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

ABSTRACT 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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Available from: Eric E Nelson, Sep 27, 2015
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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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    • "Thus, although the necessary processing of the FL ITI-signal does not appear to require the IL cortex, differences in other aspects of avoidance learning displayed between WKY and SD rats may be due to neurotransmission differences between the BLA and PL cortex. Amygdala – mPFC connectivity and functioning is documented to be different in humans with anxiety disorders, although the particular pattern of difference is still not resolved (Gilboa et al., 2004; Monk et al., 2006; McClure et al., 2007; Liberzon and Sripada, 2008; Etkin et al., 2010; Tromp et al., 2012; Demenescu et al., 2013; Stevens et al., 2013; Killgore et al., 2014). Therefore, the WKY rat can be a very useful model to study how abnormal prefrontal functioning can lead to avoidance susceptibility, avoidance extinction resistance, and overall anxiety vulnerability. "
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    ABSTRACT: As a model of anxiety disorder vulnerability, male Wistar-Kyoto (WKY) rats acquire lever-press avoidance behavior more readily than outbred Sprague-Dawley rats, and their acquisition is enhanced by the presence of a discrete signal presented during the inter-trial intervals (ITIs), suggesting that it is perceived as a safety signal. A series of experiments were conducted to determine if this is the case. Additional experiments investigated if the avoidance facilitation relies upon processing through medial prefrontal cortex (mPFC). The results suggest that the ITI-signal facilitates acquisition during the early stages of the avoidance acquisition process, when the rats are initially acquiring escape behavior and then transitioning to avoidance behavior. Post-avoidance introduction of the visual ITI-signal into other associative learning tasks failed to confirm that the visual stimulus had acquired the properties of a conditioned inhibitor. Shortening the signal from the entirety of the 3 min ITI to only the first 5 s of the 3 min ITI slowed acquisition during the first four sessions, suggesting the flashing light (FL) is not functioning as a feedback signal. The prelimbic (PL) cortex showed greater activation during the period of training when the transition from escape responding to avoidance responding occurs. Only combined PL + infralimbic cortex lesions modestly slowed avoidance acquisition, but PL-cortex lesions slowed avoidance response latencies. Thus, the FL ITI-signal is not likely perceived as a safety signal nor is it serving as a feedback signal. The functional role of the PL-cortex appears to be to increase the drive toward responding to the threat of the warning signal. Hence, avoidance susceptibility displayed by male WKY rats may be driven, in part, both by external stimuli (ITI signal) as well as by enhanced threat recognition to the warning signal via the PL cortex.
    Frontiers in Behavioral Neuroscience 11/2014; 8:403. DOI:10.3389/fnbeh.2014.00403 · 3.27 Impact Factor
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