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. 2015 Dec 15;5(12):e700.
doi: 10.1038/tp.2015.196.

Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

R A Morey  1   2   3   4 , J E Dunsmoor  5 , C C Haswell  1   3 , V M Brown  6   7 , A Vora  8 , J Weiner  1   2 , D Stjepanovic  4 , H R Wagner 3rd  1   2 , VA Mid-Atlantic MIRECC Workgroup; K S LaBar  3   4
Collaborators, Affiliations
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Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

R A Morey et al. Transl Psychiatry. .
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Abstract

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.

Figures

Figure 1
Figure 1
Stimuli and task design. (a) Generalization was assessed with images of five facial morphs of the same identity that ranged from neutral-to-fearful end points. (b) During preconditioning, participants were exposed to all the five facial morphs before fear conditioning to assess the baseline behavioral and neural responses. Fear learning was accomplished in two runs by pairing an electrical shock (US) with presentation of the S3 morph (CS+) on 6 out of 18 trials (33%), whereas S1 was never paired with shock (CS−). Morphs S2, S4 and S5 were not presented during fear conditioning. During four runs of the generalization test, all the five morphs (S1–S5) were presented and S3 was intermittently reinforced with a shock (4 of 12 trials; 33%). US, unconditioned stimulus.
Figure 2
Figure 2
Shock expectancy and post-generalization memory of fear association. (a) Subjects provided ratings during the generalization task indicating the expectation of receiving a shock with each stimulus (S1–S5). There was no significant difference in shock expectancy between the PTSD and control groups (F9,53=1.5; P>0.2) nor any fear-level × diagnosis interaction (F9,53=0.47; P>0.7). As expected, there was a strong main effect of stimulus-intensity (F9,53=38.25; P<0.0001). Error bars indicate standard error of the mean. (b) The memory of fear association exhibits generalization in PTSD with a bias toward the face expressing the greatest fear (S5). The PTSD group misidentified the S5 stimulus as the CS+ (χ21=10.19; P=0.001) more frequently (count=31; 45.2%) than the control group (count=14; 20.6%). The control group correctly identified the S3 as CS+ (count=28; 41.2%) more frequently than the PTSD group (count=15; 21.4%). There were no between-group differences for S4 (χ21=0.09; P=0.76) or S2 (χ21=2.86; P=0.10). The y axis represents count data (two per subject) and therefore does not have standard error bars. CS, conditioned stimulus; PTSD, posttraumatic stress disorder.
Figure 3
Figure 3
Regions of fear generalization bias in PTSD. Fear generalization response was biased toward higher emotional intensity than the original conditioned stimulus in R-fusiform (P<0.02), R-insula (P<0.001), locus coeruleus (P<0.04), L-thalamus (P<0.01), R-thalamus (P<0.005), R-primary visual cortex (calcarine; P<0.05) and at the trend level in R-IFG (P=0.07). Generalization bias was not observed in the amygdala, but the R-amygdala exhibited an overall increase in activation in the PTSD group for all stimulus intensities (P<0.0001). Error bars indicate standard error of the mean. IFG, inferior frontal gyrus; L, left; PTSD, posttraumatic stress disorder; R, right.
Figure 4
Figure 4
Task-modulated functional connectivity. (a) Task-modulated functional connectivity between the right amygdala and vmPFC (ROI obtained from CS−>CS+) showed a significant diagnosis × fear-level interaction (F(1,65)=4.22; P=0.04) suggestive of stronger connectivity in the trauma-exposed control group that was biased toward safety-signal learning. (b) Task-modulated functional connectivity between the right amygdala and thalamus showed trend-level diagnosis × fear-level interaction (F(1,65)=3.54; P=0.06), while connectivity between the right amygdala and the calcarine cortex showed a significant diagnosis × fear-level interaction (F(1,65)=6.35; P=0.01). Error bars indicate standard error of the mean. CS, conditioned stimulus; PTSD, posttraumatic stress disorder; ROI, region of interest; vmPFC, ventromedial prefrontal cortex.
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References

    1. Ehlers A, Hackmann A, Michael T. Intrusive re-experiencing in post-traumatic stress disorder: phenomenology, theory, and therapy. Memory 2004; 12: 403–415. - PubMed
    1. Dunsmoor JE, Paz R. Fear generalization and anxiety: behavioral and neural mechanisms. Biol Psychiatry 2015; 78: 336–343. - PubMed
    1. Parsons RG, Ressler KJ. Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 2013; 16: 146–153. - PMC - PubMed
    1. Lissek S, Powers AS, McClure EB, Phelps EA, Woldehawariat G, Grillon C et al. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav Res Ther 2005; 43: 1391–1424. - PubMed
    1. Craske MG, Kircanski K, Zelikowsky M, Mystkowski J, Chowdhury N, Baker A. Optimizing inhibitory learning during exposure therapy. Behav Res Ther 2008; 46: 5–27. - PubMed

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