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Fear generalization, the generalization of fear to innocuous stimuli, is a characteristic component of pathological anxiety. For example, after returning from war, a person might begin to experience fear in response to the sound of fireworks, a stimulus typically regarded as safe. When excessive, “overgeneralization” serves as a core feature of fear and anxiety-related disorders, such as PTSD. The present collection of studies sought to investigate the neural correlates and temporal dynamics of fear generalization in humans. The first study sought to investigate the causal role of the ventromedial prefrontal cortex (vmPFC) and hippocampus in the generalization of fear. Contrary to hypotheses, individuals with focal damage to the vmPFC (N=8) or hippocampus (N=12) did not demonstrate significantly increased fear generalization relative to individuals with brain damage outside of these regions (N=16) or normal comparison participants (N=20). Potential explanations for this finding are explored. The second study sought to investigate the time course of fear generalization in humans. Participants (N = 107) completed a fear generalization task over the course of two sessions. Results indicate that fear generalization significantly increased as the duration of time between training and testing increased. This suggests that a stimulus may elicit a generalized fear response at one arbitrarily selected time point, but not another. This study establishes a novel paradigm that can be used in future work to investigate changes in the neural correlates of fear generalization over time. Fear generalization is found across an array of anxiety disorders, making it a compelling area of study. The present work highlights the dynamic nature of fear generalization in humans. Further, the present study leads to a number of questions for future research.

Pattern separation is the means by which the brain discriminates similar experiences. It enables retrieval of individuated memories without confusing them with other memories. It is the reason one remembers where one parked the car today and does not mix it up with where one parked it previously. Adult neurogenesis refers to the ongoing production of neurons in the mature brain. One of the likely roles of adult neurogenesis in the hippocampus is facilitating pattern separation. Induced reduction of adult neurogenesis in non-human animals is associated with depression- and anxiety-like behaviors. One possible explanation is that reduced neurogenesis leads to reduced pattern separation, further leading to overgeneralization of threat situations. Instead of perceiving threats where it should, the animal risks perceiving threats everywhere. Emotional resilience is the ability to recover from adversity with a minimum of lingering negative effects such as depression or anxiety. This thesis investigates whether pattern separation in the human hippocampus supports emotional resilience. I performed a systematic review of studies that used the Mnemonic Similarity Task – a memory task commonly used to measure human pattern separation – to investigate the relationship between pattern separation and anxiety. The results are inconclusive but suggest a possible interaction effect whereby pattern separation and high-arousal states like stress predict anxiety. Together with the evidence from the non-human animal studies, this suggests that reduced pattern separation as caused by reduced neurogenesis could make one vulnerable to developing anxiety disorders.

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