Negative Overgeneralization is Associated with Anxiety and Mechanisms of Pattern Completion in Peripubertal Youth

Abstract

BACKGROUNDThis study examines neural mechanisms of negative overgeneralization in peri-puberty to identify potential contributors to escalating anxiety during this sensitive period. Theories suggest that weak pattern separation (a neurocomputational process by which overlapping representations are made distinct, indexed by DG/CA3 hippocampal subfields) is a major contributor to negative overgeneralization. We alternatively propose that neuromaturation related to generalization and anxiety-related pathology in peri-puberty predicts contributions from strong pattern completion (a partial match of cues reinstates stored representations, indexed by CA1) and related modulatory mechanisms (amygdala, medial prefrontal cortices [mPFC]). METHODSYouth (N=34, 9-14 years) recruited from community and clinic settings participated in an emotional mnemonic similarity task while undergoing MRI. At Study, participants indicated the valence of images; at Test, participants made an old/new recognition memory judgment. Critical lure stimuli, that were similar but not the same as images from Study, were presented at Test, and errors ("false alarms") to negative relative to neutral stimuli reflected negative overgeneralization. Univariate, multivariate, and functional connectivity analyses were performed to evaluate mechanisms of negative overgeneralization. RESULTSNegative overgeneralization was related to greater and more similar patterns of activation in CA1 and both dorsal and ventral mPFC for negative relative to neutral stimuli. At Study, amygdala increased functional coupling with CA1 and dorsal mPFC during negative items that were later generalized. CONCLUSIONSNegative overgeneralization is rooted in amygdala and mPFC modulation at encoding and pattern completion at retrieval. These mechanisms could prove to reflect etiological roots of anxiety that precede symptom escalation across adolescence.