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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    • "Therefore, our results showing impaired contextual fear extinction and safety discrimination as a result of acute nicotine administration [227] [228] suggest that smoking may further disrupt already impaired safety learning in patients with anxiety disorders and potentially prolong the course of the disorder. In support, there is evidence from human studies showing that PTSD patients showed altered contextual information processing during extinction [239]. Furthermore, Calhoun et al. [240] showed that the exaggerated fear response to the trauma context observed in PTSD patients was aggravated with smoking. "
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    ABSTRACT: Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), anxiety disorders are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine's effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 07/2015; 97(4). DOI:10.1016/j.bcp.2015.07.029 · 5.01 Impact Factor
    • "The age range for all participants was 18 to 67 years old. Neuroimaging and psychophysiological data from these participants related to the neurobiology of fear extinction in healthy subjects (Linnman et al., 2011a, 2012; Milad et al., 2007a,b) and in the different clinical populations (Holt et al., 2012; Linnman et al., 2011b; Rougemont-Bucking et al., 2011) have been previously published. "
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    ABSTRACT: There is substantial variability across individuals in the magnitudes of their skin conductance (SC) responses during the acquisition and extinction of conditioned fear. To manage this variability, subjects may be matched for demographic variables, such as age, gender and education. However, limited data exist addressing how much variability in conditioned SC responses is actually explained by these variables. The present study assessed the influence of age, gender and education on the SC responses of 222 subjects who underwent the same differential conditioning paradigm. The demographic variables were found to predict a small but significant amount of variability in conditioned responding during fear acquisition, but not fear extinction learning or extinction recall. A larger differential change in SC during acquisition was associated with more education. Older participants and women showed smaller differential SC during acquisition. Our findings support the need to consider age, gender and education when studying fear acquisition but not necessarily when examining fear extinction learning and recall. Variability in demographic factors across studies may partially explain the difficulty in reproducing some SC findings. Copyright © 2015. Published by Elsevier B.V.
    International journal of psychophysiology: official journal of the International Organization of Psychophysiology 07/2015; DOI:10.1016/j.ijpsycho.2015.06.010 · 2.88 Impact Factor
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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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