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Original Article |

Deficits in Conditioned Fear Extinction in Obsessive-Compulsive Disorder and Neurobiological Changes in the Fear Circuit

Mohammed R. Milad, PhD; Sharon C. Furtak, PhD; Jennifer L. Greenberg, PsyD; Aparna Keshaviah, ScM; Jooyeon J. Im, BA; Martha J. Falkenstein, BS; Michael Jenike, MD; Scott L. Rauch, MD; Sabine Wilhelm, PhD
JAMA Psychiatry. 2013;70(6):608-618. doi:10.1001/jamapsychiatry.2013.914.
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Importance Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population.

Objective To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD.

Design Cross-sectional, case-control, functional magnetic resonance imaging study.

Setting Academic medical center.

Participants Twenty-one patients with OCD and 21 healthy participants.

Main Outcomes and Measures Skin conductance responses and blood oxygenation level–dependent responses.

Results The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity.

Conclusions and Relevance As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.

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Figures

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Figure 1. Psychophysiological responses and blood oxygenation level–dependent reactivity during fear acquisition. A, Mean skin conductance responses (SCRs) during conditioning to the conditioned stimulus paired with the shock (CS+) and to that not paired (CS−). Both the obsessive-compulsive disorder (OCD) and healthy control (HC) groups significantly discriminated between the CS+ and CS− (asterisk denotes P < .05) during the fear conditioning phase. B, Blood oxygenation level–dependent responses to CS+ presentations contrasted with responses to CS− presentations across all conditioning trials within and between groups. Group differences, denoted by the red circle (bottom row), were found in the right caudate nucleus, subgenual cortex, and the hippocampus. Activation maps are illustrated with a threshold of t > ±3.0 (P < .01, uncorrected) within group and a threshold of t > ±1.0 (P < .01, uncorrected) between groups. Results are overlaid on a template structural magnetic resonance image. The scale bar is ±3-5 for within-group contrasts and ±1-4 for between-group contrasts.

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Figure 2. Psychophysiological responses and blood oxygenation level–dependent reactivity during extinction training. A, Skin conductance response (SCR) in both the obsessive-compulsive disorder (OCD) and healthy control (HC) groups did not differ at the beginning (first 4 trials, extinguished reinforced conditioned stimulus [eCS+E]) or end of extinction training (last 4 trials; lCS+E) to the CS+E. B, Blood oxygenation level–dependent responses during extinction training are displayed within and between groups. Results display responses to last 4 CS+E presentations contrasted with responses to first 4 CS+E presentations. In this contrast, both the OCD and HC groups displayed deactivation of the dorsal anterior cingulate (top 2 rows), indicating the dorsal anterior cingulate was less activated at the end of extinction training compared with at the beginning. The OCD group showed significantly less activation than the HC group in the right ventromedial prefrontal cortex, denoted by the red circle. Activation maps are illustrated with a threshold of t > ±3.0 (P < .01) within group and a threshold of t > ±1.0 (P < .01) between groups, then overlaid on a template structural magnetic resonance image. The scale bar is ±3-5 for within-group contrasts and ±1-4 for between-group contrasts.

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Figure 3. Psychophysiological responses and blood oxygenation level–dependent activations during extinction recall. A, Mean skin conductance responses (SCRs) during recall to the extinguished reinforced conditioned stimulus (CS+E), the nonextinguished CS+ (CS+NE), and the nonreinforced CS (CS−). B, The ability to recall extinction was also assessed by an extinction retention index measure (see the Methods section). There was a significant group difference (* P < .05) in the extinction retention index percentage, indicating that the healthy control (HC) group was better able to recall extinction training compared with the obsessive-compulsive disorder (OCD) group. C, Blood oxygenation level–dependent responses during extinction recall are displayed within and between groups. The OCD group showed significantly less activation than the HC group in the left ventromedial prefrontal cortex, cerebellum, posterior cingulate cortex, and putamen (bottom row, red circles). Results represent responses to the first 4 CS+NE presentations contrasted with responses to the first 4 CS+E presentations during recall. Activation maps are illustrated with a threshold of t > ±3.0 (P < .01, uncorrected) within group and a threshold of t > ±1.0 (P < .01, uncorrected) between groups, then overlaid on a template structural magnetic resonance image. The scale bar is ±3-5 for within-group contrasts and ±1-4 for between-group contrasts.

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Figure 4. Correlations of the Yale-Brown Obsessive-Compulsive Scale (YBOCS) with brain reactivity during recall. A, A voxelwise regression analysis of total YBOCS scores during extinction recall indicated a significant correlation of brain activity with symptom severity in 5 brain regions (red circles). The top row displays regions found to have a positive correlation with YBOCS scores, while the bottom row displays regions found to have a negative correlation with YBOCS scores. Activation maps are illustrated with a threshold of t > ±2.0 (P < .01, uncorrected), then overlaid on a template structural magnetic resonance image. B, Model of brain activation prediction of YBOCS scores. Results based on stepwise regression analysis found that insular cortex and cerebellum activation are the most predictive contributors of the 5 brain regions correlated with YBOCS scores. X indicates the region had no role in regression or no contribution to significance in the linear regression model. dACC indicates dorsal anterior cingulate cortex; OCD, obsessive-compulsive disorder; PCC, posterior cingulate cortex; vmPFC, ventromedial prefrontal cortex. * P <  .05; † P <  .001.

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Figure 5. Correlations of the extinction retention index (ERI) score with brain reactivity during recall. A, A voxelwise regression analysis of ERI scores during extinction recall indicated a significant correlation of brain activity with psychophysiological measurements of the ability to recall extinction memory in 5 brain regions (red circles). The top row displays regions found to have a positive correlation with ERI scores, while the bottom row displays regions found to have a negative correlation with ERI scores. Activation maps are illustrated with a threshold of t > ±2.0 (P < .01, uncorrected), then overlaid on a template structural magnetic resonance image. B, Model of brain activation prediction of ERI scores based on a stepwise regression analysis. Results found that dorsal anterior cingulate cortex (dACC) and cerebellum activation are the most predictive contributors of the 5 brain regions correlated with ERI scores. X indicates region did not have any significant contributions to the statistical model tested in the multilinear regression model. PCC indicates posterior cingulate cortex; vmPFC, ventromedial prefrontal cortex. * P <  .05; † P <  .001.

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Figure 6. Ability to recall extinction training correlates with symptom severity. Symptom severity, as measured by the Yale-Brown Obsessive-Compulsive Scale (YBOCS) score, was found to positively correlate with the individual's extinction retention index, a measure indicative of the ability to recall extinction training. The worse the individual's obsessive-compulsive disorder symptoms, the better that ability to recall extinction memory.

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