Altered Processing of Contextual Information during Fear Extinction in PTSD: An fMRI Study

Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
CNS Neuroscience & Therapeutics (Impact Factor: 3.93). 08/2011; 17(4):227-36. DOI: 10.1111/j.1755-5949.2010.00152.x
Source: PubMed


Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma-exposed subjects underwent a two-day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically-measured, cue-elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC.

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    • "PTSD patients show exaggerated fear responses to traumarelated stimuli and have difficulties inhibiting their fear response while being in a safe environment. This has been referred to as reduced fear inhibition and decreased contextual cue processing (Jovanovic et al, 2012; Rougemont-Bucking et al, 2011). Recently, we observed these deficits during cognitive processes unrelated to trauma (van Rooij et al, 2014), suggesting more general deficits in PTSD. "
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    ABSTRACT: Thirty to fifty percent of posttraumatic stress disorder (PTSD) patients do not respond to treatment. Understanding the neural mechanisms underlying treatment response could contribute to improve response rates. PTSD is often associated with decreased inhibition of fear responses in a safe environment. Importantly, the mechanism of effective treatment (psychotherapy) relies on inhibition and so-called contextual cue processing. Therefore, we investigate inhibition and contextual cue processing in the context of treatment. Forty-one male war veterans with PTSD and 22 healthy male war veterans (combat controls) were scanned twice with a six to eight month interval, in which PTSD patients received treatment (psychotherapy). We distinguished treatment responders from non-responders on the base of percentage symptom decrease. Inhibition and contextual cue processing were assessed with the stop-signal anticipation task. Behavioral and functional MRI measures were compared between PTSD patients and combat controls, and between responders and non-responders using repeated measures analyses. PTSD patients showed behavioral and neural deficits in inhibition and contextual cue processing at both time points compared to combat controls. These deficits were unaffected by treatment, therefore, they likely represent vulnerability factors or scar aspects of PTSD. Second, responders showed increased pre-treatment activation of the left inferior parietal lobe (IPL) during contextual cue processing compared to non-responders. Moreover, left IPL activation predicted percentage symptom improvement. The IPL plays an important role in contextual cue processing, and may therefore facilitate the effect of psychotherapy. Hence, increased left IPL activation may represent a potential predictive biomarker for PTSD treatment response.Neuropsychopharmacology accepted article preview online, 26 August 2014. doi:10.1038/npp.2014.220.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2014; 40(3). DOI:10.1038/npp.2014.220 · 7.05 Impact Factor
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    • "Increased insula was demonstrated in PTSD patients (Etkin & Wager, 2007; Fonzo et al. 2010; Aupperle et al. 2012). Furthermore, increased dACC activity in PTSD was found in several studies (Bryant et al. 2005; Felmingham et al. 2009; Milad et al. 2009; Rougemont-Bucking et al. 2011; Shin et al. 2011). In contrast, the sgACC is particularly associated with major depressive disorder (MDD) (Drevets et al. 1997; Mayberg et al. 1999). "
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    ABSTRACT: Background: Post-traumatic stress disorder (PTSD) is thought to be characterized by general heightened amygdala activation. However, this hypothesis is mainly based on specific studies presenting fear or trauma-related stimuli, hence, a thorough investigation of trauma-unrelated emotional processing in PTSD is needed. Methods: In this study, 31 male medication-naive veterans with PTSD, 28 male control veterans (combat controls; CC) and 25 non-military men (healthy controls; HC) were included. Participants underwent functional MRI while trauma-unrelated neutral, negative and positive emotional pictures were presented. In addition to the group analyses, PTSD patients with and without major depressive disorder (MDD) were compared. Results: All groups showed an increased amygdala response to negative and positive contrasts, but amygdala activation did not differ between groups. However, a heightened dorsal anterior cingulate cortex (dACC) response for negative contrasts was observed in PTSD patients compared to HC. The medial superior frontal gyrus was deactivated in the negative contrast in HC, but not in veterans. PTSD+MDD patients showed decreased subgenual ACC (sgACC) activation to all pictures compared to PTSD-MDD. Conclusion: Our findings do not support the hypothesis that increased amygdala activation in PTSD generalizes to trauma-unrelated emotional processing. Instead, the increased dACC response found in PTSD patients implicates an attentional bias that extends to trauma-unrelated negative stimuli. Only HC showed decreased medial superior frontal gyrus activation. Finally, decreased sgACC activation was related to MDD status within the PTSD group.
    Psychological Medicine 07/2014; DOI:10.1017/S0033291714001706 · 5.94 Impact Factor
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    • "In parallel, convergent evidence suggests that PTSD is associated with various abnormalities in fear associated learning, including greater acquisition of conditioned fear, overgeneralization of conditioning, impaired inhibitory learning, and impaired extinction (Orr et al., 2000; Lissek et al., 2005; Milad et al., 2008, 2009; Jovanovic et al., 2009, 2010; Rougemont-Bucking et al., 2011; Mahan and Ressler, 2012; Lommen et al., 2013). It has been suggested that deficits in fear associated learning may play a role in the development (see Lommen et al., 2013) and maintenance (Mahan and Ressler, 2012) of PTSD, and that abnormalities in the extinction and/or retention of conditioned fear may be particularly salient for the persistence of fear memories in PTSD (Milad et al., 2008, 2009). "
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    ABSTRACT: Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapies.
    Frontiers in Human Neuroscience 10/2013; 7:672. DOI:10.3389/fnhum.2013.00672 · 2.99 Impact Factor
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