# Sleep Disturbance and Emotion Regulation Brain Dysfunction as Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Dementia

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $897,520

## Abstract

PROJECT SUMMARY/ABSTRACT
BACKGROUND: Several independent lines of evidence suggest that sleep disturbance may directly contribute
to the generation and maintenance of neuropsychiatric symptoms (NPS) including anxiety, depression, agitation,
irritability, and apathy through fronto-limbic brain networks that regulate emotion, particularly in regions of the
prefrontal cortex (PFC) and limbic areas (amygdala). However, the model of sleep disturbance contributing to
increased NPS through impairments in fronto-limbic function has not yet been tested in a sample of participants
with or at high-risk for developing Alzheimer’s Disease (AD). OBJECTIVE: We aim to test this model in patients
with mild cognitive impairment (MCI) and mild AD by characterizing associations between sleep disruption,
fronto-limbic function while regulating emotion, and NPS at baseline and by experimentally manipulating sleep to
determine whether changes in sleep cause downstream alterations in fronto-limbic functioning and NPS.
DESIGN/METHODS: Our hypotheses will be tested in a 2-arm randomized controlled mechanistic trial with 150
patients with MCI and mild AD experiencing sleep disturbances who are also experiencing emotional distress
and other behavioral symptoms. Participants will be randomized in a 1:1 ratio to receive a sleep manipulation
(Cognitive Behavioral Therapy for Insomnia; CBT-I) or to the credible control treatment for insomnia group.
Both interventions will be administered in six sessions delivered over eight weeks. CBT-I is an efficacious
behavioral intervention specifically targeted at improving sleep patterns through a combination of sleep
restriction, stimulus control, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene
education. At baseline, and post-sleep manipulation we will assay each participant’s fronto-limbic functioning
while regulating emotions (amygdala reactivity and PFC-amygdala connectivity), NPS using the Neuropsychiatric
Inventory (NPI), and sleep efficiency using high-density EEG collected overnight during sleep. SPECIFIC AIMS
are to 1) characterize baseline associations among sleep disturbances, emotion regulation brain function, and
NPS prior to a sleep manipulation, 2) test that sleep-induced fronto-limbic brain function improvement mediates
the association between sleep improvement and NPS reductions, and 3) determine baseline predictors of the
NPS improvement. NOVELTY & IMPACT: Using a multi-methodological approach within a mechanistic trial
framework by causally manipulating sleep, we will uncover potential NPS mechanisms across multiple units of
analysis (brain circuit, physiological, behavioral, and self-report). Our results will advance a mechanistic
understanding of how sleep disturbances and fronto-limbic brain function while regulating emotions may
underlie the emotionally distressing and economically relevant problem of NPS in early AD patients. These
results would be a necessary first step in the dev...

## Key facts

- **NIH application ID:** 10214486
- **Project number:** 5R01MH120776-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Andrea Goldstein-Piekarski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $897,520
- **Award type:** 5
- **Project period:** 2019-09-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214486

## Citation

> US National Institutes of Health, RePORTER application 10214486, Sleep Disturbance and Emotion Regulation Brain Dysfunction as Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Dementia (5R01MH120776-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10214486. Licensed CC0.

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