Pathological anxiety is commonly conceptualized as an exaggerated fear state in which hyper- excitability of fear expressed as hypervigilance and increased behavioral responsivity to fearful stimuli (e.g., Rosen et al., 1998)-essentially an amplification of normal fear/defense circuit function. However, our previous research has shown that anxiety patients differ substantially in fear reactivity, within and across diagnoses, as measured by the magnitude of the probe startle reflex during fear imagery challenge (Cuthbert et al., 2003; Lang, McTeague & Cuthbert, 2005, 2007; Lang & McTeague, 2009). Thus, specific phobics show robust probe startle potentiation during fear imagery, while patients with more complex disorders (e.g, panic disorder, generalized anxiety disorder) characteristically show blunted reflex responses. Importantly, similar differences are also found within DSM diagnoses: Overall, fear potentiation decreases as the symptom picture is progressively more severe, comorbid, with higher scores on measures of negative affectivity-despite ratings of high, often much higher, fear during challenge (McTeague, Lang, et al., 2009, 2010, 2011). Considering that research both with animals and humans confirms that fear-circuit activation (amygdala mediated) potentiates the startle reflex, our research invites the novel hypothesis that the defense circuit is compromised/dysregulated in highly distressed anxiety patients. Thus, we examine reactivity to a fear imagery challenge in a broad sample of patients as they present for treatment at our health-center affiliated Fear and Anxiety Disorders Clinic (FADC). Functional MRI (fMRI) is used to asses fear/defense circuit function during fear imagery challenge, testing the hypothesis that alterations in normal defense circuit function mediates a dimension of fear reactivity that ranges from hyper-reactivity to hypo-reactivity in probe startle magnitude. A second broad aim is to test the hypothesis that increased circuit dysregulation and reflex blunting are reliably related to increased self-reports indexing a dimension of negative affectivity, as well as inversely related to treatment outcome success. The general research plan is therefore to develop biological classifiers for a dimension of pathology that cuts across anxiety/mood spectrum disorders. The approach is consistent with the NIMH Research Domain Criteria initiative (e.g, as described by Insel & Cuthbert 2009) implemented in RFA- MH-12-100.

Public Health Relevance

Anxiety disorder diagnoses (DSM-IV) are founded primarily on clinicians' observations of behavior and their assessment of the patient's report of symptoms at interview-with no support from quantitative, biological tests that are keys to the evaluation an treatment of most illnesses. The proposed research plan is to develop quantitative, biological markers (in reflex response and brain circuit function) defining a fundamental dimension of psychopathology, 'negative affectivity', that cuts across anxiety spectrum disorders, that can relate more closely to developing genetic research, provide for improved prognosis, and contribute to better targeted treatment development.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZMH1)
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Borja, Susan
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University of Florida
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Bradley, Margaret M; Zlatar, Zvinka Z; Lang, Peter J (2018) Startle reflex modulation during threat of shock and ""threat"" of reward. Psychophysiology 55:
Sege, Christopher T; Bradley, Margaret M; Lang, Peter J (2018) Avoidance and escape: Defensive reactivity and trait anxiety. Behav Res Ther 104:62-68
Lang, Peter J; Herring, David R; Duncan, Charlesynquette et al. (2018) The Startle-Evoked Potential: Negative Affect and Severity of Pathology in Anxiety/Mood Disorders. Biol Psychiatry Cogn Neurosci Neuroimaging 3:626-634
Weymar, Mathias; Bradley, Margaret M; Sege, Christopher T et al. (2018) Neural activation and memory for natural scenes: Explicit and spontaneous retrieval. Psychophysiology 55:e13197
Sege, Christopher T; Bradley, Margaret M; Weymar, Mathias et al. (2017) A direct comparison of appetitive and aversive anticipation: Overlapping and distinct neural activation. Behav Brain Res 326:96-102
Bradley, Margaret M; Sapigao, Rosemarie G; Lang, Peter J (2017) Sympathetic ANS modulation of pupil diameter in emotional scene perception: Effects of hedonic content, brightness, and contrast. Psychophysiology 54:1419-1435
Sege, Christopher T; Bradley, Margaret M; Lang, Peter J (2017) Escaping aversive exposure. Psychophysiology 54:857-863
Lang, Peter J; McTeague, Lisa M; Bradley, Margaret M (2016) RDoC, DSM, and the reflex physiology of fear: A biodimensional analysis of the anxiety disorders spectrum. Psychophysiology 53:336-47
Bradley, Margaret M; Lang, Peter J (2015) Memory, emotion, and pupil diameter: Repetition of natural scenes. Psychophysiology 52:1186-93
Bartsch, Felix; Hamuni, Gilava; Miskovic, Vladimir et al. (2015) Oscillatory brain activity in the alpha range is modulated by the content of word-prompted mental imagery. Psychophysiology 52:727-35

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