Sleep and Emotional Memory in Peripubertal Anxiety

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.

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:

1. 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.

2. take medications that affect central nervous system function

3. show high likelihood and/or serious intent of hurting themselves or others.

4. 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.

5. be a victim of previously undisclosed abuse requiring investigation or ongoing
supervision by the Department of Children and Families.

6. 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).

7. have a physical disability that interferes with their ability to lie in scanner
and/or click a mouse button rapidly.

8. have a serious hearing problem.

9. have a history of neurological or other major medical conditions affecting brain
function.

10. current sleep apnea, and circadian rhythm disturbances (i.e., advanced or delayed
sleep-phase)

11. self-reported average sleep duration < 6 hours or > 11 hours across weekday and
weekend nights, or normal bedtime later than 1:00 am.

12. 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 .