is the first evidence in juveniles that generalized anxiety disorder-associated patterns of pathologic fear circuit activation are particularly evident during certain attention states. Specifically, fear circuit hyperactivation occurred in an attention state involving focus on subjectively experienced fear. These findings underscore the importance of attention and its interaction with emotion in shaping the function of the adolescent human fear circuit.

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    • "Significant volume changes in the PFC were only detected for WM but not for GM, contrary to hypotheses. Previous structural (e.g., Schienle et al., 2011; Strawn et al., 2013; Strawn et al., 2014) and functional (e.g., McClure et al., 2007; Strawn et al., 2012; Ball et al., 2013) MRI studies have reported abnormal GM volume in various parts of the PFC, although not in all studies (Liao et al., 2014; Moon et al., 2014). Additionally, structural PFC alterations are present in disorders related to GAD such as major depression (Kempton et al., 2011; Du et al., 2012; Sacher et al., 2012). "
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    ABSTRACT: Increasing efforts have been made to investigate the underlying pathophysiology of generalized anxiety disorder (GAD), but only limited consistent information is available on gray (GM) and white matter (WM) volume changes in affected adults. Additionally, few studies employed dimensional approaches to GAD pathology. This study compares structural brain imaging data from n=19 GAD subjects and n=24 healthy comparison (HC) subjects, all medication-free and matched on age, sex and education. Separate categorical and dimensional models were employed using voxel-based morphometry for GM and WM. Significantly higher GM volumes were found in GAD subjects mainly in basal ganglia structures and less consistently in the superior temporal pole. For WM, GAD subjects showed significantly lower volumes in the dlPFC. Largely consistent findings in dimensional and categorical models point toward these structural alterations being reliable and of importance for GAD. While lower volume in the dlPFC could reflect impaired emotional processing and control over worry in GAD, basal ganglia alterations may be linked to disturbed gain and loss anticipation as implicated in previous functional GAD studies. As perturbations in anticipation processes are central to GAD, these areas may warrant greater attention in future studies.
    10/2015; DOI:10.1016/j.pscychresns.2015.10.009
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    • "Analogously, neurofunctional and neurostructural studies of youth with anxiety disorders demonstrate dysfunction in components of the prefrontal–amygdala network, a group of cortical and subcortical structures which subserve complex emotional processing . These studies observed increased functional activity in the amygdala (Beesdo et al., 2009; Killgore and Yurgelun-Todd, 2005), ventrolateral prefrontal cortex ([VLPFC]; Beesdo et al., 2009; Guyer et al., 2008; Monk et al., 2006; Strawn et al., 2012a; for review see Blackford and Pine (2012) and Strawn et al. (2012b)), and the anterior cingulate cortex (McClure et al., 2007; Strawn et al., 2014) and also suggest increased glutamaterigic tone in adolescents with GAD in the ACC (Strawn et al., 2013). Additionally, neurostructural examinations of youth with anxiety disorders have suggested abnormalities within and beyond the prefrontal–amygdala networks (De Bellis et al., 2000; De Bellis et al., 2002; Milham et al., 2005; Mueller et al., 2013; Strawn et al., 2013), although these studies have yielded inconsistent results. "
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    ABSTRACT: Depressive and anxiety disorders are among the most frequently occurring psychiatric conditions in children and adolescents and commonly present occur together. Co-occurring depression and anxiety is associated with increased functional impairment and suicidality compared to depression alone. Despite this, little is known regarding the neurostructural differences between anxiety disorders and major depressive disorder (MDD). Moreover, the neurophysiologic impact of the presence of anxiety in adolescents with MDD is unknown.
    Journal of Affective Disorders 01/2015; 171:54-59. DOI:10.1016/j.jad.2014.09.004 · 3.38 Impact Factor
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    • "Third, we attempted to characterize how CBT-related functional changes are associated with changes in worry following therapy. In accordance with existing evidence (Etkin et al., 2009; Paulesu et al., 2010; Nitschke et al., 2009a; McClure et al., 2007), we predicted that at pre-treatment GAD participants would display increased activation of the amygdala and decreased activation of the anterior cingulate/medial prefrontal cortical regions (ACC/mPFC) to threat-related stimuli. Following treatment, we predicted CBT would result in an attenuation of these amygdalar and ACC/mPFC group differences. "
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    ABSTRACT: Background The neural processes underlying the benefits of cognitive behavioral treatment (CBT) for generalized anxiety disorder (GAD) are not well understood. Methods Twenty-one (n=21) adults with a principal diagnosis of GAD and eleven (n=11) non-anxious healthy controls (HC) underwent functional magnetic resonance imaging while completing a facial emotion processing task. Responses to threat-related emotionality (i.e., the contrast of fear and angry vs. happy faces) were assessed at pretreatment and again following 10 sessions of CBT in the GAD group and a comparable waiting period in the HC group. Results At pretreatment, GAD participants displayed blunted responses in the amygdala, insula, and anterior cingulate to the happy face-processing comparison condition, and greater amygdalo–insular connectivity. CBT was associated with amygdalar and subgenual anterior cingulate activation to fear/angry faces and heightened insular responses to the happy face comparison condition, but had no apparent effects on connectivity. Pre-treatment abnormalities and treatment-related changes were not associated with symptoms of worry. Limitations There was no active control condition (e.g., treatment waitlist) for comparison of treatment effects. Conclusions Taken together, these results provide evidence for a dual-process psychotherapeutic model of neural systems changes in GAD in which cingulo-amygdalar reactivity to threat-cues is attenuated while insular responses to positive facial emotions are potentiated. Future work is needed to determine the clinical implications of these changes and their specificity to CBT.
    Journal of Affective Disorders 12/2014; 169:76–85. DOI:10.1016/j.jad.2014.07.031 · 3.38 Impact Factor
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