Fear Not: Neurobiological Mechanisms of Fear and Anxiety

Fear is a common, core emotion. Moreover, anxiety disorders are among the most common form of psychiatric disease. In this thesis neuroimaging, genetic, pharmacological, brain stimulation and behavioral techniques were used in healthy subjects and specific patient populations to shed more light on the neuroanatomical and pharmacological systems that underlie human fear and anxiety. Our results provide new insights into the limbic upregulation and prefrontal downregulation of defensive states. We delineated neuroanatomical systems that may play an important role in fear regulation in response to the on- and offset of acute stressors. We extended work that implicated common genetic variation in serotonin transporter function as a possible prelude to anxiety by showing that serotonin transporter genotype is associated with basic defensive reactivity as indexed by fear-potentiated startle and functional magnetic resonance imaging measures of anxiety. We made first steps in the development of paradigms that may aid in the discovery of new and improved medication for anxiety disorders. Finally, we performed fear-potentiated startle measurements in two very rare populations: subjects with a rare genetic defect leading to selective calcification of the lateral amygdala and subjects that received deep brain stimulation at the ventral striatum to treat severe obsessive-compulsive symptoms. The latter two studies enabled us to obtain unique information on the contribution of these brain regions to fear learning and basic defensive reactions