Sleep and Emotional Memory in Peripubertal Anxiety

Study Overview
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Brief Summary
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The current study aims to deepen understanding of the symptom dimension of negative overgeneralization in anxiety. Specifically, the study examines the malleability of memory processes that are known to occur during sleep that may underlie negative overgeneralization.

Detailed Description
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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, the proposal aims to deepen mechanistic understanding of anxiety during the sensitive period of peripuberty to inform novel treatments and reduce health risks. The focus is 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. The proposal posits that sleep plays a critical role in negative overgeneralization. Specifically, the proposal draws from basic neuroscience to posit 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. The proposal further posits 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, the proposal posits that sleep-dependent consolidation is malleable, such that Targeted Memory Reactivation (TMR) of positive memories during sleep can competitively displace consolidation of negative memories. This model is tested 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). Aims 1 and 2 do not involve a clinical trial. 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 is the clinical trial to which this registration refers. In Aim 3, the same design as the sleep condition (above) is used, but a new sample of youth with elevated anxiety (n=60) is recruited 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 TMR) not only to improve existing symptoms, but also to positively shape neurodevelopment and reduce risk in the sensitive period of peripuberty.

Official Title
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Sleep-dependent Negative Overgeneralization in Peri-pubertal Anxiety

Conditions
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Anxiety

Intervention / Treatment
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* Behavioral: Sleep with Sound Cues
* Behavioral: Sleep with Sham Cues


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 10-13 years old Able to understand and communicate in English and have a parent who is able to understand and communicate in English or Spanish included across any range of symptoms of anxiety, and may meet full diagnostic criteria for Social Phobia, Generalized Anxiety and Separation Anxiety. be right-handed. Exclusion Criteria: For youth to be excluded from participation, they must: meet diagnostic criteria for Psychotic Disorders, Major Depressive Disorder, Pervasive Developmental Disorders (including autism spectrum disorders), Obsessive Compulsive Disorder, Conduct Disorder, Bipolar Disorder, Tic disorder, Impulse Control Disorders, or Intellectual Disability. take medications that affect central nervous system function show high likelihood and/or serious intent of hurting themselves or others. have not been living with a primary caregiver for at least 6 months who is legally able to give consent for the child's participation. be a victim of previously undisclosed abuse requiring investigation or ongoing supervision by the Department of Children and Families. have a serious vision problem that is not corrected with prescription lenses, or have prescription glasses outside of the range of -5.00 to +3.00 (contact lenses are ok). have a physical disability that interferes with their ability to lie in scanner and/or click a mouse button rapidly. have a serious hearing problem. have a history of neurological or other major medical conditions affecting brain function. current sleep apnea, and circadian rhythm disturbances (i.e., advanced or delayed sleep-phase) self-reported average sleep duration < 6 hours or > 11 hours across weekday and weekend nights, or normal bedtime later than 1:00 am. Are not suitable to undergo MRI scanning due to claustrophobia, certain implanted devices/metal (e.g., cardiac pacemaker, neurostimulator, some artificial joints, metal pins, surgical/aneurysm clips, heart valves, cochlear implants, pregnant, retinal implants, shrapnel in eye, nonremovable body piercing or other non-MRI compatible metal/device, need prescription glasses that are outside of range .

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Per NIMH policy at the time of funding, the current trial is considered a clinical trial due to prospective, randomized assignment to an intervention to observe effects on behavioral or health related outcomes. The intervention for Aim 3 (n=60) includes randomized assignment to sham sounds (sounds unrelated to the memory task) or target sounds (sounds that were played during the time of the memory task) that are played during sleep to cue memory processing.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sleep with Sound Cues<br>Sounds played at time of memory encoding will be replayed during sleep to cue memory processing. | Behavioral: Sleep with Sound Cues<br>* Experimental manipulation to observe effects on memory for learned material.<br>|
| Sham Comparator: Sleep with Sham Cues<br>Sounds that were not played at time of memory encoding will be played during sleep as a sham comparison | Behavioral: Sleep with Sham Cues<br>* Sham manipulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Object Completion Memory Task (behavioral and fMRI) | Reporting old versus new in response to a picture set that includes old, new and similar pictures to those learned at baseline in order to capture metrics of memory generalization (pattern completion). | Delayed recall, 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Object Completion Memory Task (behavioral and fMRI) | Reporting old versus new in response to a picture set that includes old, new and similar pictures to those learned at baseline in order to capture metrics of memory generalization (pattern completion). | Recall, 12 hours |