Archival Report|Articles in Press

Coping in the Clinic: Effects of Clinically Elevated Anxiety on Dynamic Neurophysiological Mechanisms of Escape/Avoidance Preparation

Published:August 08, 2022DOI:



      Treatments for anxiety and related disorders target exaggerated escape/avoidance as a core feature, but current methods fail to improve escape/avoidance habits for many treatment-seeking individuals. To support developing tools that increase treatment efficacy by targeting mechanisms more directly, the current work examined potential distinctions in the neurophysiologies of escape and avoidance and tested how clinical anxiety affects these neurophysiologies.


      Twenty-five treatment-seeking individuals with varied principal diagnoses (e.g., generalized anxiety disorder, posttraumatic stress disorder) and 20 non-treatment-seeking control subjects participated. In the study task, approximately 5.25-second cues predicted aversive images that could be avoided (blocked by a button press before image onset), escaped (ended by a button press after image onset), or not controlled. To examine neural processing and defensive response modulation, anticipatory event-related potentials were derived, and startle reflexes were probed throughout each cue.


      Multidimensional profiles were observed such that 1) anticipatory event-related potential enhancement was only reliable during avoidance preparation, and event-related potentials potentially reflected perceived/instrumental control; and 2) startle reflexes were inhibited during avoidance preparation, relatively enhanced during escape preparation, and further enhanced during uncontrollable anticipation, thus potentially reflecting fear-related activation. Treatment-seeking status, then, did not affect cortical processing, but it did moderate context-dependent fear (if individuals with severe depression were excluded) such that treatment-seeking individuals without depression showed exaggerated startle during escape, but not avoidance, preparation.


      Data suggest a specific effect of anxiety on fear system activation during preparation to escape aversion. This effect warrants further investigation as a precision target for interventions that directly modulate the specific underlying neural circuitry.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Rauch S.
        • Foa E.
        Emotional processing theory (EPT) and exposure therapy for PTSD.
        J Contemp Psychother. 2006; 36: 61-65
        • Pittig A.
        • Treanor M.
        • LeBeau R.T.
        • Craske M.G.
        The role of associative fear and avoidance learning in anxiety disorders: Gaps and directions for future research.
        Neurosci Biobehav Rev. 2018; 88: 117-140
        • Treanor M.
        • Barry T.J.
        Treatment of avoidance behavior as an adjunct to exposure therapy: Insights from modern learning theory.
        Behav Res Ther. 2017; 96: 30-36
        • Eftekhari A.
        • Crowley J.J.
        • Mackintosh M.A.
        • Rosen C.S.
        Predicting treatment dropout among veterans receiving prolonged exposure therapy.
        Psychol Trauma. 2020; 12: 405-412
        • Treanor M.
        • Barry T.J.
        Treatment of avoidance behavior as an adjunct to exposure therapy: Insights from modern learning theory.
        Behav Res Ther. 2017; 96: 30-36
        • Hamm A.O.
        • Richter J.
        • Pané-Farré C.
        • Westphal D.
        • Wittchen H.U.
        • Vossbeck-Elsebusch A.N.
        • et al.
        Panic disorder with agoraphobia from a behavioral neuroscience perspective: Applying the research principles formulated by the Research Domain Criteria (RDoC) initiative.
        Psychophysiology. 2016; 53: 312-322
        • LeDoux J.E.
        • Moscarello J.
        • Sears R.
        • Campese V.
        The birth, death and resurrection of avoidance: A reconceptualization of a troubled paradigm.
        Mol Psychiatry. 2017; 22: 24-36
        • Walker D.L.
        • Cassella J.V.
        • Lee Y.
        • De Lima T.C.
        • Davis M.
        Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle.
        Neurosci Biobehav Rev. 1997; 21: 743-753
        • Menegas W.
        • Akiti K.
        • Amo R.
        • Uchida N.
        • Watabe-Uchida M.
        Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli.
        Nat Neurosci. 2018; 21: 1421-1430
        • Maia T.V.
        Two-factor theory, the actor-critic model, and conditioned avoidance.
        Learn Behav. 2010; 38: 50-67
        • Sege C.T.
        • Bradley M.M.
        • Lang P.J.
        Escaping aversive exposure.
        Psychophysiology. 2017; 54: 857-863
        • Sege C.T.
        • Bradley M.M.
        • Lang P.J.
        Avoidance and escape: Defensive reactivity and trait anxiety.
        Behav Res Ther. 2018; 104: 62-68
        • Lang P.J.
        • Davis M.
        Emotion, motivation, and the brain: Reflex foundations in animal and human research.
        Prog Brain Res. 2006; 156: 3-29
        • Luck S.J.
        An Introduction to the Event-Related Potential Technique.
        2nd ed. MIT press, Cambridge2014
        • Van Boxtel G.J.
        • Brunia C.H.
        Motor and non-motor aspects of slow brain potentials.
        Biol Psychol. 1994; 38: 37-51
        • Brunia C.H.
        • Van Boxtel G.J.M.
        Wait and see.
        Int J Psychophysiol. 2001; 43: 59-75
        • Piedimonte A.
        • Guerra G.
        • Vighetti S.
        • Carlino E.
        Measuring expectation of pain: Contingent negative variation in placebo and nocebo effects.
        Eur J Pain. 2017; 21: 874-885
        • Mühlberger C.
        • Angus D.J.
        • Jonas E.
        • Harmon-Jones C.
        • Harmon-Jones E.
        Perceived control increases the reward positivity and stimulus preceding negativity.
        Psychophysiology. 2017; 54: 310-322
        • Spielberger C.D.
        • Gorsuch R.L.
        • Lushene R.E.
        • Vagg P.R.
        • Jacobs G.A.
        Manual for the State-Trait Anxiety Inventory.
        Consulting Psychologists Press, Palo Alto, CA1983
        • Berchio C.
        • Rodrigues J.
        • Strasser A.
        • Michel C.M.
        • Sandi C.
        Trait anxiety on effort allocation to monetary incentives: A behavioral and high-density EEG study.
        Transl Psychiatry. 2019; 9: 174
        • Takashima S.
        • Najman F.A.
        • Ramos R.T.
        Disruption of volitional control in obsessive–compulsive disorder: Evidence from the bereitschaftspotential.
        Psychiatry Res Neuroimaging. 2019; 290: 30-37
        • Park J.
        • Moghaddam B.
        Impact of anxiety on prefrontal cortex encoding of cognitive flexibility.
        Neuroscience. 2017; 345: 193-202
        • Mineka S.
        • Oehlberg K.
        The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders.
        Acta Psychol (Amst). 2008; 127: 567-580
        • Beck A.T.
        • Steer R.A.
        • Brown G.K.
        2nd ed. Beck Depression Inventory (BDI-II). vol. 10. Psychological Corporation, San Antonio, Texas1996
        • Devins G.M.
        • Binik Y.M.
        • Hutchinson T.A.
        • Hollomby D.J.
        • Barre P.B.
        • Guttman R.D.
        The emotional impact of end-stage renal disease: Importance of patients’ perception of intrusiveness and control.
        Int J Psychiatric Med. 1983; 13: 327-343
        • Sheehan D.V.
        • Lecrubier Y.
        • Sheehan K.H.
        • Amorim P.
        • Janavs J.
        • Weiller E.
        • et al.
        The Mini-International Neuropsychiatric Interview (MINI): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
        J Clin Psychol. 1998; 59: 22-57
        • Dien J.
        The ERP PCA Toolkit: An open source program for advanced statistical analysis of event-related potential data.
        J Neurosci Methods. 2010; 187: 138-145
        • Dien J.
        Applying principal components analysis to event-related potentials: A tutorial.
        Dev Neuropsychol. 2012; 37: 497-517
        • Schupp H.T.
        • Cuthbert B.N.
        • Bradley M.M.
        • Birbaumer N.
        • Lang P.J.
        Probe P3 and blinks: Two measures of affective startle modulation.
        Psychophysiology. 1997; 34: 1-6
        • Jennings J.R.
        Editorial policy on analyses of variance with repeated measures.
        Psychophysiology. 1987; 24: 474-475
        • Keselman H.J.
        Testing treatment effects in repeated measures designs: An update for psychophysiological researchers.
        Psychophysiology. 1998; 35: 470-478
        • Ansari T.L.
        • Derakshan N.
        The neural correlates of cognitive effort in anxiety: Effects on processing efficiency.
        Biol Psychol. 2011; 86: 337-348
        • Judah M.R.
        • Grant D.M.
        • Mills A.C.
        • Lechner W.V.
        The neural correlates of impaired attentional control in social anxiety: An ERP study of inhibition and shifting.
        Emotion. 2013; 13: 1096-1106
        • Duan H.
        • Yuan Y.
        • Yang C.
        • Zhang L.
        • Zhang K.
        • Wu J.
        Anticipatory processes under academic stress: An ERP study.
        Brain Cogn. 2015; 94: 60-67
        • Dayan A.
        • Berger A.
        • Anholt G.E.
        Enhanced action tendencies in obsessive–compulsive disorder: An ERP study.
        Behav Res Ther. 2017; 93: 13-21
        • Wu Y.
        • Ma S.
        • He X.
        • Xiang S.
        • Qi S.
        Trait anxiety modulates the temporal dynamics of Stroop task switching: An ERP study.
        Biol Psychol. 2021; 163108144
        • Bradley M.M.
        • Codispoti M.
        • Cuthbert B.N.
        • Lang P.J.
        Emotion and motivation I: Defensive and appetitive reactions in picture processing.
        Emotion. 2001; 1: 276-298
        • McTeague L.M.
        • Lang P.J.
        The anxiety spectrum and the reflex physiology of defense: From circumscribed fear to broad distress.
        Depress Anxiety. 2012; 29: 264-281
        • Davis M.
        Neural systems involved in fear and anxiety measured with fear-potentiated startle.
        Am Psychol. 2006; 61: 741-756
        • Kuhn M.
        • Wendt J.
        • Sjouwerman R.
        • Büchel C.
        • Hamm A.
        • Lonsdorf T.B.
        The neurofunctional basis of affective startle modulation in humans: Evidence from combined facial electromyography and functional magnetic resonance imaging.
        Biol Psychiatry. 2020; 87: 548-558
        • Choi J.S.
        • Cain C.K.
        • LeDoux J.E.
        The role of amygdala nuclei in the expression of auditory signaled two-way active avoidance in rats.
        Learn Mem. 2010; 17: 139-147
        • Carver C.S.
        You want to measure coping but your protocol’s too long: Consider the brief COPE.
        Int J Behav Med. 1997; 4: 92-100
        • Motzkin J.C.
        • Philippi C.L.
        • Wolf R.C.
        • Baskaya M.K.
        • Koenigs M.
        Ventromedial prefrontal cortex is critical for the regulation of amygdala activity in humans.
        Biol Psychiatry. 2015; 77: 276-284
        • Terburg D.
        • Scheggia D.
        • Triana Del Rio R.
        • Klumpers F.
        • Ciobanu A.C.
        • Morgan B.
        • et al.
        The basolateral amygdala is essential for rapid escape: A human and rodent study.
        Cell. 2018; 175 (e16): 723-735
        • Lissek S.
        • Pine D.S.
        • Grillon C.
        The strong situation: A potential impediment to studying the psychobiology and pharmacology of anxiety disorders.
        Biol Psychol. 2006; 72: 265-270