This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Fear is a normal human response to threatening stimuli. Anxiety disorders are present when fear is expressed in an exaggerated manner or under inappropriate circumstances. Decades of research have delineated the brain circuits involved in fear learning. Even more importantly, in recent years various studies have proposed the biological processes involved in extinction of fear. Understanding the brain mechanisms of learning not to fear (or fear extinction) has important clinical implications. Fear extinction deficits may be part of the etiological factors of anxiety disorders and at the same time strengthening fear extinction could be a treatment modality for these conditions. In humans, fear extinction can be measured by physiological responses that occur during fear conditioning and extinction paradigms. Subjects with anxiety disorders have consistently been found to present increased fear conditioning as measured by startle responses (Orr et al.,2000). Neuroimaging studies of fear acquisition and extinction show that in subjects without psychopathology, fear acquisition is associated with increased amygdala response and recall of fear extinction is correlated with increased activity of the ventromedial prefrontal cortex (vmPFC) (Milad and Rauch, 2007). Similar neuroimaging studies show that patients with anxiety disorders show hyperresponsive amygdala activation during fear acquisition and decreased activity of the vmPFC (Milad and Rauch, 2007). These findings correlate well with functional and structural imaging of subjects with anxiety disorders which repeatedly show that these patients have alterations in the amygdala and prefrontal cortex areas such as the vmPFC (Rauch et al., 2003;Gilbertson et al., 2002). These same brain areas have been shown in animal and human studies to be related to fear learning and extinction. The ability to extinguish SCR responses to cues no longer paired with shock could predict a patient's response to exposure therapy (Kaplan et al., 2010;Hofmann, 2008), which is thought to be based on extinction mechanisms. Furthermore, the return of fear after extinction that is triggered by changes in context (renewal of fear) has been proposed as a risk factor for relapse after therapy (Boschen et al., 2009). Thus, being able to assess fear conditioning, extinction, and renewal in anxiety patients could help match specific therapeutic strategies to specific patients. It may not be practical, however, to routinely perform experimental fear conditioning in the clinic, because the necessary equipment and training is not readily accessible to most practitioners, especially in areas with limited resources. Alternatively, certain neuropsychological tests share common neuroanatomical substrates with fear leaning and extinction, and may be useful as predictors of conditioning, extinction, or renewal.
Specific Aim #1 : Can neuropsychological tests predict fear acquisition and extinction learning in normal subjects? Hypothesis: Scores on neuropsychological tests that activate areas of the brain such as the amygdala and vmPFC will be associated with the capacity of subjects to learn and to extinguish fear. We will be using two neuropsychological tests that have been shown to activate brain areas associated with fear circuitry. Functional MRI studies of subjects doing the Emotional Stroop Task (EST) show that brain areas very close to the vmPFC are activated in controls upon exposure to the threat words (Engels et al., 2007). Therefore we expect subjects with increased response times to the threat words to present with better extinction learning. The Multimodal Source Interference Test (MSIT) is a non-emotional form of stroop task that may not be related to fear learning.
Specific Aim #2 : Are associations between neuropsychological tests and fear learning also found in subjects with anxiety disorders? Hypothesis: Scores on these neuropsychological tests will also be associated with the capacity of subjects to learn and to extinguish fear but this association may be different in subjects with anxiety disorders due to fear extinction deficits that have been described in this population. fMRI studies of anxiety disorder patients doing the EST have found that they fail to activate the areas near vmPFC when exposed to threat words (Whalen et al., 2006). Therefore, we expect to find an association between these neuropsychological tests and fear learning but that it will be a different relationship as compared to the subjects without psychopathology.
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