# Sleep-dependent negative overgeneralization in peri-pubertal anxiety

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2021 · $647,318

## Abstract

PROJECT SUMMARY
Up to 50% of peripubertal youth with anxiety have unmet clinical needs, leaving these youth at high risk for
suicide, depression and substance abuse across adolescence. In accord with the NIMH strategic plan, we aim
to deepen mechanistic understanding of anxiety during the sensitive period of peripuberty to inform novel
treatments and reduce health risks. This proposal focuses on negative overgeneralization, which is a core
dimension of anxiety that is poorly understood, and refers to the tendency to generalize aversive responses
from one context (house fire) to other contexts (camp-fire) that share features. Amygdala activity, induced by
heightened emotional arousal, enhances plasticity in associative learning mechanisms, facilitating the binding
of contextual features in memory that are only loosely related. We posit that sleep plays a critical role in
negative overgeneralization. Specifically, we draw from basic neuroscience to propose a model by which
heightened amygdala reactivity during wakefulness, induced by increased emotional arousal, facilitates replay
of negative memories during sleep. This facilitated replay leads to the stabilization and integration
(consolidation) of negative memories into long-term memory networks via slow wave oscillatory events during
NREM sleep. We further propose that facilitated replay of negative memories during sleep promotes
generalization by influencing underlying neurocomputational mechanisms (i.e., pattern completion – a
computational process that makes neural representations similar). Finally, we propose that sleep-dependent
consolidation is malleable, such that Targeted Memory Reactivation (TMR) of positive memories during sleep
can competitively displace consolidation of negative memories, and reduce negative overgeneralization. The
current proposal tests this model using a novel multi-method approach combining neuroimaging,
polysomnography, and a memory task that captures behavioral generalization and its underlying neural
mechanisms (i.e. pattern completion). Aim 1 examines 200 peripubertal youth (ages 10-13 years) across a full
continuum of anxious symptoms in a randomized sleep (n=140) versus wake (n=60) design to demonstrate
sleep-dependent effects on behavioral and neural mechanisms of negative overgeneralization. Aim 2 focuses
on the 140 youth in the sleep condition to evaluate amygdala reactivity at encoding and sleep neurophysiology
during post-encoding sleep as mediators between anxiety and negative overgeneralization. Aim 3 uses the
same design as the sleep condition but recruits a new sample of youth with elevated anxiety (n=60) to enroll in
a randomized trial in which positive memories are cued during sleep (TMR, n=30), or sham cues are presented
during sleep (n=30), to examine malleability of sleep-dependent mechanisms of negative overgeneralization.
This project will set the stage for the long-term goal of developing novel interventions that manipulate sleep
(e.g. via T...

## Key facts

- **NIH application ID:** 10124435
- **Project number:** 5R01MH116005-04
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** DANA L MCMAKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $647,318
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124435

## Citation

> US National Institutes of Health, RePORTER application 10124435, Sleep-dependent negative overgeneralization in peri-pubertal anxiety (5R01MH116005-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124435. Licensed CC0.

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