Threat Neurocircuitry Predicts the Development of Anxiety and Depression Symptoms in a Longitudinal Study

  • Author Footnotes
    1 YP and JDK contributed equally to this work.
    Yujia Peng
    1 YP and JDK contributed equally to this work.
    School of Psychological and Cognitive Sciences and Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China

    Institute for Artificial Intelligence, Peking University, Beijing, China

    Beijing Institute for General Artificial Intelligence, Beijing, China

    Department of Psychology, University of California, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Author Footnotes
    1 YP and JDK contributed equally to this work.
    Jeffrey D. Knotts
    1 YP and JDK contributed equally to this work.
    Department of Psychology, University of California, Los Angeles, Los Angeles, California

    Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire
    Search for articles by this author
  • Katherine S. Young
    Department of Psychology, University of California, Los Angeles, Los Angeles, California

    Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

    NIHR Maudsley Biomedical Research Centre, King’s College London, London, United Kingdom
    Search for articles by this author
  • Susan Y. Bookheimer
    Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Robin Nusslock
    Department of Psychology, Northwestern University, Evanston, Illinois
    Search for articles by this author
  • Richard E. Zinbarg
    Department of Psychology, Northwestern University, Evanston, Illinois

    Family Institute at Northwestern University, Evanston, Illinois
    Search for articles by this author
  • Nicholas J. Kelley
    Department of Psychology, Northwestern University, Evanston, Illinois

    Department of Psychology, University of Southampton, Southampton, United Kingdom
    Search for articles by this author
  • Aileen M. Echiverri-Cohen
    Department of Psychology, University of California, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Michelle G. Craske
    Address correspondence to Michelle G. Craske, Ph.D.
    Department of Psychology, University of California, Los Angeles, Los Angeles, California

    Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Author Footnotes
    1 YP and JDK contributed equally to this work.
Published:January 11, 2022DOI:



      Owing to high heterogeneity and comorbidity, the shared and unique neural mechanisms underlying the development of anxiety and major depressive disorders remain unclear. Using a dimensional model describing shared versus unique symptoms associated with anxiety and depression, this study investigated how longitudinal changes in symptom dimensions relate to threat neurocircuitry.


      Participants were 18- to 19-year-olds (N = 279, 186 females) who completed self-report measures of anxiety and depression at baseline and at 10, 20, and 30 months. Linear slopes of symptom dimensions of general distress, fear, and anhedonia-apprehension were estimated through a trilevel factorial model. In addition, functional magnetic resonance imaging scans were obtained while participants performed Pavlovian fear conditioning tasks at baseline and 30 months, including three phases of fear acquisition, extinction, and extinction recall. Neural responses in regions of interest related to threat neural circuitry (e.g., amygdala, ventromedial prefrontal cortex, and subgenual anterior cingulate cortex) were extracted.


      Linear mixed models used to estimate relationships between changes of symptom dimensions and neural responses revealed two major findings: 1) greater neural responses to threatening stimuli during fear acquisition at baseline were associated with a greater increase in fear symptoms during the 30-month prospective period; and 2) elevated neural responses to the extinguished stimulus during extinction recall at 30 months were negatively associated with changes in general distress, suggesting that greater increases in general distress are associated with larger deficits in extinction memory.


      These findings improve our understanding of pathophysiological pathways underlying the development of anxiety and depression, while separating symptom dimensions that are shared versus unique between the two disorders.


      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'


        • 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
        • 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
        • 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
        • 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
        • Dvir M.
        • Horovitz O.
        • Aderka I.M.
        • Shechner T.
        Fear conditioning and extinction in anxious and non-anxious youth: A meta-analysis.
        Behav Res Ther. 2019; 120: 103431
        • McGregor T.
        • Purves K.L.
        • Constantinou E.
        • Baas J.M.P.
        • Barry T.J.
        • Carr E.
        • et al.
        Large-scale remote fear conditioning: Demonstration of associations with anxiety using the FLARe smartphone app.
        Depress Anxiety. 2021; 38: 719-730
        • Etkin A.
        • Wager T.D.
        Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.
        Am J Psychiatry. 2007; 164: 1476-1488
        • Brühl A.B.
        • Delsignore A.
        • Komossa K.
        • Weidt S.
        Neuroimaging in social anxiety disorder—A meta-analytic review resulting in a new neurofunctional model.
        Neurosci Biobehav Rev. 2014; 47: 260-280
        • Craske M.G.
        • Stein M.B.
        • Eley T.C.
        • Milad M.R.
        • Holmes A.
        • Rapee R.M.
        • Wittchen H.U.
        Anxiety disorders [published correction appears in Nat Rev Dis Primers 2017; 3:17100].
        Nat Rev Dis Primers. 2017; 3: 17024
        • Drevets W.C.
        Neuroimaging studies of mood disorders.
        Biol Psychiatry. 2000; 48: 813-829
        • Schiller D.
        • Levy I.
        • Niv Y.
        • LeDoux J.E.
        • Phelps E.A.
        From fear to safety and back: Reversal of fear in the human brain.
        J Neurosci. 2008; 28: 11517-11525
        • Schiller D.
        • Delgado M.R.
        Overlapping neural systems mediating extinction, reversal and regulation of fear.
        Trends Cogn Sci. 2010; 14: 268-276
        • Fullana M.A.
        • Harrison B.J.
        • Soriano-Mas C.
        • Vervliet B.
        • Cardoner N.
        • Àvila-Parcet A.
        • Radua J.
        Neural signatures of human fear conditioning: An updated and extended meta-analysis of fMRI studies.
        Mol Psychiatry. 2016; 21: 500-508
        • Harrison B.J.
        • Fullana M.A.
        • Via E.
        • Soriano-Mas C.
        • Vervliet B.
        • Martínez-Zalacaín I.
        • et al.
        Human ventromedial prefrontal cortex and the positive affective processing of safety signals.
        Neuroimage. 2017; 152: 12-18
        • Fullana M.A.
        • Albajes-Eizagirre A.
        • Soriano-Mas C.
        • Vervliet B.
        • Cardoner N.
        • Benet O.
        • et al.
        Fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants.
        Neurosci Biobehav Rev. 2018; 88: 16-25
        • Dunsmoor J.E.
        • Kroes M.C.W.
        • Li J.
        • Daw N.D.
        • Simpson H.B.
        • Phelps E.A.
        Role of human ventromedial prefrontal cortex in learning and recall of enhanced extinction.
        J Neurosci. 2019; 39: 3264-3276
        • Battaglia S.
        • Garofalo S.
        • di Pellegrino G.
        • Starita F.
        Revaluing the role of vmPFC in the acquisition of Pavlovian threat conditioning in humans.
        J Neurosci. 2020; 40: 8491-8500
        • Shackman A.J.
        • Fox A.S.
        Contributions of the central extended amygdala to fear and anxiety.
        J Neurosci. 2016; 36: 8050-8063
        • Phelps E.A.
        • Delgado M.R.
        • Nearing K.I.
        • LeDoux J.E.
        Extinction learning in humans: Role of the amygdala and vmPFC.
        Neuron. 2004; 43: 897-905
        • Milad M.R.
        • Wright C.I.
        • Orr S.P.
        • Pitman R.K.
        • Quirk G.J.
        • Rauch S.L.
        Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert.
        Biol Psychiatry. 2007; 62: 446-454
        • Delgado M.R.
        • Nearing K.I.
        • Ledoux J.E.
        • Phelps E.A.
        Neural circuitry underlying the regulation of conditioned fear and its relation to extinction.
        Neuron. 2008; 59: 829-838
        • Sheline Y.I.
        • Barch D.M.
        • Donnelly J.M.
        • Ollinger J.M.
        • Snyder A.Z.
        • Mintun M.A.
        Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study.
        Biol Psychiatry. 2001; 50: 651-658
        • Siegle G.J.
        • Steinhauer S.R.
        • Thase M.E.
        • Stenger V.A.
        • Carter C.S.
        Can’t shake that feeling: Event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals [published correction appears in Biol Psychiatry 2002; 52:771].
        Biol Psychiatry. 2002; 51: 693-707
        • Dannlowski U.
        • Ohrmann P.
        • Bauer J.
        • Kugel H.
        • Arolt V.
        • Heindel W.
        • et al.
        Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: A 3 T fMRI study.
        J Psychiatry Neurosci. 2007; 32: 423-429
        • Koenigs M.
        • Grafman J.
        The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex.
        Behav Brain Res. 2009; 201: 239-243
        • Prenoveau J.M.
        • Zinbarg R.E.
        • Craske M.G.
        • Mineka S.
        • Griffith J.W.
        • Epstein A.M.
        Testing a hierarchical model of anxiety and depression in adolescents: A tri-level model.
        J Anxiety Disord. 2010; 24: 334-344
        • de Vos S.
        • Wardenaar K.J.
        • Bos E.H.
        • Wit E.C.
        • de Jonge P.
        Decomposing the heterogeneity of depression at the person-, symptom-, and time-level: Latent variable models versus multimode principal component analysis.
        BMC Med Res Methodol. 2015; 15: 88
        • Krueger R.F.
        • Kotov R.
        • Watson D.
        • Forbes M.K.
        • Eaton N.R.
        • Ruggero C.J.
        • et al.
        Progress in achieving quantitative classification of psychopathology.
        World Psychiatry. 2018; 17: 282-293
        • Eisenberg I.W.
        • Bissett P.G.
        • Zeynep Enkavi A.
        • Li J.
        • MacKinnon D.P.
        • Marsch L.A.
        • Poldrack R.A.
        Uncovering the structure of self-regulation through data-driven ontology discovery.
        Nat Commun. 2019; 10: 2319
        • Peng Y.
        • Knotts J.D.
        • Taylor C.T.
        • Craske M.G.
        • Stein M.B.
        • Bookheimer S.
        • et al.
        Failure to identify robust latent variables of positive or negative valence processing across units of analysis.
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2021; 6: 518-526
        • Naragon-Gainey K.
        • Prenoveau J.M.
        • Brown T.A.
        • Zinbarg R.E.
        A comparison and integration of structural models of depression and anxiety in a clinical sample: Support for and validation of the tri-level model.
        J Abnorm Psychol. 2016; 125: 853-867
        • Young K.S.
        • Bookheimer S.Y.
        • Nusslock R.
        • Zinbarg R.E.
        • Damme K.S.F.
        • Chat I.K.Y.
        • et al.
        Dysregulation of threat neurociruitry during fear extinction: The role of anhedonia.
        Neuropsychopharmacology. 2021; 46: 1650-1657
        • Kramer A.M.
        • Kelley N.J.
        • Chat I.K.Y.
        • Young K.S.
        • Nusslock R.
        • Craske M.G.
        • Zinbarg R.
        Replication of a tri-level model of anxiety and depression in a sample of young adults.
        PsyArXiv. 2019;
        • He Y.
        • Song N.
        • Xiao J.
        • Cui L.
        • McWhinnie C.M.
        Levels of neuroticism differentially predict individual scores in the depression and anxiety dimensions of the tripartite model: A multiwave longitudinal study.
        Stress Health. 2018; 34: 435-439
        • Williams A.L.
        • Craske M.G.
        • Mineka S.
        • Zinbarg R.E.
        Neuroticism and the longitudinal trajectories of anxiety and depressive symptoms in older adolescents.
        J Abnorm Psychol. 2021; 130: 126-140
        • Wardenaar K.J.
        • van Veen T.
        • Giltay E.J.
        • Zitman F.G.
        • Penninx B.W.J.H.
        The use of symptom dimensions to investigate the longitudinal effects of life events on depressive and anxiety symptomatology.
        J Affect Disord. 2014; 156: 126-133
        • Besteher B.
        • Gaser C.
        • Nenadić I.
        Brain structure and subclinical symptoms: A dimensional perspective of psychopathology in the depression and anxiety spectrum.
        Neuropsychobiology. 2020; 79: 270-283
        • Geer J.H.
        The development of a scale to measure fear.
        Behav Res Ther. 1965; 3: 45-53
        • Rapee R.M.
        • Craske M.G.
        • Barlow D.H.
        Assessment instrument for panic disorder that includes fear of sensation-producing activities: The Albany Panic and Phobia Questionnaire.
        Anxiety. 1994-1995; 1: 114-122
        • Mattick R.P.
        • Clarke J.C.
        Development and validation of measures of social phobia scrutiny fear and social interaction anxiety.
        Behav Res Ther. 1998; 36: 455-470
        • Zinbarg R.E.
        • Barlow D.H.
        Structure of anxiety and the anxiety disorders: A hierarchical model.
        J Abnorm Psychol. 1996; 105: 181-193
        • Zimmerman M.
        • Coryell W.
        • Corenthal C.
        • Wilson S.
        A self-report scale to diagnose major depressive disorder.
        Arch Gen Psychiatry. 1986; 43: 1076-1081
        • Watson D.
        • Weber K.
        • Assenheimer J.S.
        • Clark L.A.
        • Strauss M.E.
        • McCormick R.A.
        Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales.
        J Abnorm Psychol. 1995; 104: 3-14
        • Meyer T.J.
        • Miller M.L.
        • Metzger R.L.
        • Borkovec T.D.
        Development and validation of the Penn State Worry Questionnaire.
        Behav Res Ther. 1990; 28: 487-495
        • Foa E.B.
        • Huppert J.D.
        • Leiberg S.
        • Langner R.
        • Kichic R.
        • Hajcak G.
        • Salkovskis P.M.
        The obsessive-compulsive Inventory: Development and validation of a short version.
        Psychol Assess. 2002; 14: 485-496
        • Treanor M.
        • Rosenberg B.M.
        • Craske M.G.
        Pavlovian learning processes in pediatric anxiety disorders: A critical review.
        Biol Psychiatry. 2021; 89: 690-696
        • Avery S.N.
        • Clauss J.A.
        • Winder D.G.
        • Woodward N.
        • Heckers S.
        • Blackford J.U.
        BNST neurocircuitry in humans.
        Neuroimage. 2014; 91: 311-323
        • Cohen J.
        • Cohen P.
        • West S.G.
        • Aiken L.S.
        Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences.
        Psychology Press, New York2014
        • Winkler A.M.
        • Ridgway G.R.
        • Webster M.A.
        • Smith S.M.
        • Nichols T.E.
        Permutation inference for the general linear model.
        Neuroimage. 2014; 92: 381-397
        • Wen Z.
        • Chen Z.S.
        • Milad M.R.
        Fear extinction learning modulates large-scale brain connectivity.
        Neuroimage. 2021; 238: 118261
        • Garcia R.
        • Vouimba R.M.
        • Baudry M.
        • Thompson R.F.
        The amygdala modulates prefrontal cortex activity relative to conditioned fear.
        Nature. 1999; 402: 294-296
        • Rauch S.L.
        • Whalen P.J.
        • Shin L.M.
        • McInerney S.C.
        • Macklin M.L.
        • Lasko N.B.
        • et al.
        Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: A functional MRI study.
        Biol Psychiatry. 2000; 47: 769-776
        • Britton J.C.
        • Phan K.L.
        • Taylor S.F.
        • Fig L.M.
        • Liberzon I.
        Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery.
        Biol Psychiatry. 2005; 57: 832-840
        • Straube T.
        • Mentzel H.J.
        • Glauer M.
        • Miltner W.H.R.
        Brain activation to phobia-related words in phobic subjects.
        Neurosci Lett. 2004; 372: 204-208
        • LeDoux J.E.
        • Pine D.S.
        Using neuroscience to help understand fear and anxiety: A two-system framework.
        Am J Psychiatry. 2016; 173: 1083-1093
        • Taschereau-Dumouchel V.
        • Cortese A.
        • Chiba T.
        • Knotts J.D.
        • Kawato M.
        • Lau H.
        Towards an unconscious neural reinforcement intervention for common fears.
        Proc Natl Acad Sci U S A. 2018; 115: 3470-3475
        • Quirk G.J.
        • Repa C.
        • LeDoux J.E.
        Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: Parallel recordings in the freely behaving rat.
        Neuron. 1995; 15: 1029-1039
        • Quirk G.J.
        • Armony J.L.
        • LeDoux J.E.
        Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala.
        Neuron. 1997; 19: 613-624
        • Armony J.L.
        • Quirk G.J.
        • LeDoux J.E.
        Differential effects of amygdala lesions on early and late plastic components of auditory cortex spike trains during fear conditioning.
        J Neurosci. 1998; 18: 2592-2601
        • Quirk G.J.
        • Russo G.K.
        • Barron J.L.
        • Lebron K.
        The role of ventromedial prefrontal cortex in the recovery of extinguished fear.
        J Neurosci. 2000; 20: 6225-6231
        • Marin M.F.
        • Zsido R.G.
        • Song H.
        • Lasko N.B.
        • Killgore W.D.S.
        • Rauch S.L.
        • et al.
        Skin conductance responses and neural activations during fear conditioning and extinction recall across anxiety disorders.
        JAMA Psychiatry. 2017; 74: 622-631
        • Bouton M.E.
        Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction.
        Biol Psychiatry. 2002; 52: 976-986
        • Vinograd M.
        • Williams A.
        • Sun M.
        • Bobova L.
        • Wolitzky-Taylor K.B.
        • Vrshek-Schallhorn S.
        • et al.
        Neuroticism and interpretive bias as risk factors for anxiety and depression.
        Clin Psychol Sci. 2020; 8: 641-656
        • Blaney P.H.
        Affect and memory: A review.
        Psychol Bull. 1986; 99: 229-246
        • Clark D.M.
        • Teasdale J.D.
        Diurnal variation in clinical depression and accessibility of memories of positive and negative experiences.
        J Abnorm Psychol. 1982; 91: 87-95
        • Diener E.
        • Larsen R.J.
        • Emmons R.A.
        Bias in mood recall in happy and unhappy persons.
        in: Presented at the 92nd Annual Meeting of the American Psychological Association, August 24–28, Toronto, Ontario, Canada. 1984
        • DeMonbreun B.G.
        • Craighead W.E.
        Distortion of perception and recall of positive and neutral feedback in depression.
        Cogn Ther Res. 1977; 1: 311-329
        • Gotlib I.H.
        Perception and recall of interpersonal feedback: Negative bias in depression.
        Cogn Ther Res. 1983; 7: 399-412
        • Ridout N.
        • Astell A.
        • Reid I.
        • Glen T.
        • O’Carroll R.
        Memory bias for emotional facial expressions in major depression.
        Cogn Emot. 2003; 17: 101-122
        • Raes F.
        • Hermans D.
        • Williams J.M.G.
        Negative bias in the perception of others’ facial emotional expressions in major depression: The role of depressive rumination.
        J Nerv Ment Dis. 2006; 194: 796-799
        • Colombo D.
        • Fernández-Álvarez J.
        • Patané A.
        • Semonella M.
        • Kwiatkowska M.
        • García-Palacios A.
        • et al.
        Current state and future directions of technology-based ecological momentary assessment and intervention for major depressive disorder: A systematic review.
        J Clin Med. 2019; 8: 465
        • Sandman C.F.
        • Young K.S.
        • Burklund L.J.
        • Saxbe D.E.
        • Lieberman M.D.
        • Craske M.G.
        Changes in functional connectivity with cognitive behavioral therapy for social anxiety disorder predict outcomes at follow-up.
        Behav Res Ther. 2020; 129: 103612
        • Young K.S.
        • Burklund L.J.
        • Torre J.B.
        • Saxbe D.
        • Lieberman M.D.
        • Craske M.G.
        Treatment for social anxiety disorder alters functional connectivity in emotion regulation neural circuitry.
        Psychiatry Res Neuroimaging. 2017; 261: 44-51

      Linked Article

      • Neural Correlates of Affective States in Emerging Adulthood
        Biological Psychiatry: Cognitive Neuroscience and NeuroimagingVol. 8Issue 1
        • Preview
          Many of our research efforts are aimed at understanding the nature of psychiatric pathology. Although adding to fundamental knowledge is a goal worth pursuing in itself, practical goals are often in play as well. We hope that by understanding the fundaments of certain complaints we will be able to treat them more efficiently or treat them at earlier stages.
        • Full-Text
        • PDF