Flor H. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP C01: Learning and brain plasticity in posttraumatic stress disorder:. 01/2012-12/2015.
The goal of this study is the analysis of learning processes and plastic brain changes in the development and maintenance of posttraumatic stress disorder (PTSD). We hypothesize that enhanced cue and deficient context conditioning along with high stress sensitivity lead to an enhanced risk to develop PTSD after traumatic experience and suggest that these alterations in associative and non-associative learning are accompanied by enhanced amygdalar and reduced hippocampal activation during acquisition and deficient midfrontal-amygdalar and midfrontal-hippocampal connectivity during extinction. In addition, we believe that traumatic stress, which alters the brain structure in these regions and leads to altered stress reactivity of the ypothalamus-pituitary-adrenal axis (HPA), contributes to the occurrence of PTSD along with peritraumatic factors. In the last funding period we continued the longitudinal study and added another 125 students in schools for rescue workers to the original 120 subjects (we plan to have 300 complete cases by the end of 2011) and characterized them with psychometric, psychophysiological, neuroimaging, endocrine and genetic methods. Since we do not yet have enough subjects who converted to PTSD we focused on predictors of cue and context conditioning in this sample. We found that hippocampal volume predicts context conditioning and that larger amygdala volume is associated with better cue conditioning, whereas cue conditioning is reduced with larger hippocampal volume. We also found that polymorphisms related to the minor alleles of HPA axis-related genes predict enhanced amygdala activation during cue conditioning and reduced prefrontal activation and prefrontal-amygdala connectivity during extinction. A polymorphism on the neurogranin gene, which has been associated with high risk for schizophrenia and memory disturbance, was found to predict hippocampal activation during context conditioning. In addition, traumatized persons with and without PTSD and healthy controls participated in cross-sectional neuroimaging studies. We found enhanced stress sensitivity as indexed by higher stress analgesia in the patients with PTSD and this was linked to enhanced activation in the rostral anterior cingulate. We also observed better second order conditioning with trauma cues as unconditioned stimuli in the PTSD patients accompanied by amygdala deactivation, which was associated with delayed extinction and abnormal dorsolateral prefrontal activation. In the PTSD group renewal was enhanced and associated with reduced hippocampal activation. A study on reinstatement is still ongoing as is the assessment of the effects of exposure treatment on renewal and einstatement. We also observed enhanced hippocampal activation during simple contextual conditioning in the PTSD group. These data are in line with our hypothesis of deficient context conditioning as a core pathological factor in PTSD. In the new funding period we will complete the longitudinal study by adding another 150 subjects to arrive at a total of 450, will retest persons who developed PTSD symptoms and compare them to persons who were traumatized without developing the disorder and matched controls from the rescue worker samples. In addition to retesting these predefined subjects we will use regression analyses to predict symptoms from the baseline tests in the entire sample. In the cross-sectional study we will expand the analysis of the role of deficient contextual processing in PTSD. Study 1 will test the hypothesis that PTSD patients focus their attention more on emotional cues at the expense of contexts compared to traumatized persons without PTSD and controls and that this is an early attentional process related to the perception rather than the evaluation of the stimuli that also determines that cues are better remembered than contexts. The study combines electroencephalographic recordings and eye tracking. A second study will examine the relationship of cued and contextual fear by combining differential fear conditioning to cues and contexts in one study. The contexts will be more complex than previous contexts in order to be able to model configural versus single item processing. Extinction to cues, contexts and their combination will be tested on a separate day and in a third session the response to the cues and contexts will be reversed (the previous danger cue/context will signal safety and vice versa) and tested with and without a retrieval cue. This will permit to test the role of inhibitory mechanisms and safety signals and will provide the possibility to determine how easily aversive memories can be updated. Functional magnetic resonance imaging will be employed to study the role of medial prefrontal and orbitofrontal circuits in this task. In these studies the effects of exposure treatment will also be examined to test if the deficient processing of cue-context interactions is an enduring deficit or can be reversed by effective treatment. Finally, we will address the specificity of the altered onditioning mechanisms and the brain correlates by using comorbidity, medication effects and trauma load as covariates and by comparing our patient group to others in and outside the collaborative research center with respect to the specificity of alterations in context conditioning.