Differential effects of emotional valence on mnemonic performance with greater hippocampal maturity.

The hippocampal formation (HF) facilitates declarative memory, with subfields providing unique contributions to memory performance. Maturational differences across subfields facilitate a shift toward increased memory specificity, with peripuberty sitting at the inflection point. Peripuberty is also a sensitive period in the development of anxiety disorders. We believe HF development during puberty is critical to negative overgeneralization, a common feature of anxiety disorders. To investigate this claim, we examined the relationship between mnemonic generalization and a cross-sectional pubertal maturity index (PMI) derived from partial least squares correlation (PLSC) analyses of subfield volumes and structural connectivity from T1-weighted and diffusion-weighted scans, respectively. Participants aged 9-14 yr, from clinical and community sources, performed a recognition task with emotionally valent (positive, negative, and neutral) images. HF volumetric PMI was positively associated with generalization for negative images. Hippocampal-medial prefrontal cortex connectivity PMI evidenced a behavioral relationship similar to that of the HF volumetric approach. These findings reflect a novel developmentally related balance between generalization behavior supported by the hippocampus and its connections with other regions, with maturational differences in this balance potentially contributing to negative overgeneralization during peripuberty.

Sleep fails to depotentiate amygdala-reactivity to negative emotional stimuli in youth with elevated symptoms of anxiety.

Sleep-related problems often precede escalating anxiety in early adolescence. Pushing beyond broad sleep-mental health associations and toward mechanistic theories of their interplay can inform etiological models of psychopathology. Recent studies suggest that sleep depotentiates neural (e.g., amygdala) reactivity during reexposure to negative emotional stimuli in adults. Persistent amygdala reactivity to negative experiences and poor sleep characterize anxiety, particularly at the transition to adolescence. We propose that sleep depotentiates amygdala reactivity in youth but fails to do so among youth with anxiety. Participants (n = 34; 18 males; age, mean [M] = 11.35, standard deviation [SD] = 2.00) recruited from the community and specialty anxiety clinics viewed valenced images (positive, negative, and neutral) across two fMRI sessions (Study, Test), separated by a 10-12-hour retention period of sleep or wake (randomized). Mixed linear models regressed basolateral amygdala (BLA) activation and BLA-medial prefrontal cortex (mPFC) functional connectivity to negative images on Time, Condition, and Anxiety Severity. There were greater reductions in BLA activations to negative target images from Study to Test in the Sleep Condition, which was blunted with higher anxiety (b = -0.065, z = -2.355, p = 0.019). No such sleep- or anxiety-related effects were observed for BLA-mPFC functional connectivity (ps > 0.05). Sleep supports depotentiation of amygdala reactivity to negative stimuli in youth, but this effect is blunted at higher levels of anxiety. Disruptions in sleep-related affective habituation may be a critical, modifiable driver of anxiety.

General additive models address statistical issues in diffusion MRI: An example with clinically anxious adolescents.

Statistical models employed to test for group differences in quantized diffusion-weighted MRI white matter tracts often fail to account for the large number of data points per tract in addition to the distribution, type, and interdependence of the data. To address these issues, we propose the use of Generalized Additive Models (GAMs) and supply code and examples to aid in their implementation. Specifically, using diffusion data from 73 periadolescent clinically anxious and no-psychiatric-diagnosis control participants, we tested for group tract differences and show that a GAM allows for the identification of differences within a tract while accounting for the nature of the data as well as covariates and group factors. Further, we then used these tract differences to investigate their association with performance on a memory test. When comparing our high versus low anxiety groups, we observed a positive association between the left uncinate fasciculus and memory overgeneralization for negatively valenced stimuli. This same association was not evident in the right uncinate or anterior forceps. These findings illustrate that GAMs are well-suited for modeling diffusion data while accounting for various aspects of the data, and suggest that the adoption of GAMs will be a powerful investigatory tool for diffusion-weighted analyses.

Negative overgeneralization is associated with anxiety and mechanisms of pattern completion in peripubertal youth.

This study examines neural mechanisms of negative overgeneralization, the increased likelihood of generalizing negative information, in peri-puberty. Theories suggest that weak pattern separation [overlapping representations are made distinct, indexed by dentate gyrus/ cornu ammonis (CA)3 hippocampal subfield activation] underlies negative overgeneralization. We alternatively propose that neuro-maturational changes that favor pattern completion (cues reinstate stored representations, indexed by CA1 activation) are modulated by circuitry involved in emotional responding [amygdala, medial prefrontal cortices (mPFC)] to drive negative overgeneralization. Youth (n = 34, 9-14 years) recruited from community and clinic settings participated in an emotional mnemonic similarity task while undergoing magnetic resonance imaging. At study, participants indicated the valence of images; at test, participants made recognition memory judgments. Critical lure stimuli, which were similar to images at study, were presented at test, and errors ('false alarms') to negative relative to neutral stimuli reflected negative overgeneralization. Negative overgeneralization was related to greater and more similar patterns of activation in CA1 and both dorsal mPFC (dmPFC)and ventral mPFC (vmPFC) for negative relative to neutral stimuli. At study, amygdala exhibited greater functional coupling with CA1 and dmPFC during negative items that were later generalized. Negative overgeneralization is rooted in amygdala and mPFC modulation at encoding and pattern completion at retrieval.