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Response to Learned Threat: An fMRI Study in Adolescent and Adult Anxiety
Jennifer C. Britton, Ph.D.; Christian Grillon, Ph.D.; Shmuel Lissek, Ph.D.; Maxine A. Norcross, B.S.; Kristin L. Szuhany, B.S.; Gang Chen, Ph.D.; Monique Ernst, M.D., Ph.D.; Eric E. Nelson, Ph.D.; Ellen Leibenluft, M.D.; Tomer Shechner, Ph.D.; Daniel S. Pine, M.D.
Am J Psychiatry 2013;170:1195-1204. doi:10.1176/appi.ajp.2013.12050651
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The authors report no financial relationships with commercial interests.

Supported in part by grant K99-MH-091183 from the Intramural Research Program of NIMH/NIH (to Dr. Britton).

The skin conductance results during fear acquisition partially overlap with data published by Lau et al. (see reference 12). The data are presented as an applied example of the methodology described by Chen et al. (see reference 21).

From the Department of Psychology, University of Miami, Coral Gables, Fla.; the National Institute of Mental Health, Bethesda, Md.; Department of Psychology, University of Minnesota, Minneapolis; School of Medicine, Johns Hopkins University, Baltimore; and Department of Psychology, Boston University, Boston.

Presented at the annual meeting of the American College of Neuropsychopharmacology, Miami Beach, Fla., Dec. 5–9, 2010, and Waikoloa, Hawaii, Dec. 4–8, 2011; and the annual meeting of the Anxiety and Depression Association of America, Baltimore, March 4–7, 2010, and New Orleans, March 24–27, 2011.

Address correspondence to Dr. Britton (j.britton@miami.edu).

Copyright © 2013 by the American Psychiatric Association

Received May 19, 2012; Revised August 30, 2012; January 25, 2013; March 08, 2013; March 21, 2013; Accepted March 25, 2013.


Objective  Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, the neural correlates of threat-safety discrimination have not been investigated in this population. The authors compared prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning.

Method  Anxious and healthy adolescents and adults (N=114) completed fear conditioning and extinction in the clinic. The conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Three weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in an MRI scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+.

Results  During conditioning and extinction, the anxious groups reported more fear than the healthy groups, but the anxious adolescent and adult groups did not differ on physiological measures. During imaging, both anxious adolescents and adults exhibited lower activation in the subgenual anterior cingulate cortex than their healthy counterparts, specifically when appraising threat. Compared with their age-matched counterpart groups, anxious adults exhibited reduced activation in the ventromedial prefrontal cortex when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation in response to the most extreme CS+ and CS–.

Conclusions  Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced subgenual anterior cingulate cortex engagement is a shared feature in adult and adolescent anxiety disorders, but ventromedial prefrontal cortex dysfunction is age-specific. The unique U-shaped pattern of activation in the ventromedial prefrontal cortex in many anxious adolescents may reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.

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FIGURE 1. Experimental Procedures Among Anxious and Healthy Adolescents and Adultsa

a During fear acquisition, one female face (conditioned stimulus [CS+]) was paired with a fearful face coterminating with a scream (unconditioned stimulus [UCS]). The other female face (CS–) was never paired with the UCS. During extinction, the two female faces were presented without the UCS. Several weeks later, participants viewed morphed images continuously varying in similarity from the CS– to CS+. Participants reported whether they were afraid (threat appraisal), whether the CS screamed in the past (explicit memory), or whether the CS had jet black hair (physical discrimination).

FIGURE 2. Whole-Brain Analyses Indicate Four-Way Interactions (diagnosis-by-age group-by-cognitive instruction-by-quadratic trend)a

a The subgenual anterior cingulate cortex (coordinates: −9, 26, −9) and the ventromedial prefrontal cortex (coordinates: 4, 49, −6) survived a 15-voxel cluster threshold, defined using a voxel-wise probability threshold of p<0.005, which yields a corrected threshold of p<0.05 for medial prefrontal cortical regions. Images are displayed in radiological convention (left is right). Green lines in the axial slice indicate the position of sagittal slices.

FIGURE 3. Response Patterns During Threat Appraisal and Explicit Memorya

a The graphs show group differences in the subgenual anterior cingulate cortex and the ventromedial prefrontal cortex during threat appraisal (panels A and B, respectively) and during the explicit-memory task (panels C and D, respectively). Panel A plots the percent-signal change values relative to baseline. Panels B–D plot the beta coefficients across morphed images for the quadratic response. The significance is defined as an alpha level ≤0.05.

b Group difference in neural activation.

c Significant quadratic trend across morphs.

d Group difference in the quadratic pattern.

FIGURE 4. Response Patterns Across Morphed Imagesa

a To further illustrate effects (as shown in Figure 3), the neural patterns across morphed images are plotted for the subgenual anterior cingulate cortex and the ventromedial prefrontal cortex during threat appraisal (panels A and B, respectively) and during the explicit-memory task (panels C and D, respectively). For illustrative purposes, the percent-signal change values, relative to baseline, for every two morphed images other than 0%, 50%, and 100% are averaged together. Only group differences in neural activation are reflected here. Significance is defined as an alpha level ≤0.05.

b Group difference in neural activation.

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TABLE 1.Fear Conditioning and Extinction Results in Anxious and Healthy Adolescents and Adults
Table Footer Note

a There was a significant age-group difference in IQ (p<0.005). In all initial analyses, IQ was included as a covariate of no interest, and results indicated that IQ did not alter the significant findings.



Quirk  GJ;  Garcia  R;  González-Lima  F:  Prefrontal mechanisms in extinction of conditioned fear.  Biol Psychiatry 2006; 60:337–343
[CrossRef] | [PubMed]
Pine  DS;  Cohen  P;  Gurley  D;  Brook  J;  Ma  Y:  The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders.  Arch Gen Psychiatry 1998; 55:56–64
[CrossRef] | [PubMed]
Walkup  JT;  Albano  AM;  Piacentini  J;  Birmaher  B;  Compton  SN;  Sherrill  JT;  Ginsburg  GS;  Rynn  MA;  McCracken  J;  Waslick  B;  Iyengar  S;  March  JS;  Kendall  PC:  Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety.  N Engl J Med 2008; 359:2753–2766
[CrossRef] | [PubMed]
Milad  MR;  Pitman  RK;  Ellis  CB;  Gold  AL;  Shin  LM;  Lasko  NB;  Zeidan  MA;  Handwerger  K;  Orr  SP;  Rauch  SL:  Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.  Biol Psychiatry 2009; 66:1075–1082
[CrossRef] | [PubMed]
Britton  JC;  Lissek  S;  Grillon  C;  Norcross  MA;  Pine  DS:  Development of anxiety: the role of threat appraisal and fear learning.  Depress Anxiety 2011; 28:5–17
[CrossRef] | [PubMed]
Kim  JH;  Richardson  R:  The effect of temporary amygdala inactivation on extinction and reextinction of fear in the developing rat: unlearning as a potential mechanism for extinction early in development.  J Neurosci 2008; 28:1282–1290
[CrossRef] | [PubMed]
Milad  MR;  Quirk  GJ:  Neurons in medial prefrontal cortex signal memory for fear extinction.  Nature 2002; 420:70–74
[CrossRef] | [PubMed]
Quirk  GJ;  Beer  JS:  Prefrontal involvement in the regulation of emotion: convergence of rat and human studies.  Curr Opin Neurobiol 2006; 16:723–727
[CrossRef] | [PubMed]
Indovina  I;  Robbins  TW;  Núñez-Elizalde  AO;  Dunn  BD;  Bishop  SJ:  Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.  Neuron 2011; 69:563–571
[CrossRef] | [PubMed]
Critchley  HD;  Mathias  CJ;  Dolan  RJ:  Fear conditioning in humans: the influence of awareness and autonomic arousal on functional neuroanatomy.  Neuron 2002; 33:653–663
[CrossRef] | [PubMed]
Kalisch  R;  Korenfeld  E;  Stephan  KE;  Weiskopf  N;  Seymour  B;  Dolan  RJ:  Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network.  J Neurosci 2006; 26:9503–9511
[CrossRef] | [PubMed]
Lau  JY;  Britton  JC;  Nelson  EE;  Angold  A;  Ernst  M;  Goldwin  M;  Grillon  C;  Leibenluft  E;  Lissek  S;  Norcross  M;  Shiffrin  N;  Pine  DS:  Distinct neural signatures of threat learning in adolescents and adults.  Proc Natl Acad Sci USA 2011; 108:4500–4505
[CrossRef] | [PubMed]
Lau  JY;  Lissek  S;  Nelson  EE;  Lee  Y;  Roberson-Nay  R;  Poeth  K;  Jenness  J;  Ernst  M;  Grillon  C;  Pine  DS:  Fear conditioning in adolescents with anxiety disorders: results from a novel experimental paradigm.  J Am Acad Child Adolesc Psychiatry 2008; 47:94–102
[CrossRef] | [PubMed]
Lissek  S;  Powers  AS;  McClure  EB;  Phelps  EA;  Woldehawariat  G;  Grillon  C;  Pine  DS:  Classical fear conditioning in the anxiety disorders: a meta-analysis.  Behav Res Ther 2005; 43:1391–1424
[CrossRef] | [PubMed]
First  MB;  Spitzer  RL;  Gibbon  M;  Williams  JBW:  Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) .  New York,  New York State Psychiatric Institute, Biometrics Research,2002
Kaufman  J;  Birmaher  B;  Brent  D;  Rao  U;  Flynn  C;  Moreci  P;  Williamson  D;  Ryan  N:  Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data.  J Am Acad Child Adolesc Psychiatry 1997; 36:980–988
[CrossRef] | [PubMed]
Lissek  S;  Rabin  S;  Heller  RE;  Lukenbaugh  D;  Geraci  M;  Pine  DS;  Grillon  C:  Overgeneralization of conditioned fear as a pathogenic marker of panic disorder.  Am J Psychiatry 2010; 167:47–55
[CrossRef] | [PubMed]
Lissek  S;  Rabin  SJ;  McDowell  DJ;  Dvir  S;  Bradford  DE;  Geraci  M;  Pine  DS;  Grillon  C:  Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder.  Behav Res Ther 2009; 47:111–118
[CrossRef] | [PubMed]
Greenberg  T;  Carlson  JM;  Cha  J;  Hajcak  G;  Mujica-Parodi  LR:  Neural reactivity tracks fear generalization gradients.  Biol Psychol 2013; 92:2–8
[CrossRef] | [PubMed]
Lissek  S;  Biggs  AL;  Rabin  SJ;  Cornwell  BR;  Alvarez  RP;  Pine  DS;  Grillon  C:  Generalization of conditioned fear-potentiated startle in humans: experimental validation and clinical relevance.  Behav Res Ther 2008; 46:678–687
[CrossRef] | [PubMed]
Chen  G;  Saad  ZS;  Britton  JC;  Pine  DS;  Cox  RW:  Linear mixed-effects modeling approach to FMRI group analysis.  Neuroimage 2013; 73:176–190
[CrossRef] | [PubMed]
Glenn  CR;  Klein  DN;  Lissek  S;  Britton  JC;  Pine  DS;  Hajcak  G:  The Development of Fear Learning and Generalization in 8 to 13 year-olds.  Dev Psychobiol 2012;54:675–684
Neumann  DL;  Waters  AM;  Westbury  HR;  Henry  J:  The use of an unpleasant sound unconditional stimulus in an aversive conditioning procedure with 8- to 11-year-old children.  Biol Psychol 2008; 79:337–342
Roberson-Nay  R;  Klein  DF;  Klein  RG;  Mannuzza  S;  Moulton  JL  3rd;  Guardino  M;  Pine  DS:  Carbon dioxide hypersensitivity in separation-anxious offspring of parents with panic disorder.  Biol Psychiatry 2010; 67:1171–1177
Pine  DS;  Klein  RG;  Coplan  JD;  Papp  LA;  Hoven  CW;  Martinez  J;  Kovalenko  P;  Mandell  DJ;  Moreau  D;  Klein  DF;  Gorman  JM:  Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group.  Arch Gen Psychiatry 2000; 57:960–967
Milad  MR;  Wright  CI;  Orr  SP;  Pitman  RK;  Quirk  GJ;  Rauch  SL:  Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert.  Biol Psychiatry 2007; 62:446–454
Phelps  EA;  Delgado  MR;  Nearing  KI;  LeDoux  JE:  Extinction learning in humans: role of the amygdala and vmPFC.  Neuron 2004; 43:897–905
Blechert  J;  Michael  T;  Vriends  N;  Margraf  J;  Wilhelm  FH.  Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses.  Behav Res Ther 2007; 45:2019–2033
Craske  MG;  Waters  AM;  Lindsey Bergman  R;  Naliboff  B;  Lipp  OV;  Negoro  H;  Ornitz  EM:  Is aversive learning a marker of risk for anxiety disorders in children? Behav Res Ther 2008; 46:954–967
Delgado  MR;  Nearing  KI;  Ledoux  JE;  Phelps  EA:  Neural circuitry underlying the regulation of conditioned fear and its relation to extinction.  Neuron 2008; 59:829–838
Dunsmoor  JE;  Prince  SE;  Murty  VP;  Kragel  PA;  LaBar  KS:  Neurobehavioral mechanisms of human fear generalization.  Neuroimage 2011; 55:1878–1888
Milad  MR;  Quirk  GJ;  Pitman  RK;  Orr  SP;  Fischl  B;  Rauch  SL:  A role for the human dorsal anterior cingulate cortex in fear expression.  Biol Psychiatry 2007; 62:1191–1194
Carter  CS;  Heckers  S;  Nichols  T;  Pine  DS;  Strother  S:  Optimizing the design and analysis of clinical functional magnetic resonance imaging research studies.  Biol Psychiatry 2008; 64:842–849[Review]
Kim  JH;  Richardson  R:  New findings on extinction of conditioned fear early in development: theoretical and clinical implications.  Biol Psychiatry 2010; 67:297–303
Casey  BJ;  Ruberry  EJ;  Libby  V;  Glatt  CE;  Hare  T;  Soliman  F;  Duhoux  S;  Frielingsdorf  H;  Tottenham  N:  Transitional and translational studies of risk for anxiety.  Depress Anxiety 2011; 28:18–28
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