Skip to main content Accessibility help

Reactivity to unpredictable threat as a treatment target for fear-based anxiety disorders

  • S. M. Gorka (a1), L. Lieberman (a2), H. Klumpp (a1), K. L. Kinney (a1) (a2), A. E. Kennedy (a1) (a3), O. Ajilore (a1), J. Francis (a1), J. Duffecy (a1), M. G. Craske (a4), J. Nathan (a1), S. Langenecker (a1), S. A. Shankman (a1) (a2) and K. L. Phan (a1) (a2) (a3) (a5)...



Heightened reactivity to unpredictable threat (U-threat) is a core individual difference factor underlying fear-based psychopathology. Little is known, however, about whether reactivity to U-threat is a stable marker of fear-based psychopathology or if it is malleable to treatment. The aim of the current study was to address this question by examining differences in reactivity to U-threat within patients before and after 12-weeks of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT).


Participants included patients with principal fear (n = 22) and distress/misery disorders (n = 29), and a group of healthy controls (n = 21) assessed 12-weeks apart. A well-validated threat-of-shock task was used to probe reactivity to predictable (P-) and U-threat and startle eyeblink magnitude was recorded as an index of defensive responding.


Across both assessments, individuals with fear-based disorders displayed greater startle magnitude to U-threat relative to healthy controls and distress/misery patients (who did not differ). From pre- to post-treatment, startle magnitude during U-threat decreased only within the fear patients who received CBT. Moreover, within fear patients, the magnitude of decline in startle to U-threat correlated with the magnitude of decline in fear symptoms. For the healthy controls, startle to U-threat across the two time points was highly reliable and stable.


Together, these results indicate that startle to U-threat characterizes fear disorder patients and is malleable to treatment with CBT but not SSRIs within fear patients. Startle to U-threat may therefore reflect an objective, psychophysiological indicator of fear disorder status and CBT treatment response.


Corresponding author

*Address for correspondence: S. M. Gorka, Ph.D., Department of Psychiatry, University of Illinois at Chicago, 1747 Roosevelt Road, Chicago, IL 60608, USA. (Email:


Hide All
Aiken, LS, West, SG, Reno, RR (1991). Multiple Regression: Testing and Interpreting Interactions. Sage: Newbury Park, CA.
Alvarez, RP, Chen, G, Bodurka, J, Kaplan, R, Grillon, C (2011). Phasic and sustained fear in humans elicits distinct patterns of brain activity. Neuroimage 1, 389400.
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders: DSM-5. American Psychiatric Association: Washington, DC.
Barlow, DH (2000). Unraveling the mysteries of anxiety and its disorders from the perspective of emotion theory. American Psychologist 55, 12471263.
Barlow, DH, Craske, MG (2006). Mastery of your Anxiety and Panic. Oxford University Press: New York.
Beck, AT (1979). Cognitive Therapy of Depression. Guilford Press: New York.
Blumenthal, TD, Cuthbert, BN, Filion, DL, Hackley, S, Lipp, OV, van Boxtel, A (2005). Committee report: guidelines for human startle eyeblink electromyographic studies. Psychophysiology 42, 115.
Bradley, MM, Cuthbert, BN, Lang, PJ (1999). Affect and the startle reflex. In Startle Modification: Implication for Neuroscience, Cognitive Science, and Clinical Science (ed. Dawson, M.E., Schell, A.M. and Bohmet, A.H.), pp. 157193. Cambridge University Press: New York.
Butler, AC, Chapman, JE, Forman, EM, Beck, AT (2006). The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clinical Psychology Review 26, 1731.
Carleton, RN (2012). The intolerance of uncertainty construct in the context of anxiety disorders: theoretical and practical perspectives. Expert Review of Neurotheraputics 12, 937947.
Carleton, RN (2016 a). Fear of the unknown: one fear to rule them all? Journal of Anxiety Disorders 41, 521.
Carleton, RN (2016 b). Into the Unknown: a review and synthesis of contemporary models involving uncertainty. Journal of Anxiety Disorders 39, 3043.
Clark, LA, Watson, D (2006). Distress and fear disorders: an alternative empirically based taxonomy of the ‘mood'and ‘anxiety'disorders. British Journal of Psychiatry 189, 481483.
Cuthbert, BN, Kozak, MJ (2013). Constructing constructs for psychopathology: the NIMH research domain criteria. Journal of Abnormal Psychology 122, 928937.
Craske, MG, Barlow, DH, O'Leary, TA (1992). Mastery of your Anxiety and Worry. Graywind Publications: Albany.
Davis, M (1998). Are different parts of the extended amygdala involved in fear versus anxiety? Biological Psychiatry 44, 12391247.
Davis, M (2006). Neural systems involved in fear and anxiety measured with fear-potentiated startle. American Psychologist 61, 741756.
Davis, M, Walker, DL, Miles, L, Grillon, C (2010). Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105135.
Gorka, SM, Lieberman, L, Shankman, SA, Phan, KL (2016). Startle potentiation to uncertain threat as a psychophysiological indicator of fear-based psychopathology: an examination across multiple internalizing disorders. Journal of Abnormal Psychology 126, 818.
Gorka, SM, Nelson, BD, Phan, KL, Shankman, SA (2014). Insula response to unpredictable and predictable aversiveness in individuals with panic disorder and comorbid depression. Biology of Mood and Anxiety Disorders 4, 1.
Gorka, SM, Nelson, BD, Shankman, SA (2013). Startle response to unpredictable threat in comorbid panic disorder and alcohol dependence. Drug and Alcohol Dependence 132, 216222.
Grillon, C, Baas, JP, Lissek, S, Smith, K, Milstein, J (2004). Anxious responses to predictable and unpredictable aversive events. Behavioral Neuroscience 118, 916924.
Grillon, C, Baas, JM, Pine, DS, Lissek, S, Lawley, M, Ellis, V, Levine, J (2006). The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biological Psychiatry 60, 760766.
Grillon, C, Chavis, C, Covington, MF, Pine, DS (2009 a). Two-week treatment with the selective serotonin reuptake inhibitor citalopram reduces contextual anxiety but not cued fear in healthy volunteers: a fear-potentiated startle study. Neuropsychopharmacology 34, 964971.
Grillon, C, Heller, R, Hirschhorn, E, Kling, MA, Pine, DS, Schulkin, J, Vythilingam, M (2011). Acute hydrocortisone treatment increases anxiety but not fear in healthy volunteers: a fear-potentiated startle study. Biological Psychiatry 69, 549555.
Grillon, C, Lissek, S, Rabin, S, McDowell, D, Dvir, S, Pine, DS (2008). Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as psychophysiologic marker of panic disorder. American Journal of Psychiatry 165, 898904.
Grillon, C, Pine, DS, Lissek, S, Rabin, S, Bonne, O, Vythilingam, M (2009 b). Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biological Psychiatry 66, 4753.
Grupe, DW, Nitschke, JB (2013). Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nature Reviews Neuroscience 14, 488501.
Guy, W (1976). ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs: Rockville, MD, Vol. 76, No. 338.
Hamilton, M (1959). The assesment of anxiety states by rating. British Journal of Medical Psychology 32, 5055.
Hamilton, M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, & Psychiatry 23, 5662.
Hettema, JM, Prescott, CA, Myers, JM, Neale, MC, Kendler, KS (2005). The structure of genetic and environmental risk factors for anxiety disorders in men and women. Archives of General Psychiatry 62, 182189.
Hieronymus, F, Emilsson, JF, Nilsson, S, Eriksson, E (2016). Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Molecular Psychiatry 21, 523530.
Johnsen, TJ, Friborg, O (2015). The effects of cognitive behavioral therapy as an anti-depressive treatment Is falling: a meta-analysis. Psychological Bulletin 141, 747768.
Kaye, JT, Bradford, DE, Curtin, JJ (2016). Psychometric properties of startle and corrugator response in NPU, affective picture viewing, and resting state tasks. Psychophysiology 53, 12411255.
Kendler, KS, Prescott, CA, Myers, J, Neale, MC (2003). The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry 60, 929937.
Kennedy, SH, Konarski, JZ, Segal, ZV, Lau, MA, Bieling, PJ, McIntyre, RS, Mayberg, HS (2007). Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. American Journal of Psychiatry 164, 778788.
Kozak, MJ, Cuthbert, BN (2016). The NIMH research domain criteria initiative: background, issues, and pragmatics. Psychophysiology 53, 286297.
Lieberman, L, Gorka, SM, Shankman, SA, Phan, KL (2017). Impact of panic on psychophysiological and neural reactivity to unpredictable threat in depression and anxiety. Clinical Psychological Science 5, 5263.
Lovibond, SH, Lovibond, PF (1995). Manual for the Depression Anxiety Stress scale, 2nd edn. Psychology Foundation: Sydney.
Morris, SE, Cuthbert, BN (2012). Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior. Dialogues in Clinical Neuroscience 14, 2937.
Münsterkötter, AL, Notzon, S, Redlich, R, Grotegerd, D, Dohm, K, Arolt, V, Kugel, H, Zwanzger, P, Dannlowski, U (2015). Spider or no spider? Neural correlates of sustained and phasic fear in spider phobia. Depression and Anxiety 32, 656663.
Nelson, BD, McGowan, SK, Sarapas, C, Robison-Andrew, EJ, Altman, SE, Campbell, ML, Gorka, SM, Katz, A, Shankman, SA (2013). Biomarkers of threat and reward sensitivity demonstrate unique associations with risk for psychopathology. Journal of Abnormal Psychology 122, 662671.
Sanislow, CA, Pine, DS, Quinn, KJ, Kozak, MJ, Garvey, MA, Heinssen, RK, Wang, PS, Cuthbert, BN (2010). Developing constructs for psychopathology research: research domain criteria. Journal of Abnormal Psychology 119, 631639.
Schmitz, A, Grillon, C (2012). Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test). Nature Protocols 7, 527532.
Shankman, SA, Nelson, BD, Sarapas, C, Robison-Andrew, EJ, Campbell, ML, Altman, SE, McGowan, SK, Katz, AC, Gorka, SM (2013). A psychophysiological investigation of reward and threat sensitivity in individuals with depression and/or panic disorder. Journal of Abnormal Psychology 122, 322338.
Simmons, AN, Flagan, TM, Wittmann, M, Strigo, IA, Matthews, SC, Donovan, H, Lohr, JB, Paulus, MP (2013). The effects of temporal unpredictability in anticipation of negative events in combat veterans with PTSD. Journal of Affective Disorders 146, 426432.
Soto, CJ, Tackett, JL (2015). Personality traits in childhood and adolescence structure, development, and outcomes. Current Directions in Psychological Science 24, 358362.
Watson, D (2009). Differentiating the mood and anxiety disorders: a quadripartite model. Annual Review of Clinical Psychology 5, 221247.
Watson, D, O'Hara, MW, Naragon-Gainey, K, Koffel, E, Chmielewski, M, Kotov, R, Stasik, SM, Ruggero, CJ (2012). Development and validation of new anxiety and bipolar symptom scales for an expanded version of the IDAS (the IDAS-II). Assessment 19, 399420.


Reactivity to unpredictable threat as a treatment target for fear-based anxiety disorders

  • S. M. Gorka (a1), L. Lieberman (a2), H. Klumpp (a1), K. L. Kinney (a1) (a2), A. E. Kennedy (a1) (a3), O. Ajilore (a1), J. Francis (a1), J. Duffecy (a1), M. G. Craske (a4), J. Nathan (a1), S. Langenecker (a1), S. A. Shankman (a1) (a2) and K. L. Phan (a1) (a2) (a3) (a5)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed