Behavioral and Magnetoencephalographic Correlates of Fear Generalization Are Associated With Responses to Later Virtual Reality Exposure Therapy in Spider Phobia



      Because overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pretreatment levels of fear generalization in spider-phobic patients are related to their response to exposure-based treatment to identify pretreatment moderators of treatment success.


      A total of 90 patients with spider phobia completed pretreatment clinical and magnetoencephalography assessments, one session of virtual reality exposure therapy, and a posttreatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms), they were categorized as responders or nonresponders. In a pretreatment magnetoencephalography fear generalization paradigm involving fear conditioning with 2 unconditioned stimuli (UCS), we obtained fear ratings, UCS expectancy ratings, and event-related fields to conditioned stimuli (CS: CS−, CS+) and 7 different generalization stimuli on a perceptual continuum from CS− to CS+.


      Before treatment, nonresponders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of magnetoencephalography source estimations revealed that nonresponders showed a decline of their (inhibitory) frontal activations to safety-signaling CS− and generalization stimuli compared with CS+ over time, while responders maintained these activations at early (<300 ms) and late processing stages.


      Results provide initial evidence that pretreatment differences of behavioral and neural markers of fear generalization may act as moderators of later responses to behavioral exposure. Stimulating further research on fear generalization as a potential predictive marker, our findings are an important first step in the attempt to identify patients who may not benefit from exposure therapy and to personalize and optimize treatment strategies for this vulnerable patient group.


      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'


        • Bandelow B.
        • Wiltink J.
        • Alpers G.W.
        • Benecke C.
        • Deckert J.
        • Eckhardt-Henn A.
        • et al.
        Deutsche S3-Leitlinie Behandlung von Angststörungen.
        Universität Mannheim, Düsseldorf2014
        • Loerinc A.G.
        • Meuret A.E.
        • Twohig M.P.
        • Rosenfield D.
        • Bluett E.J.
        • Craske M.G.
        Response rates for CBT for anxiety disorders: Need for standardized criteria.
        Clin Psychol Rev. 2015; 42: 72-82
        • Böhnlein J.
        • Altegoer L.
        • Muck N.K.
        • Roesmann K.
        • Redlich R.
        • Dannlowski U.
        • et al.
        Factors influencing the success of exposure therapy for specific phobia: A systematic review.
        Neurosci Biobehav Rev. 2020; 108: 796-820
        • Craske M.G.
        • Liao B.
        • Brown L.
        • Vervliet B.
        Role of inhibition in exposure therapy.
        J Exp Psychopathol. 2012; 3: 322-345
        • Bouton M.E.
        • Moody E.W.
        Memory processes in classical conditioning.
        Neurosci Biobehav Rev. 2004; 28: 663-674
        • Lonsdorf T.B.
        • Merz C.J.
        More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls.
        Neurosci Biobehav Rev. 2017; 80: 703-728
        • Jovanovic T.
        • Kazama A.
        • Bachevalier J.
        • Davis M.
        Impaired safety signal learning may be a biomarker of PTSD.
        Neuropharmacology. 2012; 62: 695-704
        • Lissek S.
        • Powers A.S.
        • McClure E.B.
        • Phelps E.A.
        • Woldehawariat G.
        • Grillon C.
        • Pine D.S.
        Classical fear conditioning in the anxiety disorders: A meta-analysis.
        Behav Res Ther. 2005; 43: 1391-1424
        • Duits P.
        • Cath D.C.
        • Lissek S.
        • Hox J.J.
        • Hamm A.O.
        • Engelhard I.M.
        • et al.
        Updated meta-analysis of classical fear conditioning in the anxiety disorders.
        Depress Anxiety. 2015; 32: 239-253
        • Lissek S.
        • Rabin S.
        • Heller R.E.
        • Lukenbaugh D.
        • Geraci M.
        • Pine D.S.
        • Grillon C.
        Overgeneralization of conditioned fear as a pathogenic marker of panic disorder.
        Am J Psychiatry. 2010; 167: 47-55
        • Lissek S.
        • Kaczkurkin A.N.
        • Rabin S.
        • Geraci M.
        • Pine D.S.
        • Grillon C.
        Generalized anxiety disorder is associated with overgeneralization of classically conditioned fear.
        Biol Psychiatry. 2014; 75: 909-915
        • Dunsmoor J.E.
        • Paz R.
        Fear generalization and anxiety: Behavioral and neural mechanisms.
        Biol Psychiatry. 2015; 78: 336-343
        • Dymond S.
        • Dunsmoor J.E.
        • Vervliet B.
        • Roche B.
        • Hermans D.
        Fear generalization in humans: Systematic review and implications for anxiety disorder research.
        Behav Ther. 2015; 46: 561-582
        • McTeague L.M.
        • Gruss L.F.
        • Keil A.
        Aversive learning shapes neuronal orientation tuning in human visual cortex.
        Nat Commun. 2015; 6: 7823
        • Greenberg T.
        • Carlson J.M.
        • Cha J.
        • Hajcak G.
        • Mujica-Parodi L.R.
        Neural reactivity tracks fear generalization gradients.
        Biol Psychol. 2013; 92: 2-8
        • Dymond S.
        • Schlund M.W.
        • Roche B.
        • Whelan R.
        The spread of fear: Symbolic generalization mediates graded threat-avoidance in specific phobia.
        Q J Exp Psychol (Hove). 2014; 67: 247-259
        • Hartley C.A.
        • Phelps E.A.
        Changing fear: The neurocircuitry of emotion regulation.
        Neuropsychopharmacology. 2010; 35: 136-146
        • Dunsmoor J.E.
        • Prince S.E.
        • Murty V.P.
        • Kragel P.A.
        • LaBar K.S.
        Neurobehavioral mechanisms of human fear generalization.
        Neuroimage. 2011; 55: 1878-1888
        • Onat S.
        • Büchel C.
        The neuronal basis of fear generalization in humans.
        Nat Neurosci. 2015; 18: 1811-1818
        • Lissek S.
        • Bradford D.E.
        • Alvarez R.P.
        • Burton P.
        • Espensen-Sturges T.
        • Reynolds R.C.
        • Grillon C.
        Neural substrates of classically conditioned fear-generalization in humans: A parametric fMRI study.
        Soc Cogn Affect Neurosci. 2014; 9: 1134-1142
        • Greenberg T.
        • Carlson J.M.
        • Cha J.
        • Hajcak G.
        • Mujica-Parodi L.R.
        Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization.
        Depress Anxiety. 2013; 30: 242-250
        • Landowska A.
        • Roberts D.
        • Eachus P.
        • Barrett A.
        Within- and between-session prefrontal cortex response to virtual reality exposure therapy for acrophobia.
        Front Hum Neurosci. 2018; 12: 362
        • Roesmann K.
        • Wiens N.
        • Winker C.
        • Rehbein M.A.
        • Wessing I.
        • Junghoefer M.
        Fear generalization of implicit conditioned facial features - Behavioral and magnetoencephalographic correlates.
        Neuroimage. 2020; 205: 116302
        • Hajcak G.
        • Nieuwenhuis S.
        Reappraisal modulates the electrocortical response to unpleasant pictures.
        Cogn Affect Behav Neurosci. 2006; 6: 291-297
        • Ball T.M.
        • Knapp S.E.
        • Paulus M.P.
        • Stein M.B.
        Brain activation during fear extinction predicts exposure success.
        Depress Anxiety. 2017; 34: 257-266
        • Lange I.
        • Goossens L.
        • Michielse S.
        • Bakker J.
        • Vervliet B.
        • Marcelis M.
        • et al.
        Neural responses during extinction learning predict exposure therapy outcome in phobia: Results from a randomized-controlled trial.
        Neuropsychopharmacology. 2020; 45: 534-541
        • Waters A.M.
        • Pine D.S.
        Evaluating differences in Pavlovian fear acquisition and extinction as predictors of outcome from cognitive behavioural therapy for anxious children.
        J Child Psychol Psychiatry. 2016; 57: 869-876
        • Schwarzmeier H.
        • Leehr E.J.
        • Böhnlein J.
        • Seeger F.R.
        • Roesmann K.
        • Gathmann B.
        • et al.
        Theranostic markers for personalized therapy of spider phobia: Methods of a bicentric external cross-validation machine learning approach.
        Int J Methods Psychiatr Res. 2020; 29: e1812
      1. Wittchen H-U, Wunderlich U, Gruschwitz S, Zaudig M (1997): SKID-I: Strukturiertes Klinisches Interview für DSM-IV. Achse I: Psychische Störungen. Interviewheft und Beurteilungsheft. Eine deutschsprachige, erweiterte Bearb. d. amerikanischen Originalversion des SKID I. Göttingen: Hogrefe.eDoc: 396152.

        • Rinck M.
        • Bundschuh S.
        • Engler S.
        • Muller A.
        • Wissmann J.
        • Ellwart T.
        • Becker E.S.
        Reliability and validity of German versions of three instruments measuring fear of spiders.
        Diagnostica. 2002; 48: 141-149
        • Tottenham N.
        • Tanaka J.W.
        • Leon A.C.
        • McCarry T.
        • Nurse M.
        • Hare T.A.
        • et al.
        The NimStim set of facial expressions: Judgments from untrained research participants.
        Psychiatry Res. 2009; 168: 242-249
        • Bradley M.M.
        • Lang P.J.
        International affective digitized sounds (IADS): Stimuli, instruction manual and affective ratings (Tech. Rep. No. B-2).
        The Center for Research in Psychophysiology, University of Florida, Gainesville1999
        • Schubert T.W.
        The sense of presence in virtual environments: A three-component scale measuring spatial presence, involvement, and realness.
        Z für Medienpsychologie. 2003; 15: 69-71
        • Lonsdorf T.B.
        • Menz M.M.
        • Andreatta M.
        • Fullana M.A.
        • Golkar A.
        • Haaker J.
        • et al.
        Don’t fear ‘fear conditioning’: Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.
        Neurosci Biobehav Rev. 2017; 77: 247-285
        • Maris E.
        • Oostenveld R.
        Nonparametric statistical testing of EEG- and MEG-data.
        J Neurosci Methods. 2007; 164: 177-190
        • Leehr E.J.
        • Roesmann K.
        • Böhnlein J.
        • Dannlowski U.
        • Gathmann B.
        • Herrmann M.J.
        • et al.
        Clinical predictors of treatment response towards exposure therapy in virtuo in spider phobia: A machine learning and external cross-validation approach.
        J Anxiety Disord. 2021; 83: 102448
        • Balderston N.L.
        • Hsiung A.
        • Ernst M.
        • Grillon C.
        Effect of threat on right dlPFC activity during behavioral pattern separation.
        J Neurosci. 2017; 37: 9160-9171
        • Lueken U.
        • Zierhut K.C.
        • Hahn T.
        • Straube B.
        • Kircher T.
        • Reif A.
        • et al.
        Neurobiological markers predicting treatment response in anxiety disorders: A systematic review and implications for clinical application.
        Neurosci Biobehav Rev. 2016; 66: 143-162
        • Poldrack R.A.
        • Huckins G.
        • Varoquaux G.
        Establishment of best practices for evidence for prediction: A review.
        JAMA Psychiatry. 2020; 77: 534-540
        • Schweckendiek J.
        • Klucken T.
        • Merz C.J.
        • Tabbert K.
        • Walter B.
        • Ambach W.
        • et al.
        Weaving the (neuronal) web: Fear learning in spider phobia.
        Neuroimage. 2011; 54: 681-688
        • Andreatta M.
        • Leombruni E.
        • Glotzbach-Schoon E.
        • Pauli P.
        • Mühlberger A.
        Generalization of contextual fear in humans.
        Behav Ther. 2015; 46: 583-596
        • Vanbrabant K.
        • Boddez Y.
        • Verduyn P.
        • Mestdagh M.
        • Hermans D.
        • Raes F.
        A new approach for modeling generalization gradients: A case for hierarchical models.
        Front Psychol. 2015; 6: 652