A Novel Use of a Sleep Intervention to Target the Emotion Regulation Brain Network to Treat Depression and Anxiety
Phase: NA
Conditions: Insomnia, Depression
Sponsor: Stanford University

 
 
 
 
A Novel Use of a Sleep Intervention to Target the Emotion 
Regulation Brain Network to Treat Depression and Anxiety 
 
 
Study Protocol and Statistical Analysis Plan 
NCT04424407 
December 10, 2020 

TIRED–BRAIN Study 
 
Version 1.1 
Protocol IRB-56961 
 
 
 
10-DEC-2020 
 
 
  
 
Study Protocol 
TARGETING INSOMNIA RELATED EMOTION BRAIN 
DYSREGULATOIN (TIRED-BRAIN) 
Protocol Number: IRB-56961  
National Clinical Trial (NCT) Identified Number:  NCT04424407 
Principal Investigator:  
Andrea N. Goldstein-Piekarski, PhD 
Grant Title: A Novel Use of a Sleep Intervention to Target the Emotional 
Regulation Brain Network and Treat Depression and Anxiety 
Grant Number: 1 R61 MH120245-01 
Funded by: The National Institute of Mental Health 
Version Number:  v.1.1 
10-DEC-2020 
 
 
 
Important Note: The aforementioned grant encompasses R61 and R33 phases. 
The enclosed information refers only to the R61 phase.  
 
 

TIRED–BRAIN Study 
 
Version 1.1 
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Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
Not Applicable; this is the first version 
of the protocol 
 
 
 
 
 

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CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ....................................................................................................................................... 6 
INVESTIGATOR’S SIGNATURE ........................................................................................................................................ 7 
1 
PROTOCOL SUMMARY ...................................................................................................................................... 8 
1.1 
Synopsis .................................................................................................................................................. 8 
1.2 
Schema ................................................................................................................................................. 10 
1.3 
Schedule of Activities ........................................................................................................................... 11 
2 
INTRODUCTION ............................................................................................................................................... 12 
2.1 
Study Rationale .................................................................................................................................... 12 
2.2 
Background ........................................................................................................................................... 13 
2.2.1 
Significance ....................................................................................................................... 13 
2.2.2 
Innovation ......................................................................................................................... 17 
2.3 
Risk/Benefit Assessment ...................................................................................................................... 17 
2.3.1 
Known Potential Risks ....................................................................................................... 17 
2.3.2 
Known Potential Benefits ................................................................................................. 18 
2.3.3 
Assessment of Potential Risks and Benefits ..................................................................... 19 
3 
OBJECTIVES AND ENDPOINTS ......................................................................................................................... 19 
3.1 
Primary objectives ................................................................................................................................ 19 
3.1.1 
Go/No-Go Milestones ....................................................................................................... 19 
3.1.2 
primary Analyses .............................................................................................................. 20 
3.1.3 
Secondary Analyses ...................................................................................................... 20 
3.2 
Exploratory Analyses ............................................................................................................................ 20 
3.3 
Study Measures .................................................................................................................................... 21 
3.3.1 
Emotion Regulation Network Function ............................................................................ 22 
3.3.2 
Insomnia 22 
3.3.3 
Depressive symtpoms ....................................................................................................... 22 
3.3.4 
Current functioning (secondary measures) ...................................................................... 22 
4 
STUDY DESIGN ................................................................................................................................................. 22 
4.1 
Overall Design ...................................................................................................................................... 22 
4.1.1 
Randomization ................................................................................................................ 23 
4.1.2 
Sleep manipulation ........................................................................................................ 23 
4.1.3 
Study sites ....................................................................................................................... 23 
4.2 
Scientific Rationale for Study Design .................................................................................................... 24 
4.2.1 
Justification of a Single-arm mechanistic trial .................................................................. 24 
4.3 
Justification for Intervention ................................................................................................................ 24 
4.3.1 
General Intervention considerations ................................................................................ 24 
4.3.2 
Consideration of generalizability ...................................................................................... 25 
4.4 
End-of-Study Definition ........................................................................................................................ 25 
5 
STUDY POPULATION ....................................................................................................................................... 25 
5.1 
Inclusion Criteria ................................................................................................................................... 25 
5.2 
Exclusion Criteria .................................................................................................................................. 26 
5.3 
Lifestyle Considerations ....................................................................................................................... 27 
5.4 
Screen Failures ..................................................................................................................................... 27 
5.5 
Strategies for Recruitment and Retention ........................................................................................... 27 
5.5.1 
Recruitment strategies ..................................................................................................... 27 
5.5.2 
retention and engagement strategies .............................................................................. 28 

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5.5.3 
Inclusion of women and minorities .................................................................................. 29 
5.5.4 
Anticipated recruitment, enrollment, and retention ....................................................... 30 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .................................................................. 31 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration .............................................. 31 
6.1.1 
Study Intervention or Experimental Manipulation Description ....................................... 31 
6.1.2 
Administration and/or Dosing .......................................................................................... 32 
6.2 
Fidelity .................................................................................................................................................. 32 
6.2.1 
Interventionist Training and Tracking ............................................................................... 32 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................................... 32 
6.3.1 
Randomization Procedures ............................................................................................... 32 
6.3.2 
Blinding Procedures .......................................................................................................... 32 
6.4 
Study Intervention/Experimental Manipulation Adherence ................................................................ 33 
6.5 
Concomitant Therapy ........................................................................................................................... 33 
6.5.1 
Rescue Therapy ................................................................................................................. 33 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................................................. 33 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation .................................................... 33 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................................................... 34 
7.3 
Lost to Follow-Up ................................................................................................................................. 34 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................................... 35 
8.1 
Endpoint and Other Non-Safety Assessments ..................................................................................... 35 
8.1.1 
physical examination ........................................................................................................ 35 
8.1.2 
Clinical Interviews ............................................................................................................. 35 
8.1.3 
Questionnaires .................................................................................................................. 35 
8.1.4 
Performance based assessments ...................................................................................... 38 
8.1.5 
Sleep assessments ............................................................................................................ 38 
8.1.6 
Neuroimaging ................................................................................................................... 39 
8.1.7 
Genetics 41 
8.2 
Safety Assessments .............................................................................................................................. 41 
8.2.1  PHYSICAL EXAMINATION 41 
8.2.1 
Questionnaires .................................................................................................................. 41 
8.2.2 
Imaging 42 
8.3 
Adverse Events and Serious Adverse Events ........................................................................................ 42 
8.3.1 
Definition of Adverse Events ............................................................................................ 42 
8.3.2 
Definition of Serious Adverse Events ................................................................................ 42 
8.3.3 
Classification of an Adverse Event .................................................................................... 42 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .................................. 44 
8.3.5 
Adverse Event Reporting .................................................................................................. 44 
8.3.6 
Serious Adverse Event Reporting...................................................................................... 44 
8.3.7 
Reporting Events to Participants ...................................................................................... 45 
8.3.8 
Events of Special Interest.................................................................................................. 45 
8.3.9 
Reporting of Pregnancy .................................................................................................... 45 
8.4 
Unanticipated Problems ....................................................................................................................... 46 
8.4.1 
Definition of Unanticipated Problems .............................................................................. 46 
8.4.2 
Unanticipated Problems Reporting .................................................................................. 46 
8.4.3 
Reporting Unanticipated Problems to Participants .......................................................... 47 

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STATISTICAL CONSIDERATIONS ....................................................................................................................... 47 
9.1 
Statistical Hypotheses .......................................................................................................................... 47 
9.2 
Sample Size Determination .................................................................................................................. 47 
9.3 
Populations for Analyses ...................................................................................................................... 48 
9.4 
Statistical Analyses ............................................................................................................................... 48 
9.4.1 
General Approach ............................................................................................................. 48 
9.4.2 
Analysis of the Primary Endpoint(s) .................................................................................. 48 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 48 
9.4.4 
Safety Analyses ................................................................................................................. 49 
9.4.5 
Baseline Descriptive Statistics .......................................................................................... 49 
9.4.6 
Planned Interim Analyses ................................................................................................. 49 
9.4.7 
Sub-Group Analyses .......................................................................................................... 50 
9.4.8 
Tabulation of Individual Participant Data ......................................................................... 50 
9.4.9 
Exploratory Analyses ........................................................................................................ 50 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................................... 50 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................................... 50 
10.1.1 
Informed Consent Process ................................................................................................ 50 
10.1.2 
Study Discontinuation and Closure ................................................................................... 51 
10.1.3 
Confidentiality and Privacy ............................................................................................... 51 
10.1.4 
Future Use of Stored Specimens and Data ....................................................................... 53 
10.1.5 
Key Roles and Study Governance ..................................................................................... 54 
10.1.6 
Safety Oversight ................................................................................................................ 55 
10.1.7 
Quality Assurance and Quality Control ............................................................................. 61 
10.1.8 
Data Handling and Record Keeping .................................................................................. 61 
10.1.9 
Protocol Deviations ........................................................................................................... 62 
10.1.10 
Publication and Data Sharing Policy ................................................................................. 62 
10.1.11 
Conflict of Interest Policy .................................................................................................. 63 
10.2 
Additional Consideratio ........................................................................................................................ 63 
10.3 
Abbreviations and Special Terms ......................................................................................................... 63 
10.4 
Protocol Amendment History ............................................................................................................... 65 
11 
REFERENCES .................................................................................................................................................... 66 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human 
Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) 
must be obtained before any participant is consented. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to the 
consent form(s) will be IRB approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved consent 
form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances that this 
study will be conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and according to local legal and regulatory requirements and applicable US federal regulations 
and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name:  Andrea Goldstein-Piekarski 
 
Title: 
Clinical Assistant Professor 
 
Investigator Contact Information 
Affiliation: Stanford University School of Medicine 
Email: agoldpie@stanford.edu 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
A Novel Use of a Sleep Intervention to Target the Emotional Regulation Brain 
Network and Treat Depression and Anxiety 
Grant Number: 
1 R61 MH120245-01 
Study Description: 
Background: Several lines of evidence suggest that insomnia contributes to 
emotionally distressing depressive mood symptoms through disruption of 
brain networks that regulate emotional functions. Of particular concern, 
insomnia is associated with an increased risk for suicide, even when 
accounting for the presence of other depressive symptoms. However, we do 
not yet know to what degree that the emotion regulation brain network is 
modified by the restoration of sleep, or whether the degree to which a sleep 
intervention engages these neural targets mediates reductions in depressive 
symptoms and suicidality. Objective: This proposal investigates the impact of 
a proven sleep intervention on engagement of the emotion regulation brain 
network as a putative mechanistic target. DESIGN/METHODS: In the R61 
phase, a mechanistic trial will demonstrate feasibility and establish whether 
the emotion regulation brain network is modified (the target is engaged) when 
patients show improvements in insomnia symptoms following a proven 
psychosocial sleep intervention. Participants will be 70 adults experiencing 
elevated depressive symptoms and clinically meaningful insomnia. Depressive 
symptoms and insomnia will be assessed prior to, and weekly while receiving 
six Cognitive Behavioral Therapy for Insomnia (CBT-I) sessions across a period 
of eight weeks. CBT-I improves sleep patterns through a combination of sleep 
restriction, stimulus control, mindfulness training, cognitive therapy targeting 
dysfunctional beliefs about sleep, and sleep hygiene education. Emotion 
regulation network neural targets will be assayed prior to and following 
completion of CBT-I treatment. If the Go milestone criteria are met, the R33 
phase (years 3-5) will include a 2-arm randomized controlled trial. We will 
enroll new participants (n=150) and randomize them in a 1:1 ratio to the 
CBT-I or to the credible control treatment for insomnia group. Participants 
will complete a refined measurement protocol based on the R61 phase 
study. Specific aims: R61 aims are to demonstrate (1) feasibility and (2) that 
CBT-I modifies emotion regulation network function according to pre-
specified Go milestone criteria. IMPACT: Characterizing these associations 
may offer the potential to gain a deeper understanding of the 
neurobiological mechanisms underlying depression in the presence of 
insomnia. Our results will advance an evidence-based mechanistic approach 
to treating, and ultimately preventing, the emotionally distressing and 
potentially life-threatening impact of insomnia. 
 

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Objectives: 
 
1. Demonstrate feasibility and 2. target engagement in a single arm clinical 
trial (Study 1). We will enroll 70 adults with elevated depressive symptoms 
(BDI ≥ 14) who are also experiencing clinically meaningful insomnia (≥15 ISI). 
Given the high comorbidity rates, anxiety will not be exclusionary. Participants 
will receive six sessions of CBT-I over eight weeks. CBT-I is an efficacious 
intervention that improves subjective and objective measures of insomnia. At 
both baseline and post-treatment, we will assay emotion regulation neural 
targets (using fMRI), depressive symptoms and suicidality, and each subject 
will complete an over-night sleep EEG recording. Depression, suicidality, and 
insomnia symptoms (actigraphy and ISI) will be assayed at baseline and each 
week throughout treatment to assess week-to-week improvements following 
an increasing number of CBT-I sessions. Milestones (Go/NoGo Criteria): 1. 
Feasibility: Enroll 70 participants and retain ≥80% at the end of treatment; 2. 
Target Engagement:  For a go decision at least 1 of 3 emotion regulation tasks 
must exhibit an improved group mean (M) value with a boundary value 
(Standard Deviation (SD)/2) in the direction of improvement for both 
amygdala reactivity ((M-SD/2) ≤-0.35) and amygdala-mPFC connectivity 
((M+SD/2) ≥0.35. The targets that meet these criteria will be carried over as 
primary targets of emotion regulation network function in the R33 phase.  
Endpoints: 
Primary Endpoint: emotion regulation brain function 
Study Population: 
70 patients with moderate to severe sleep disturbance and at least mild 
depressive symptoms as measured by the Beck Depression Inventory (BDI).  
Phase or Stage: 
1 
Description of 
Sites/Facilities Enrolling 
Participants: 
The study will be conducted at Stanford University School of Medicine.   
Description of Study 
Intervention/Experimental 
Manipulation: 
SLEEP MANIPULATION 
The sleep manipulation is Cognitive Behavioral Therapy for Insomnia (CBT-I). 
Treatments will be delivered in six 50-minute treatment sessions within an 
eight-week period by a PhD psychologist who is experienced in administering 
the study treatments. The CBT-I therapy will be delivered according to 
protocols and materials from our large-scale VA implementation of CBT-I. 
These materials include a published sleep self-help book, a published therapist 
guide, and the CBT-I therapist manual. 
Study Duration: 
24 months 
Participant Duration: 
This study lasts 11-weeks, and includes screening, baseline visit, treatment, 
and end-of treatment visit. Participants will be scheduled for 6 treatment visits 
across an eight-week period. All study measures will be collected at baseline 
and week 11 end of treatment visit. 
 
 
 
 
 
 
 
 

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1.2 
SCHEMA  
 
 
 
 
 
 
 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES  
Participant Schedule:  
 
 
 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Insomnia is a defining characteristic of depressive disorder, risk factor for developing depression, and can 
exacerbate the severity of other depressive symptoms. Of particular concern, insomnia is associated with an 
increased risk for suicide, even when accounting for the presence of other depressive symptoms. Sleep 
problems, including insomnia, also disrupt function of the amygdala and its connectivity with the medial 
prefrontal cortex (mPFC): regions that regulate emotion and contribute to depression pathophysiology. Thus, 
these regions are promising targets for the mechanisms by which an empirically supported insomnia 
intervention may improve depression. We aim to assess whether 1) amygdala and amygdala-mPFC connectivity 
are response biomarkers of the effects of Cognitive Behavioral Therapy for Insomnia (CBT-I) on depressive 
symptoms, 2) changes in amygdala and its mPFC connectivity mediate reductions in depressive symptoms, and 
3) baseline amygdala and its mPFC connectivity are predictive biomarkers for reductions of depressive 
symptoms following CBT-I. 
OBJECTIVE: 1. Demonstrate feasibility and 2. target engagement in a single arm clinical trial (Study 1). We will 
enroll 70 adults with elevated depressive symptoms (BDI ≥ 14) who are also experiencing clinically meaningful 
insomnia (≥15 ISI) and at least mild depressive symptoms as measured by the Beck Depression Inventory (BDI). 
Participants will receive six sessions of Cognitive Behavioral Therapy for Insomnia (CBT-I) over eight weeks. CBT-
I is an efficacious intervention that improves sleep patterns through a combination of sleep restriction, stimulus 
control, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene education. At both 
baseline and post-treatment, we will assay emotion regulation neural targets (using functional magnetic 
resonance imaging), emotional distress, and each subject will complete an over-night sleep EEG recording. 
Depression, suicidality, and insomnia symptoms (actigraphy and ISI) will be assayed at baseline and each week 
throughout treatment to assess week-to-week improvements following an increasing number of CBT-I sessions.  
Milestones (Go/No-Go Criteria): Feasibility: Enroll 70 participants and retain ≥80% at the end of treatment; 
Target Engagement: For a go decision at least 1 of 3 emotion regulation tasks must exhibit an improved group 
mean (M) value with a boundary value (Standard Deviation (SD)/2) in the direction of improvement for both 
amygdala reactivity ((M-SD/2) ≤-0.35) and amygdala-mPFC connectivity ((M+SD/2) ≥0.35. The targets that meet 
these criteria will be carried over as primary targets of emotion regulation network function in the R33 phase. 
NOVELTY & IMPACT: Characterizing these associations may offer the potential to gain a deeper understanding 
of the neurobiological mechanisms underlying depression in the presence of unhealthy sleep patterns. Our 
results will advance an evidence-based mechanistic approach to treating, and ultimately preventing, the 
emotionally distressing and potentially life-threatening impact of sleep disruption. 
 
 
 
 
 

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2.2 
BACKGROUND  
2.2.1 SIGNIFICANCE 
Depression and insomnia are prevalent, costly, and commonly comorbid. An estimated 16 million American 
adults experience major depressive disorder (MDD)1 each year, which is a leading cause of disability, lost 
productivity, and death in the United States2, estimated at over $210.5  billion per year3-7. Sleep problems, 
especially insomnia, are a core feature of depressive disorder and predict the severity of other depressive 
symptoms, such as low mood, emotion regulation deficits, and suicide risk.8-15 For example, in a large sample of 
adults with depression, 83% of individuals endorsed at least one insomnia complaint16. Moreover, conservative 
estimates indicate that those with mood disorders are at least twice as likely to develop sleep difficulties13,16. 
Sleep complaints are often unresolved following depression treatment and residual sleep impairments 
significantly increase risk for depression relapse17. Of particular concern, insomnia is associated with an 
increased risk for suicide, even when accounting for the severity of other depressive symptoms18-22.  Thus, 
optimizing the precision and potency of sleep interventions, particularly among those with depression, and 
elucidating the mechanism of such effects, promises sizable mental and public health benefits. Addressing this 
critical need, this R61/R33 project aims to advance the mechanistic understanding of how insomnia and 
recovery impacts depressive and suicidal symptoms through the emotion regulation brain network (Figure 1). 
Using a precision medicine approach, we aim to prototype a model to identify which patients demonstrate a 
reduction in depressive and suicidal symptoms as a result  
Figure 1. Conceptual Framework: (Below) Sleep disturbance contributes to 
depressive symptoms through impairments in emotion regulation brain function, 
particularly in fronto-limbic regions of the amygdala and mPFC (part of the 
Negative Affect Network23,24). (Right) Conversely, sleep restoration is hypothesized 
to alleviate depressive symptoms by normalizing fronto-limbic regulation of 
emotion.  

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of a targeted sleep 
intervention. 
Insomnia 
is 
a 
modifiable, 
transdiagnostic target 
for both preventing 
and 
treating 
depressive symptoms. 
Insomnia is both a 
symptom of psychiatric 
illness, and a strong 
predictive factor in its 
development10-13 
and 
prognosis17,25. 
Mechanistic, 
pre-
clinical studies show 
that sleep deprivation 
increases anxiety and 
depression11,26-31.  
Individual differences in 
sleep architecture and 
physiology 
are 
also 
associated with depressive symptoms and suicidal ideation19,31-36. MDD is frequently accompanied by decreased 
sleep continuity and depth37, which can be improved by a behavioral insomnia treatment38,39. Depression is also 
associated with increased REM pressure37. More recent work has described sleep abnormalities associated with 
depressive symptoms using spectral analysis of the EEG signal, including decreased delta activity during Non-
Rapid Eye Movement Sleep (NREM) associated with perceptions of stress, and increased alpha activity during 
NREM associated with depression symptoms40. Additionally, individual differences in REM sleep spectral 
profiles are associated with next-day emotion regulation network function and behavioral performance on 
emotion tasks31,32,34. Importantly, these spectral markers are highly localized over the frontal cortex such that 
using full-scalp EEG, as proposed in the current application, is necessary to obtain spatial coverage and 
resolution necessary to detect region-specific  

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changes.  
While 
limited 
in 
number, 
these 
studies support the 
hypothesis 
that 
sleep disruption and 
abnormal 
sleep 
physiology may be a 
causal risk factor in 
the 
development, 
maintenance, 
and 
exacerbation 
of 
depressive 
symptoms as well as 
other indicators of 
emotional distress in 
psychiatric 
disorders. Critically, 
there is evidence from PI Goldstein-Piekarski’s (Figure 2) that sleep disruption is a modifiable target that can 
reduce other depressive symptoms, including suicide risk specifically, making sleep-targeted behavioral 
therapies attractive and tractable therapeutic opportunities. Findings from  
 Co-I Manber also suggest that at least with respect to subjective sleep measures, improvements in sleep 
mediate changes in depression symptoms, but not the reverse41. While promising, these studies were designed 
with sleep improvement as the primary outcome measures, not depression. As a result, the effect sizes from 
these studies are likely underestimated, and we do not have a true characterization of the efficacy of using 
sleep treatment to improve depression in those with insomnia. Indeed, when restricting analyses to those with 
relatively higher depression scores at baseline (BDI ≥ 14; the proposed inclusion criteria for the current study), 
Co-I Manber and Bernert found a large effect for CBT-I in reducing other depressive symptoms (Cohen’s d = 
1.45). Similarly, a large effect size was found for reducing suicidal ideation posttreatment (Cohen’s d = 1.83). 
However, we currently lack a complete understanding of neurobiological mechanisms mediating relationships 
between improved sleep and reduced depressive symptoms, which hinders our ability to identify  
which individuals will experience a reduction in depression following a targeted sleep intervention.  
Impaired emotion regulation brain function may causally link insomnia and depression. Neuroimaging studies 
implicate an extended limbic network (Emotion Regulation Network (ERN)), that includes the amygdala and 
associated 
medial 
Prefrontal 
Cortex 
(mPFC), 
that 
optimizes 
emotional 
behaviors, 
including 
identifying/attending to salient stimuli and generating/regulating the emotional response to these stimuli23,42-
48. The amygdala is particularly involved in attending and generating bottom-up emotional responses to 
emotionally-salient stimuli, while the PFC is involved in top-down regulation of amygdala activation in response 
to negative emotions42-47. Both hyper-reactivity of the amygdala as well as hypo-connectivity of mPFC-amygdala 
are theorized to contribute to the development and maintenance of maladaptive behaviors commonly 
observed in MDD49-53 including poor emotion regulation54-56. Supporting this hypothesis, MDD show profiles of 
dysfunction within the ERN, including hyper-reactivity in the amygdala57-64 and reduced top-down control, as 
measured by hypo-connectivity between the amygdala and mPFC during emotion tasks65-69 and at rest67,70-72. 
Preliminary data shown below also support these associations (see Figure 3) 
 
 
Figure 2. Preliminary Data: Associations between insomnia (ISI) and depressive symptoms (BDI 
after excluding the sleep items). Data from 106 older adults seeking treatment for insomnia. This 
study excluded Axis-I diagnoses. A. Insomnia was associated with depressive symptoms at 
baseline. B. Depressive symptoms decreased after receiving CBT-I C. The reduction in insomnia 
severity was associated with the reduction in depressive symptoms, such that those with the 
greatest reduction in insomnia experienced the greatest reduction in other depressive 
symptoms.  

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These 
same 
regions 
are 
impaired 
by 
experimentally induced and naturalistic sleep 
disruption (including insomnia) and may be 
improved by intervening sleep. Acute sleep 
deprivation, sleep restriction, and poor habitual 
sleep (including insomnia) all amplify amygdala 
reactivity to negative experiences30,31,73-77. This 
signature of excessive amygdala reactivity caused 
by sleep disruption, has routinely been linked to 
decreases in functional connectivity with the 
mPFC73-77. These alterations in brain function are 
also paired with changes in affective behavioral 
outcomes and subjective reports of significant 
clinical relevance. For example, inter-individual 
differences 
in 
mPFC-amygdala 
connectivity 
following sleep deprivation are significantly correlated with concurrent sleep-loss increases in subjective 
anxiety76. Preliminary data from a sample of unmedicated participants with a range of depressive symptoms, 
demonstrates robust associations between amygdala hyperactivity and insomnia severity as measured by the 
insomnia item from the BDI; this converges with evidence that insomnia symptom severity mediates known 
associations between depression and amygdala hyperactivity (Figure 3). Critically, and guiding our hypothesis 
that CBT-I may reduce depressive symptoms through improving ERN dysfunction, a full night of sleep normalizes 
amygdala reactivity and re-establishes 
mPFC-amygdala connectivity the following 
day32. 
Taken 
together 
with 
the 
aforementioned background this evidence 
strongly suggests that sleep disruption, 
including 
insomnia, 
causes 
a 
dysfunctional brain state as well as 
emotional 
distress 
that 
strongly 
resembles that of MDD, and that may be 
reversible 
with 
a 
targeted 
sleep 
intervention.  
In this R61/R33 project, we aim to test the 
hypothesis 
that 
alleviating 
insomnia 
reduces other depressive symptoms by 
normalizing ERN function (Figure 4). In the 
R61 phase, we will conduct a mechanistic 
trial to determine whether an insomnia intervention with proven efficacy engages ERN functioning (R61 Aim 1). 
Then, if the Go criteria are met, in the R33 phase we will test ERN engagement against an active control condition 
(R33 Aim 1). We will also test the hypothesis that changes in ERN function mediate improvements in depressive 
symptoms (R33 Aim 2).  
Discrete patterns of emotion regulation brain function and sleep physiology may identify patients whose 
other depressive symptoms are a consequence of insomnia. Identifying these patterns will aide in the 
delivery of sleep interventions to the appropriate patient population. PI Goldstein-Piekarski and Co-I Williams, 
as well as others, have identified distinct profiles of engagement of the ERN78,79 that predict response to 
antidepressant and behavioral treatments for depression. Similarly, PI Goldstein-Piekarski and others have 
identified biomarkers related to sleep physiology that predict next-day ERN engagement as well as emotional 
 
Figure 3. Preliminary Data: Emotion regulation network function 
(amygdala reactivity to subliminal threat) is associated with both A. 
Depressive symptoms (BDI) and B. Sleep disturbance (Insomnia item of 
the BDI) in a sample of 87 unmedicated individuals ranging from no 
depression through clinical depression. 
Figure 4. Conceptual frame work and Specific Aims 1 and 2 for the R33 
phase 
 

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consequences following acute sleep deprivation31,80, which may inform treatment response. These findings 
support the hypothesis that discrete profiles of ERN function, as well as sleep architecture and physiology prior 
to treatment, may prospectively identify individuals that would show a reduction in depressive symptoms, 
including suicide risk, by treating insomnia (R33 Aim 3). 
 
2.2.2 INNOVATION 
 
This study represents innovation at three levels: (1) Conceptual novelty: To date, three largely nonoverlapping 
lines of research have characterized the association between (i) insomnia and depression, (ii)depression and 
ERN function, (iii) sleep and ERN function. Together, these lines of research suggest that maladaptive ERN 
function may be an intermediate step between insomnia and depression, and that sleep is a modifiable target 
through which emotional distress can be reduced. However, this study represents the first study to explicitly 
evaluate ERN engagement as a mediator and predictor of depressive symptom improvement following an 
insomnia intervention. As such, these aims will clarify mechanisms through which insomnia can lead to other 
depressive symptoms and help develop personalized, mechanism-focused preventative strategies and 
treatments. The current approach represents a necessary first step in identifying individuals in which depression 
is a direct consequence of insomnia. (2) Methodological & Technical: Our study implements a multimodal, 
neuroimaging approach that fuses sleep EEG with full-scalp coverage, fMRI, and ERN function assessments 
during emotion reactivity and regulation. While each technique alone has proven useful in the context of 
depression research, combining these techniques promises to elucidate ERN engagement and sleep physiology 
mechanisms that mediate changes in depressive symptoms following a sleep intervention in a manner not 
previously possible. Moreover, by capitalizing on these multimodal domains, we can more clearly identify 
individuals whose depression is caused by insomnia and thus who are mostly likely to benefit from such an 
intervention. (3) Public & Mental health: While depression is one of the most prevalent and costly psychiatric 
conditions across the lifespan, there are currently no means to tailor treatment to a specific, underlying 
dysfunction. A major outcome of this study will therefore be a novel and clinically-useful mechanistic model 
that predicts treatment response to better treat depressed individuals with co-morbid insomnia. 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
From past experience, potential risk to participants is expected to be minimal. During data collection, the 
potential risks to participants will be as follows:  
Brain Imaging Assessments: The principal piece of equipment used in this protocol is a 3 Tesla GE magnetic 
resonance imaging (MRI) scanner. The risks associated with MRI are minimal. A small number of people may 
feel claustrophobic inside the machine. The study will be immediately stopped via button press if this occurs. 
Study personnel and technicians will be on site during all acquisitions to address any such discomfort. To 
minimize fatigue, sufficient breaks are provided to participants during the scanning procedure, and the 
experimenter regularly inquires as to whether there is anything that s/he can do to facilitate the participant’s 
comfort. Routine contraindications to MRI include presence of any metal implants (pacemaker, aneurysm clips, 
neurostimulators, cochlear, eyes, tattoos with ink contraindicated for MRI scanning). All participants will be 
appropriately screened for the presence of any such implants and/or health conditions that prohibit their MRI 
scanning for research purposes, using Stanford’s CNI MRI screening forms. Participants who can participate in 
the MRI session will be screened with a metal detector before entering the magnet room for their safety. During 

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the scan there is a slight risk participants might experience changes in temperature in specific body parts or 
peripheral nerve stimulation despite adequate measures taken to prevent these from occurring. Study 
personnel and MRI technologists will be on site during all acquisitions and will be trained to monitor and address 
any such discomfort in a timely manner. Upon participation in MRI studies, research subjects are exposed to 
the risk of a brain abnormality being observed. We will follow an established procedure to inform and protect 
our research participants in case of an incidental MRI finding. 
Ambulatory Polysomnographic Recording: The polysomnographic evaluation is strictly non-invasive. The 
equipment is well-maintained and appropriate grounding procedures are used to protect participants. Small 
sensors (electrodes) are positioned on the participant's scalp, face and body. Minor skin irritation may result 
from the application of these electrodes. Other than the time duration, there are no known adverse effects on 
participants resulting from either the assessment procedures. Some participants may have face or bodily hair 
that may cause minor discomfort during removal similar to a bandage. Disposable razors will be available for 
participants who wish to remove hair prior electrode placement.  
Self-Report and Cognitive Assessments: The risks associated with the web-based self-report and cognitive 
assessments are minimal. They have not caused distress in the 5,000 healthy participants or the 1,100 patients 
who have completed these assessments in prior studies  
Cognitive Behavioral Therapy for Insomnia Intervention: The CBT-I intervention has been well tolerated in the 
past. The study therapist will be experienced and sensitive to clinical issues. While treatments are intended to 
contribute to the development of nonpharmacological alternatives to current treatments for insomnia with 
comorbid emotional distress, the treatment protocol is not intended as a withdrawal procedure from sleeping 
medications. Those volunteers who are taking sleeping or other psychotropic medications at the time of 
recruitment will be admitted to the study only if they withdraw from the medication under the supervision of 
their physician. They may then be evaluated for inclusion in the study when they have been successfully 
withdrawn from the medication for a minimum of three weeks. Thus, no side-effects of medication withdrawal 
in these patients is planned as part of the treatment protocol.  
COVID-19 Mitigation: There is a risk of contracting COVID-19 as a result of interacting with new individuals and 
places. The research team has put together mitigation protocols to help minimize the risk of contracting COVID-
19. All researchers and participants will be required to wear face coverings, use hand sanitizer upon entering 
buildings, observe room density requirements set forth by Stanford, and maintain social distancing (> 6 feet 
separation) throughout the session when possible. There will be times during the scanning session and sleep 
recording hook-up where it will not be possible to maintain social distance. During these times researchers will 
wear additional protective equipment including a face shield to minimize potential exposure. Researchers will 
disinfect all surfaces and equipment the participant comes into contact with. Researchers will be required to 
complete a Health Check prior to entering the lab. Participants will complete a COVID-19 screening call prior to 
arrival on campus. Only researchers and participants who do not present symptoms of COVID-19 will be allowed 
to participate in research. 
All interviews, questionnaires, and laboratory procedures have been carefully selected with regard to their 
reliability and validity, their relevance to the hypotheses of the study, and evidence from prior research (in our 
own laboratories and as reported in the literature) that these methods can be used without adverse effects on 
the participants. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Participants are expected to benefit from this proposal since CBT-I has been shown to be efficacious for treating 
insomnia. Further, recent studies including preliminary data from our own lab, have found that these benefits 

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may go beyond treating insomnia, but also alleviating other emotional distress including anxiety and depressive 
symptoms. Additionally, results of the proposed study may help to identify which individuals would benefit 
from a sleep intervention as well as develop new interventions for other individuals with similar conditions and 
guide future research endeavors. Other potential benefits include 1) participants will have their psychiatric 
symptoms evaluated by a trained Clinical Psychologist; 2) participants’ quality of life may be improved. Overall, 
the risk/benefit ratio is favorable since the procedures used in the research study are similar to those used in 
clinical practice. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
This innovative project contributes to the understanding how sleep disruption and emotion regulation brain 
functions contribute depressive symptoms. The outcomes will help further a neural system-based 
understanding of emotional distress-related dysfunction that arises from loss of sleep, and may be remedied 
with a sleep intervention. Understanding these neural and sleep mechanisms will advance the evidence base 
for classification and treatment personalization for this population. Thus, the benefit to society could be 
substantial. 
Although all research has risks, the risks to patients of the proposed research are well understood and will be 
explained to participants. There is little risk from the assessment procedures.  
The long-term potential benefit of this research is to provide a neural and sleep based model to support 
classification and clinical management of depressive symptoms that arise from sleep disruption. Reflecting 
these goals, the potential benefits of the research are substantial. The risks associated with participation in 
these studies are minimal compared to the potential benefits of improvement for clinical practice. 
 
 
3 
OBJECTIVES AND ENDPOINTS  
3.1 
PRIMARY OBJECTIVES  
3.1.1 GO/NO-GO MILESTONES 
1. Feasibility of recruitment and retention: enroll 70 participants and retain ≥80% at 11 weeks. In our study of 
older adults (mean age=68.51, SD=5.78) described above, 87% of our sample was retained at the end of 
treatment visit at 11 weeks. In a prior study that included adults with comorbid depression and insomnia (mean 
age=47.4, SD=12.6), 93% of the individuals completed treatment81.  
2. Emotion Regulation Network Target Engagement: This will be determined using the precision interval 
approach. The goal is to demonstrate sufficient variation for further investigation82,83. We hypothesize that CBT-
I will improve ERN function by reducing amygdala reactivity and increasing amygdala-mPFC connectivity. Thus, 
for the amygdala, improvement is likely reflected in an absolute negative mean change value with a lower fixed-
width interval boundary (M-SD/2), where M is the mean and SD is the standard deviation, which is also 
substantially in the negative direction. Similarly, the amygdala-mPFC improvement is reflected by an absolute 
increase mean change with an upper fixed-width interval boundary (M+SD/2). For a GO decision, we will require 
at least 1 of 3 emotion regulation neuroimaging tasks must exhibit improvement by having both a group mean 
change of amygdala activation with symmetric 1 SD intervals whose lower bound is less than an absolute precision 
criterion of (M-SD/2) ≤ -0.35, and a positive group mean change of the amygdala-mPFC connectivity whose upper 
bound is greater than an absolute precision criteria of (M+SD/2) ≥ 0.35. The criterion ±0.35 was selected as a value 

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clearly indicating more than “noise,” as it places a substantial portion of the subjects in the improvement range, 
and thus is of potential clinical importance to warrant further study82.  
 
3.1.2 PRIMARY ANALYSES 
We hypothesize that in this single-arm study treatment with CBT-I will lead to improvements in Emotion 
Regulation Network function. Specifically, we predict that sleep restoration will be associated with greater 
decreases in amygdala reactivity and increases in mPFC-Amygdala Connectivity. An extended analysis of 
covariance (ANCOVA) will be used to test the primary hypothesis of change in Emotion Regulation Network 
function from baseline to end of treatment. We will characterize the association between our primary measures 
of Emotion Regulation Network function and that of our proximal outcome (sleep disruption as defined by 
sleep-EEG derived sleep efficiency) using a regression framework with age and sex included as covariates.  
3.1.3 SECONDARY ANALYSES 
We will examine the treatment effect on outcomes as measured by validated self-report questionnaires and 
sleep disruption measurements. We will also examine the association of change in Emotion Regulation Network 
function with change in outcomes from other domains. We will also explore associations between emotion 
regulation related behaviors and physiology including behavior on the neuroimaging emotion regulation tasks 
(implicit threat priming, emotional conflict, and emotional response), measures of emotional reappraisal and 
suppression as assessed with the Emotion Regulation Questionnaire and the other domains, and Respiratory 
Sinus Arrhythmia (RSA). The statistical approach to analysis of the treatment effect on these outcomes will use 
ANCOVA, analogous to the analysis of target engagement (above). 
Some measures will be collected daily (e.g. actigraphy and sleep logs) and weekly (BAI, BDI, CSSRS, BSS) over 
the course of treatment. Our general approach is to apply mixed linear models, using the daily/weekly reports 
to construct an individual specific estimate (functionally the mean and coefficient of variation of daily 
measurements for each naturalistic measure over a week) for baseline and follow-up, and then testing the 
effect of time (thus testing the within-person change over time). Random intercepts and slopes (and their 
covariance) at the person level will be included in our models. Random intercepts will be used to account for 
the clustering of observations within individuals across time; random slopes for key within-person predictors 
(e.g. ‘time’ or pre to post in this case) will be included to allow within-person slopes to be stronger for some 
individuals and weaker for others. In cases where random slopes are observed, we will test for potential 
subgroups/moderation (e.g., by age, sex, etc.; although we note that the small sample size somewhat limits our 
statistical power for such moderation tests).  
3.2 
EXPLORATORY ANALYSES 
 
 
 
 
 
 
 
 
 

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3.3 
STUDY MEASURES 
All study measures will be collected at baseline and at the week 11 end of treatment visit. The primary study 
measures are listed in Table 1 and the secondary measures are listed in Table 2. 
Table 1a. Primary Endpoints 
 
Abbreviations: functional Magnetic Resonance Imaging (fMRI); medial Prefrontal Cortex (mPFC); Polysomnography (PSG);  
Table 2. Secondary Endpoints 
 
 
Abbreviations: Heart Rate Variablity (HRV); Emotion Regulation Questionnaire (ERQ)84; Wake After Sleep Onset (WASO); Total Sleep Time (TST); 
Sleep Efficiency (SE); Sleep Onset Latency (SOL); Rapid-Eye Movement Sleep (REM); Non-REM (NREM); World Health Organization Quality of Life 

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3.3.1 EMOTION REGULATION NETWORK FUNCTION 
Primary measures of ERN function will include amygdala reactivity, as well as mPFC-amygdala connectivity as 
measured by generalized psychophysiological interaction (gPPI)86. ERN function will be assessed using three 
validated neuroimaging tasks of emotional reactivity and regulation described in detail below (Section 8.1.6). 
Prior work from PI Goldstein-Piekarski and others has suggested that sleep disruption may differentially impact 
the reactivity to emotional faces from that of emotional scenes30,31,73,87. Thus, we have selected three tasks that 
span emotional reactivity and regulation across both face and scene stimuli.  We will focus a priori on regions 
of the amygdala and mPFC due to prior findings that they are sensitive to sleep status and are altered in anxiety 
and depression. We will also examine the degree of target engagement as indexed by changes in the 
corresponding behavioral responses from these tasks as well as emotion regulation ability as assessed by 
questionnaires as secondary analyses (summarized in Table 2).  
3.3.2 INSOMNIA  
Eligibility will be determined on the subjective report of insomnia (ISI). Sleep Efficiency (SE) measured on the 
overnight PSG recordings will verify that the sleep intervention produces improvements in insomnia as a mediator 
of the target-depressive symptom relationship and as a proximal outcome measure. SE as measured by 
actigraphy across the duration of the study will serve as a secondary and convergent measure of insomnia. We 
recognize that subjective measures of sleep disturbance do not always correspond with the objective measures 
of sleep disturbances determined using PSG sleep architecture. Recent evidence suggests that the differences 
between subjective and objective sleep disruption may be explained by hyperarousal during sleep as reflected 
in high frequency EEG spectral power including alpha, beta, and sigma activity, using spectral analysis of the 
PSG88. Thus, we will also examine alpha, beta, and sigma activity during NREM as additional secondary measures 
of sleep disturbance.   
3.3.3 DEPRESSIVE SYMTPOMS  
The BDI89 total score after removing the sleep items will be used as the primary outcome measure of depressive 
symptoms. Given that suicide is a risk associated with insomnia independent of other depressive symptoms, 
suicidality (CSSRS and BSS) will be included as a secondary outcome measure. Given the high comorbidity 
between insomnia, depression, and anxiety, we will also assess anxiety using the Beck Anxiety Inventory (BAI90) 
as a secondary outcome. In addition to the baseline and end of treatment assessments, the BDI, BAI, BSS and 
CSSRS will be assessed weekly prior to each treatment session. Additional secondary measures related to 
specific aspects of emotional distress relevant to depression are listed in Table 2.  
3.3.4 CURRENT FUNCTIONING (SECONDARY MEASURES) 
Cognitive function and current functioning measures are listed in Table 2. These measures are included because 
sleep disruption and depression have documented negative impact on cognition, current functioning, and 
quality of life92-95.  
 
4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
(WHOQo); Repeatable Battery for the Assessment of Neuropsychological Status(RBANS)85 

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The R61 phase is a single-arm clinical trial with 70 eligible participants. The R61 phase aims to assess feasibility 
of recruitment and retention, as well as to establish a proven sleep intervention's ability to engage neural 
circuits involved in the regulation of emotion. 
Figure 5. Study 1 Design and flow of testing 
 
4.1.1 
RANDOMIZATION 
N/A 
4.1.2 
SLEEP MANIPULATION 
CBT-I improves sleep through a combination of behavioral interventions (stimulus control (SC), sleep restriction 
(SR)), cognitive therapy (CT) as well as additional components such as mindfulness training and sleep hygiene 
education. SC is an intervention that re-establishes the connection between the bed/bedroom with sleep to 
help develop a more consistent sleep/wake pattern96-99. SR leads to higher quality sleep by limiting time spent 
in bed99 to the actual amount of sleep, thereby creating mild sleep deprivation and increasing the homeostatic 
sleep drive101-105. Like CT for other disorders, CT for insomnia targets maladaptive thoughts and cognitions that 
may interfere with sleep106,107. 
4.1.3 
STUDY SITES 
 
The study will be conducted at the Stanford University. All study personnel have Stanford affiliation and have 
access to the resources.    

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Recruitment and screening: Recruitment activities will occur at the Psychiatry Building at Stanford University 
Medical Center or digitally off-campus using Stanford VPN. Additionally, recruitment materials will be posted 
around the VA, Stanford campus, social media and other online sites, and public spaces that allow postings. 
Participants will be screened in private interview rooms available in the Stanford Psychiatry building located at 
401 Quarry Rd. 
Phone/RedCap screens: Phone screens will be conducted at the Stanford Psychiatry Building or digitally off-
campus using Stanford VPN and the secure jabber phone lines. The data will be stored on a secure RedCap 
database administered by Stanford. Alternatively, the participant may complete the phone screen questions via
Stanford RedCap. 
Consent: This will be undertaken in the Stanford Psychiatry Building. Private and confidential rooms are available
for the consent process. 
   
Clinical interviews and behavioral testing: This will be undertaken at the Center for Cognitive and Neurobiological 
Imaging (CNI) and in the Stanford Psychiatry Building. Both locations have private interview rooms available for
this purpose. The behavioral testing will be undertaken both using physical testing batteries and a computerized 
battery.  
Imaging: Scans for functional imaging will be undertaken at the Center for Cognitive and Neurobiological Imaging 
(CNI) for the fMRI component of the study. The 3.0 Tesla MRI machine as well as relevant computers and 
electronics 
is 
well 
established. 
Treatments: The sleep manipulation interventions and control treatment will be administered in private rooms 
at the Stanford Psychiatry Building. 
Data Analysis: Data analysis will be conducted at the Stanford Psychiatry Building on computers with Stanford 
LAN access. All data will be stored on Stanford servers and in locked file cabinets in the Stanford Psychiatry
Building.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
4.2.1 JUSTIFICATION OF A SINGLE-ARM MECHANISTIC TRIAL 
This phase of the study is a single-arm mechanistic trial. For this phase, the aims are to determine feasibility 
and target engagement. The measures of emotion regulation network function that meet the Go criteria will 
be carried over as primary targets of emotion regulation network function in the R33 phase.  
 
4.3 
JUSTIFICATION FOR INTERVENTION 
The CBT-I intervention will be delivered according to protocols and materials from our large-scale VA 
implementation of CBT-I108 . The intervention materials include a published sleep self-help book, a published 
therapist guide, and the CBT-I therapist manual108,109.  
  
Participants must complete 5 sessions of treatment to have evaluable data for analyses related to the primary 
objectives to ensure there is sufficient improvement in sleep.  
4.3.1 GENERAL INTERVENTION CONSIDERATIONS  
To minimize the documented effects of expectancy/demand factors111,112, participants will be given the counter-
demand intervention information that improvement is not anticipated until after the intervention ends. During 
the sleep manipulation phase, the participant and study psychologist meet on a weekly basis. In these sessions, 

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participants will have the chance to discuss any problems they may encounter in complying with the 
intervention and to ask questions about the rationale of the intervention. The study psychologist and 
participant work collaboratively to come up with solutions for dealing with the significant life-style changes that 
treatment compliance can involve. 
4.3.2 CONSIDERATION OF GENERALIZABILITY 
 To test the hypothesis that sleep restoration reduces depressive symptoms, it is important that the therapists 
remain focused on insomnia and avoid providing general psychotherapy. We will instruct the therapist to limit 
their interventions to the target symptoms.  To that end, the therapist will not provide general psychotherapy 
for depression and/or anxiety. In particular, the CBT-I manual instructs the therapist to limit cognitive 
restructuring to sleep-related cognitions and to refrain from explicit generalization to other domains. When 
participants raise issues that are either outside the scope of the specific treatment or outside the scope of the 
study, the provider will respectfully redirect focus to sleep symptoms and treatment. The only exception is 
when the clinical presentation necessitates an immediate intervention, such as when the participant expresses 
suicidal thoughts; however, therapists will be trained to redirect this to the PI, where procedures will follow 
this study’s DSMP. Any safety planning or referral back to the PI will be tracked for future study. Past research 
supports feasibility and integrity of treatment delivery using CBT-I. Our experience indicates that participants 
and treatment providers are able to adhere to and accept similar limits.  
 
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed the baseline assessment, all 
6 intervention sessions, and the end of treatment assessment.  
 
The end of the study is defined as completion of the end of treatment assessment shown in the Schedule of 
Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION  
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
  
 
1. Males and females of any racial or ethnic group, aged 25-60 to avoid age-related brain
pathologies that could interfere with assessments to be made in the study. Children 
below the age of 18 will not be included in this study based on evidence of altered
circadian rhythmicity in adolescence, which could confound sleep-stage effects and 
because a separate, age-specific study in children is warranted and preferable.  
2. Subjective complaint of insomnia associated with daytime impairment or distress (ISI ≥ 
15) 
3. Insomnia complaint ≥ 3 months in duration 

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4. Subjective complaint of depressive symptoms as defined by scores ≥ 14 on the BDI 
5. Fluent and literate in English  
6. Written, informed consent.  
7. Low risk for complications from COVID-19 
5.2 
EXCLUSION CRITERIA 
   
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Presence of other sleep or circadian rhythm disorder as these disorders may have distinct underlying 
neural causes and thus confound emotion regulation network brain function biomarkers targeted 
here. 
The presence of these disorders will be assessed by the DUKE structured interview for Sleep Disorders 
2. Use of psychotropic medications that would significantly impact sleep, alertness, or mood  
3. Use of non-prescription medications or substances that would significantly impact sleep and are 
unwilling or unable to discontinue for >2 weeks.  
4. Excessive alcohol consumption (>14 drinks per week or > 4 drinks per occasion)  
5. Presence of suicidal ideations representing imminent risk as determined by the empirically-supported, 
standardized suicide risk assessment (described fully below in Tables 1 & 2 and in the Data and Safety 
Monitoring Plan document). 
6. General medical condition, disease or neurological disorder that interferes with the assessments  
7. Substance abuse or dependence  
8. Mild traumatic brain injury (history of physical brain injury or blow to the head resulting in loss of 
consciousness >5 minutes)  
9. Severe impediment to vision, hearing and/or hand movement, likely to interfere with the ability to 
complete the assessments, or are unable and/or unlikely to follow the study protocols  
10. Pregnant or breast feeding  
11. Current or lifetime history of bipolar disorder or psychosis  
12. Current or expected cognitive behavior therapy for another condition 
13. Received cognitive behavioral therapy for insomnia within the past year  
14. Acute or unstable chronic illness: including but not limited to: uncontrolled thyroid disease, kidney, 
prostate or bladder conditions causing excessively frequent urination (> 3 times per night); medically 
unstable congestive heart failure, angina, other severe cardiac illness as defined by treatment regimen 
changes in the prior 3 months; stroke with serious sequelae; cancer if < 1 year since end of treatment; 
asthma, emphysema, or other severe respiratory diseases uncontrolled with medications; and 
neurological disorders such as Alzheimer’s disease, Parkinson’s disease and unstable epilepsy as 
defined by treatment regimen changes in the prior 3 months; unstable adult onset diabetes as defined 
by treatment regimen changes in the prior 3 months. 
15. Current exposure to trauma, or exposure to trauma within the past 3 months  
16. Working a rotating shift or an unconventional daytime shift (ending after 1900 h) 
17. Underlying health condition that is at risk for complications from COVID-19 

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5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study participants will be asked to:  
• 
Wear study equipment while sleeping on 3 separate nights. 
• 
Complete sleep diary entries daily. 
• 
For CBT-I, participants will have their time in bed restricted initially and will be assigned earlier bedtimes 
and rise times. If daytime sleepiness increases during the time in bed restriction phase, participants will 
be discouraged from driving vehicles. Daytime napping will also be restricted to 30-45 minutes 7-9 
hours after wake time.  
• 
Adhere to basic sleep hygiene recommendations, including eliminating caffeine after lunchtime, 
limiting consumption of alcohol, nicotine, and heavy foods close to bedtime, and scheduling rigorous 
exercise earlier in the day. If nocturnal urination is a cause of sleep disruption, consumption of liquids 
will be limited two hours before bedtime.  
• 
Refrain from starting new medications or dietary supplements for sleep. 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in this study or phone screen but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not meet the 
criteria for participation in this trial (screen failure) because of meeting one or more exclusion criteria that are 
likely to change over time may be rescreened. Examples include not meeting criteria for insomnia or taking 
sleeping pills. Rescreened participants will be assigned the same participant number as for the initial screening. 
Screen failures could also occur when an individual is no longer interested in participating in study procedures. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.5.1 RECRUITMENT STRATEGIES 
Recruitment and retention strategies have been developed from the study team’s extensive experience 
recruiting participants with cognitive impairment, sleep disturbance, and neuropsychiatric symptoms 
in past projects. Based off of this experience we will continue to target potential participants using 
referrals, community outreach, and online postings.  
Referrals. We will recruit participants through referrals from both other research studies and clinics 
within the Stanford Hospital and the Palo Alto VA. We will also recruit participants through referrals 
from collaborating Community Health Centers (CHCs), including community clinics, in the Alameda, San 
Francisco, San Mateo, and Santa Clara counties. These CHCs and community clinics have multiple 
locations throughout the different counties and provide affordable healthcare, including mental health 
resources and therapy options, to low income and underrepresented populations.  
Community Outreach. The community outreach recruitment activities will consist of posting flyers, 
sending postcards in the mail, tabling in clinics, and giving presentations. Flyers will be posted on 
bulletin boards in coffee shops, in grocery stores, around Stanford University’s campus, and in any other 
public spaces that allow postings. In addition, postcards will periodically be sent through a company 
that does targeted mailings around the Bay Area. In-person community outreach will be done through 
presentations and tabling. Presentations about CBT-I and Insomnia will be done at local community 

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group meeting (i.e. Rotary, Lions Club, Kiwanis) to raise awareness for the problem of sleep disruption 
and to spread word about the research study. In addition, study staff will set up a table with flyers and 
brochures about the research study in local clinics to talk with individuals about the study and give 
information on how to participate 
Online Postings. We will utilize online recruitment methods including social media, Craigslist, and 
online community newspapers. We will create an electronic flyer that can be posted on various 
websites and easily shared from one person to another. We will also utilize lab accounts on social media 
sites like Facebook and Twitter to post information about the study.  
Collaborative Approach for Asian American and Pacific Islanders Research and Education (CARE) 
Registry: The CARE Registry will provide researchers contact information of volunteers that may be 
eligible for their study. The researchers must contact potential participants within one month of 
receiving their contact information. 
 
Consideration of Study Staff Safety. When recruiting in the community, study staff will always go in 
groups. They will never go into a private area with a potential participant, such as a car, house, or other 
enclosed areas. If a potential participant is posing a potential danger or is making study staff 
uncomfortable, they are permitted to end the conversation and destroy participant’s contact 
information.  
5.5.2 RETENTION AND ENGAGEMENT STRATEGIES 
As an integral part of our recruitment and retention plan, we will implement a series of strategies that 
have proven effective in our previous clinical trials to achieve participant engagement, retention and 
data completeness. These include the following:  
1. careful staff selection and standardized training in trial-specific protocols, rapport building, 
motivational interviewing, and problem solving as appropriate to their study roles;  
2. legally adequate, effective informed consent;  
3. prudent participant incentives and flexible scheduling;  
4. promotion of study identity;  
5. ongoing monitoring of recruitment and retention;  
6. up-to-date participant contact information and two emergency contacts;  
7. diligent efforts to re-engage inactive participants; and  
8. alternative means of obtaining measurements.  
To maximize retention and ensure that participants fully understand the demands and nature of the 
study before they enroll, recruitment staff will, as part of a detailed informed consent process, carefully 
review study requirements with the participants, explain the concept of the study and stress the 
importance of follow-up assessment. We additionally maintain a sophisticated participant database in 
REDCap, with robust reporting functions that will prompt assessment staff which participants are due 
to be scheduled for a visit and permit continuous monitoring of visit completion status. Research 
personnel will be persistent in attempting to recontact and engage noncompliant participants in 
subsequent follow-ups. Protocols of Co-Is with similarly, but more stringent inclusion criteria, yet 
excellent retention profile (low attrition through treatment completion and follow-up), and no AE (e.g. 
NCT01958541, NCT01770587) will be modeled and adapted to support retention and recruitment 

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within the current study. In addition to this and a detailed tracking database, we will also track website 
data analytics, source of new contacts, and ratio of screen:eligibility and eligibility:enrollment metrics 
to further evaluate the efficiency of recruitment strategies and further refinements to enhance 
feasibility of study target goals and enrollment milestones.  
The methods to track enrollment described above will also aid in participant engagement and retention. 
Additional measures will nonetheless be taken to further increase retention. During screening, study 
staff will collect multiple forms of contact information (i.e. cell phone, email, mailing address, home 
phone) from each participant. This information will be stored in the encrypted database to be utilized 
for appointment reminders. Study staff will remind participants and confirm their appointment times 
through the participants’ preferred method of contact. Study staff will also send reminder text 
messages (with the participants’ permission) from a lab cell phone. 
 
We will offer financial hs 
 for time taken to complete assessment visits and completing the study. Participants will be thanked 
for their time, following the study, and asked for feedback regarding feasibility and their experience 
completing the study.  
Based on the above, and feasibility data from similar protocols by our group, we expect ≥80% retention 
rate through treatment and end of treatment assessments for Studies 1 and 2, and a ≥70% retention 
rate for the 6 month follow-up for Study 2. These numbers are consistent with Co-I Bernert’s previously 
collected RCT on a behavioral insomnia intervention for suicide risk (NCT01958541) in a sample of N=77 
high risk participants. In this study, which had more stringent inclusion criteria and a higher-risk sample, 
for which retention tends to be poor, feasibility data revealed discontinuation prior to treatment in only 
9% of cases; retention was otherwise 100% through post-treatment phases. Attrition at follow-up was 
3.8%, with no AE reported throughout the trial and excellent treatment adherence observed (>85% 
completed 75% of treatment sessions; >74% completed 100% of treatment sessions). The methods in 
NCT01958541 used to support retention and adherence will be adapted to the current project and 
aligned with in-use strategies to support the above strategy. 
 
5.5.3 INCLUSION OF WOMEN AND MINORITIES 
No one will be excluded from participation in the research on the basis of gender, race, or ethnicity. 
Individuals of both sexes and all racial and ethnic origins will be eligible for participation in the study.  
 
Based on the records from our previous studies completed in the Bay Area as well as the race/ethnicity 
distribution in Santa Clara County, we estimate the following breakdown by age, gender, race and 
ethnicity: 
All minority participants who qualify for inclusion in the proposed research based on diagnostic 
considerations will be included. For our sample, we plan to recruit an equal number of men and women 
(50%). Our recruiting procedures in the past have allowed us to obtain a representative sampling of 
participants in the Palo Alto/Stanford area according to minority status (See Table 3). Based on data 
from area census reports and on the distribution of subjects who have participated in our previous 
studies, we estimate enrollment of approximately 25.6% Hispanic and 74.4% non-Hispanic individuals. 
We estimate further that the distribution across the NIH-specified racial categories will be 
approximately: 1.2% American Indian/Alaska Native, 37.5% Asian, 0.5% Native Hawaiian or Other 

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Pacific Islander, 2.8% Black or African American, 25.6% Hispanic, and 31.6% white. We will continually 
monitor our recruitment numbers related to diversity. If our numbers are not meeting the anticipated 
percentages by minority group, we will increase our targeted efforts to reach each group through 
targeted postcard distribution, and engagement in local community centers.  We have an outreach 
program for our other clinical programs and expect that the recruited sample for the proposed study 
will exceed past participation of minority participants. The ultimate goal of these efforts is to increase 
our presence in minority communities and thereby to increase minority representation among our 
participants. 
We will track accrual by sex, race and ethnicity each week throughout the study enrollment period. We 
will conduct valid analyses of the intervention effect as modified by sex and race/ethnicity, without 
requiring high statistical power for each subgroup given their exploratory nature. 
 
Table 3. Anticipated Enrollment Break-down 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/Alaskan Native 
1 
0 
0 
0 
1 
Asian 
13 
14 
0 
0 
27 
Native Hawaiian or 
other Pacific Islander 
0 
1 
0 
0 
1 
Black or African 
American 
1 
1 
0 
0 
2 
White 
11 
10 
9 
9 
39 
More than one Race 
0 
0 
0 
0 
0 
Total 
26 
26 
9 
9 
70 
5.5.4 ANTICIPATED RECRUITMENT, ENROLLMENT, AND RETENTION 
We anticipate needing to recruit a total of 175 participants to achieve our target enrolment of 70 
eligible participants after the phone and in person screening session (See Figure 5). With all these 
measures, we expect greater than an 80% retention rate or better for the end of treatment follow-up 
(See Figure 5).  
Figure 5. Consort Diagram 
 

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6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
6.1.1.1 COGNITIVE BEHAVIORAL THERAPY 
 
BACKGROUND AND RATIONALE FOR CBT-I 
CBT for insomnia is based largely on Spielman's conceptual model for primary insomnia. This 
model identifies predisposing factors, precipitating events, and perpetuating mechanisms that 
contribute to the development of chronic insomnia. Some individuals may be particularly 
predisposed or vulnerable to sleep difficulties by virtue of having a highly sensitive, or 
malfunctioning biological sleep system or a hyperactive arousal system that interferes with sleep. 
Circumstances such as stressful life events often precipitate sleep difficulties. This is more likely to 
occur in individuals with a predisposition for insomnia. In most cases the sleep difficulties are 
transient and resolve when the original distress subsides. In some cases, the patient becomes 
overly focused on the sleep problem. This focus tends to perpetuate sleep difficulties as it can 
produce heightened anxiety about sleep and lead to the development of maladaptive strategies 
and practices that, although intended to improve sleep, actually worsen it. Such maladaptive 
strategies include avoidance behaviors during waking hours (e.g., cancelling planned activities due 
to fatigue or fear such activities will interfere with next night’s sleep), varying bed time and/or 
wake time, spending excessive time in bed, and developing rigid sleep-related rituals. 

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These behaviors are manifestations of increased sleep effort. Simply stated, the patient is trying 
too hard to sleep. In response to poor sleep patients also develop sleep-interfering cognitions, 
such as overestimating and worrying about the negative consequences of poor sleep, approaching 
bedtime with fear of failure, etc. Thus, patients’ cognitive responses to their sleep problems and 
many of the practices that they adopt for coping with it end up prolonging or exacerbating the 
very problem they are trying to solve. The cognitive-behavioral approach to insomnia aims to 
modify behaviors that sustain or add to patients' sleep problems and correct cognitions that lead 
to heightened anxiety about sleep and to maladaptive sleep-related behaviors.  
 
6.1.2 ADMINISTRATION AND/OR DOSING 
 
CBT-I will consist of 6 sessions administered ideally once a week over a period of six to eight weeks. A 
full-dose will be defined as completing all 6 sessions. Sessions will occur either face-to-face or via 
Stanford Zoom with a PhD/PsyD psychologist, or graduate student under the supervision of a licensed 
PhD/PsyD psychologist, who is experienced in administering the study treatments and has completed 
the CBT-I training. Study sessions will occur in treatment rooms at Stanford or via Stanford Zoom. The 
full description of treatment details can be found in Section 6.1.1, Study Intervention or Experimental 
Manipulation Description and Appendix C. 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
All treatment sessions will be audio and/or video recorded, and the recordings will be securely uploaded 
to an encrypted server. Treatment fidelity will be monitored in a randomly selected subset of 10% of the 
sessions. Treatment fidelity will be rated using a treater fidelity questionnaire (Appendix D).   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
6.3.1 RANDOMIZATION PROCEDURES 
N/A 
 
6.3.2 
BLINDING PROCEDURES 
N/A 
 

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6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Since compliance with CBT treatment elements has been found to be variable, it will be measured for potential 
influence on outcomes112. Weekly review of daily sleep logs and their correspondence with actiwatch data will 
be used as an additional proxy of treatment compliance during the course of treatment. At the end of treatment 
participants will complete a treatment adherence questionnaire explicitly designed for CBT-I114. We have used 
this method to check for compliance in earlier research115.  
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, participants may not use psychotropic medications that may significantly impact sleep, 
alertness, or mood until after visit 9 (end of treatment). The use of medications specifically used for sleep are 
not allowed during until after visit 9 (end of treatment). Medication usage will be assessed at each study visit 
and documented in the relevant Case Report Form (CRF). 
 
Participants may not receive cognitive behavioral therapy for other conditions (e.g. depression) until after visit 
9 (end of treatment). 
 
6.5.1 RESCUE THERAPY 
N/A 
 
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
When a participant discontinues from CBT-I but not from the study, remaining study procedures will be 
completed as indicated by the study protocol.  If a clinically significant finding is identified (including, but not 
limited to changes from baseline) after enrollment, the investigator or qualified designee will determine if any 
change in participant management is needed. Any new clinically relevant finding will be reported as an adverse 
event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for determining the 
need to discontinue 

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• 
The participant will complete the emotional distress and sleep questionnaires that are administered at 
each treatment session at the time of discontinuation. Thereafter, the participant will be included in all 
future scheduled assessments (including emotional distress and sleep questionnaires), even though not 
participating in the intervention. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance, including repeated failure to complete sleep diaries, 
adhere to treatment protocol requirements (ex. prescribed sleep schedule), or engage productively in 
treatment sessions. 
• 
Lost-to-follow up; unable to contact participant (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up study 
data would not be in the best interest of the participant  
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
• 
Increase in bothersome nightmares for a week under treatment. We have not seen consistent reporting 
of nightmares with the proposed treatments, however that is always possible, hence again we would 
want to make sure that that occurred for at least a week before a patient was discontinued.  
 
Patients will be allowed to continue in the protocol after an SAE independent of treatment, e.g. hospitalization 
following a fall. All treatments are considered active and patients will be allowed to continue their treatment 
as a courtesy. Similarly, patients will be allowed to continue if it is discovered following treatment initiation that 
they meet an exclusion criterion (either newly developed or not previously recognized) if the study physician 
and psychologist deem there are no additional risks to the participant in continuing treatment. However, data 
from such participants will not be included in statistical analyses since such SAEs and other exclusions may 
affect sleep. Patients will not be restarted if their sleep deteriorates meeting the above criteria and they are 
discontinued from the protocol.  
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the electronic Case 
Report Form (eCRF). Participants who sign the informed consent form, but have not yet received the study 
intervention, and subsequently withdraw, or are discontinued from the study will be replaced. 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she receives treatment and fails to return for 3 
scheduled visits and study staff are unable to contact the participant after at least 3 attempts.  
 
The following actions must be taken if a participant fails to return to the laboratory for a required study visit: 
 
• 
Study personnel will attempt to contact the participant, the ideal will be to reschedule the missed visit 
within one week for treatment sessions, and within two weeks for the end of treatment visit, counsel 

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the participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study.  
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls or emails and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts will be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
8.1.1 PHYSICAL EXAMINATION 
N/A 
 
8.1.2 CLINICAL INTERVIEWS 
DUKE116. The Duke Structured Interview for Sleep Disorders is a structured interview which screens for 
sleep disorders in accordance with criteria of both the DSM-IV and the international classification of 
sleep disorders (ICSD-2). The DUKE is composed of 4 modules that assess sleep disorder symptoms 
associated with complaints of insomnia, sleep disorders associated with complaints of hypersomnia, 
circadian rhythm sleep disorders, and sleep disorders associated with parasomnias.   
MINI117.The Mini International Neuropsychiatric Interview is a brief structured diagnostic interview for 
DSM-IV and ICD-10 psychiatric disorders. It assesses the 17 most common mental health disorders 
selected based on current prevalence rates. The MINI uses branching tree logic. 
 
8.1.3 QUESTIONNAIRES 
Columbia Suicide Severity Rating Scale117 . The Columbia Suicide Severity Rating Scale (CSSRS) is an 
assessment tool the evaluates suicidal ideation and behavior.  
Beck Scale for Suicidal Ideation. The Beck Scale for Suicidal Ideation is a 21 questions evaluation of 
suicidal thinking that helps identify individuals at risk. It also helps measure a broad spectrum of attitudes 
and behaviors.   
Insomnia Severity Index (ISI)118. The Insomnia Severity Index (ISI) is a 7-item self-report measure of 
insomnia type, severity, and impact on functioning. The items consist of: severity of sleep onset, sleep 
maintenance, early morning awakenings, sleep dissatisfaction, interference with daytime functioning, 
noticeability of sleep problems by others, and distress caused by sleep difficulties. Items are scored from 
0 to 4 (0 = no problem, 4 = very severe problem). Score ranges of insomnia are: 0-7 absent, 8-14 sub-
threshold, 15-21 moderate, and 22-28 severe. The ISI has good validity and reliability.  
Pittsburg Sleep Quality Index119. The Pittsburg Sleep Quality Index (PSQI) is a 19-item self-report 
questionnaire that measures sleep quality from seven categories: subjective sleep quality, sleep latency, 

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sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime 
dysfunction. Items are scored from 0 - 3, and a global sum of 5 or greater indicates poor sleep quality. 
The PSQI has high validity and reliability (Cronbach's alpha = 0.83). 
Dysfunctional Beliefs About Sleep (DBAS)120. The DBAS-16 is self-report questionnaire consisting of 16 
questions. The DBAS-16 uses a personal rating response format of 0-10 to assess 4 factors consisting of 
perceived consequences of insomnia, worry/helplessness about insomnia, sleep expectations, and 
medication. 
Morningness Eveningness Questionnaire121. The MEQ consists of 19 questions that assess degree of 
alertness and activity associated with differences in morningness and eveningness. The MEQ mainly uses 
questions with a 4-choice format that correspond to a definite morning type, moderate evening type, 
and definite evening type. 
Beck Depression Inventory (BDI)89 . The BDI-II is a 21-item self-report scale that assesses the severity of 
depression symptoms. The depression items consist of: sadness, pessimism, past failure, loss of pleasure, 
guilty feelings, punishment feelings, self-dislike, self-criticalness, suicidal thoughts or wishes, crying, 
agitation, loss of interest, indecisiveness, worthlessness, loss of energy, changes in sleeping pattern, 
irritability, changes in appetite, concentration difficulty, tiredness or fatigue, and loss of interest in sex. 
Items are scored from 0 to 3, and higher scores indicate greater levels of severity. The ranges for 
depression are: 0-13 minimal, 14-19 mild, 20-28 moderate, and 29-63 severe. The BDI-II has high validity 
and reliability. 
Beck Anxiety Inventory (BAI)90. The BAI is a 21-item self-report scale that assesses the severity of anxiety 
symptoms. Items are scored from 0 to 3 (0 = not at all, 3 = severe). Higher scores indicate greater levels 
of severity, and the ranges for anxiety levels are: 0-9 normal to minimal, 10-18 mild to moderate, 19-29 
moderate to severe, and 30-63 severe. The BAI consists of two factors: somatic and cognitive.  
World Health Organization Quality of Life Assessment (WHOQOL)122. The WHOQOL-BRIEF is a 26-item 
brief version of the WHOQOL, that measures quality of life based on six domains: physical health, 
psychological 
state, 
level 
of 
independence, 
social 
relations, 
environment, 
and 
spirituality/religion/personal beliefs. Four general items about subjective overall QOL and health are also 
included. Only domain and general item scores are calculated in the WHOQOL-BREF. Items are scored 
on scales of 1 to 5, and higher scores indicate higher quality of life. 
Patient Health Questionnaire (PHQ-9)123. PHQ-9 is a self-administered instrument for screening, 
diagnosing, monitoring, and measuring the severity of depression. It rates the frequency of symptoms 
as "0" (not at all) to "3" (nearly every day) and has been validated for use in primary care. The PHQ-9 
total score ranges from 0 to 27 and is categorized as follows: None or minimal depression 0-4, Mild 
depression 5-9, Moderate depression 10-14, Moderately severe depression 15-19, and Severe 
depression 20-27. Cronbach's alpha coefficients range from 0.86 to 0.89 and test-retest correlations 
range from 0.84-0.95 within 48 hours and from 0.81-0.96 at 7-day reassessment. PHQ-9 scores were 
found to be highly correlated with Beck Depression Inventory scores in the general population (r=0.73). 
Generalized Anxiety Disorder Scale (GAD-7)124. GAD-7 is a valid and reliable 7-question scale to screen 
for 4 anxiety disorders: Post Traumatic Stress Disorder, Panic Disorder, Generalized Anxiety Disorder, 
and Social Phobia. A score of ≥10 indicates a high probability of 1 or more of these disorders. Cronbach's 
alpha is 0.92 and test-retest correlation is 0.83. GAD-7 scores also correlate highly with scores of 2 
commonly- used anxiety scales: the Beck Anxiety Inventory (r=0.72) and the anxiety subscale of the 
Symptom Checklist-90 (r=0.74). 
Emotion Regulation Questionnaire (ERQ)125. ERQ is a 10-item self-report survey assessing individual 
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and expressive suppression (4 items). Cognitive reappraisal is a strategy that involves interpreting an 
emotion-eliciting situation in a way that changes its emotional impact, whereas expressive suppression 
is a form of response modulation that involves restraining emotion expressive behavior. The ERQ shows 
high levels of internal consistency in measuring both strategies in a large, diverse sample (Reappraisal 
factor α=.79 and Suppression α= .73). Test-retest reliability across 3 months was .69 for both scales. 
Penn State Worry Questionnaire (PSWQ)126. The PSWQ is a 16-item questionnaire that aims to measure 
the trait of worry, using Likert rating from 1 (not at all typical of me) to 5 (very typical of me). Research 
suggests that the instrument has a strong ability to differentiate patients with generalized anxiety 
disorder (GAD) for other anxiety disorders.  
Stanford Sleepiness Scale (SSS). The SSS is a single item subjective measure of sleepiness using a Likert 
rating from 1 (feeling active and vital) to 7 (almost in reverie).    
Consensus Sleep Log128. The consensus sleep log contains information from seven days of reporting the 
following measures: Wake after Sleep onset (WASO), Time in Bed (TIB), Sleep onset Latency (SOL), Total 
Sleep Time (TST), caffeine and alcohol use, and naps.  
Profile of Mood States(POMS)128. The POMS is a questionnaire with 24 items and four scales to assess 
mood. The four scales are depression and anxiety, fatigue, vigor, and irritability. These scales are 
internally consistent and have good scale fit.  
Snaith-Hamilton Pleasure Scale (SHAPS). The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-
administered, paper-and-pencil questionnaire with 14 items assessing four domains of pleasure 
response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink. 
CHICa (Irritability and Cognitive Subscales)129. The CHICa is a 26 item self-report measure of impaired 
thermoregulation, disrupted appetite, affective problems, and lowered level of cognitive functioning. 
Each question is a four-point scale from 0 (‘definitely no/untrue’) to 3 (‘definitely yes/true’).  
Difficulty in Emotion Regulation Scale (DERS). The DERS is a 36 item self-report measure of emotion 
regulation deficits that is designed to capture clinically relevant problems.  
SF-36 (RAND) Version 1130. The SF-36 is a 36-item, self-administered survey to assess comprehensive 
quality-of-life measures. It consists of eight sections: vitality, physical functioning, bodily pain, general 
health perceptions, physical role functioning, emotional role functioning, and mental health. This survey 
is widely used and has been proven to be a reliable indicator of quality-of-life measures.  
Toronto Alexithymia Scale (TAS-20)131. The TAS-20 is a 20-item self-report measure of alexithymia 
from multiple perspectives: difficulty identifying and distinguishing between feelings and bodily 
sensations, difficulty describing feelings, reduced daydreaming, and externally-oriented thinking.     
Ruminative Response Scale (RRS-Short). The RRS is a 10-item questionnaire that measure ruminative 
tendencies.  
Ford Insomnia Response to Stress Test (FIRST)132. The FIRST is a 9 item questionnaire regarding sleep 
disturbance in response to commonly experienced stressful situations, such as before an important 
meeting the next day or after an argument.  
Credibility/Expectancy Questionnaire133. The Credibility/Expectancy Questionnaire is a scale for 
measuring treatment expectancy and rationale credibility. The questionnaire derives two predicted 
factors: cognitive based credibility and relatively more affectively based expectancy. The participant will 
see one section related to thinking and one section related to feeling. It has high internal consistency 
within each factor and good test-retest reliability.  
Working Alliance Inventory135.  The Working Alliance Inventory is a measure of therapeutic alliance 
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development of an affective bond. A high score on the survey is associated with improved outcomes for 
clients. The reliability compared to the Helping Alliance Questionnaire was good (α> 0.80).  
Treatment Adherence Survey. The Treatment Adherence Survey is a self-report survey assessing the 
participant’s adherence to the insomnia treatment.  
Treatment Satisfaction Survey. The Treatment Satisfaction Survey is a self-report survey assessing the 
satisfaction and effect of the insomnia treatment.  
 
8.1.4 PERFORMANCE BASED ASSESSMENTS 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)135. RBANS is a brief, 
individually administered battery that measures cognitive decline in older patients and a 
neuropsychological screening in younger patients.  
 
8.1.5 SLEEP ASSESSMENTS 
On nights prior to study entrance, habitual sleep time and quantity will be measured with sleep logs and 
wrist actigraphy. Apnea link will be used on the night of the screening visit to assess for obstructive sleep 
apnea. Full nights of polysomnography will be acquired using full-scalp electrode coverage to test 
hypotheses related to sleep physiology. 
 
8.1.5.1 APNEA LINK 
Participants will undergo a screening for Obstructive Sleep Apnea (OSA) as part of the study 
screening session. The participants will take the device home and wear it while they sleep in 
their own bed. The device measures movement, respiration, and oxygen desaturation while the 
participant is asleep in order to report an Apnea Hypopnea Index (AHI), used to diagnose OSA. If 
a participant is found to have an moderate sleep apnea (AHI >= 15), they will be excluded from 
the study. Participants will return the next morning to return the Apnea Link.  
 
8.1.5.2 POLYSOMNOGRAPHY (PSG) 
Acquisition. PSG will be used to measure sleep on the nights before the baseline, baseline, end of 
intervention, and follow-up experimental visits as has done by PI Goldstein-Piekarski in previous 
studies30,31,136. PSG will be acquired using a 32-channel, EEG system (Compumedics, Siesta), 
validated for sleep recording. Electroencephalography (EEG) will be recorded at 26 standard 
locations conforming to the extended International 10-20 System (FP1, FP2, F7, F3, FZ, F4, F8, FC3, 
FC4, T7, C3, CZ, C4, T8, TP7, CP3, CPZ, CP4, TP8, P7, P3, PZ, P4, P8, O1, O2) using an EEG cap 
(Compumedics, QuickCap). Electrooculography (EOG) will be recorded at the right and left outer 
canthi (right superior; left inferior). Electromyography (EMG) will be recorded via three electrodes 
(one mental, two submental). Reference electrodes will be recorded at both the left and right 
mastoid (A1, A2). Data will be sampled first at 800Hz by the amplifier, digitized at 400Hz. All data 
will be stored unfiltered (recovered frequency range of 0.1-100Hz), except for a 60 Hz notch filter 
to remove mainline noise. 
Sleep Scoring. Sleep-staging will be performed in accordance with standardized techniques using 
C3, C4, O1, O2, right and left EOG and EMG channels. EEG and EOG will be referenced to the 
contralateral mastoid and filtered to 0.3-35Hz. EMG will use a bipolar montage filtered to 10-70Hz 
and 0.1-12Hz, respectively. Sleep will be visually scored in 30-second epochs using the C3-A2 

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derivation according to standard criteria137. Polygraph data collected by the Siesta is transferred 
to a PC computer system equipped with Compumedics' Profusion PSG4 software. The software 
quantifies the manual scoring and produces concise reports that include measures of all sleep 
stages, sleep latency, total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency 
(SE). Manual scoring will be conducted on recordings that do not have the subject's name, 
diagnosis, or study phase attached. 10% of the records will be randomly distributed to a second 
technologist who will score them blindly (will require 90% concordance across scorers). 
Sleep Architecture Variables of Interest.  
Sleep Onset Latency (SOL) is the time (minutes) from "lights out" or start of total recording time, 
to actually falling asleep as indicated by EEG changes.  
Number of Arousals is determined by number of times of awakening by EEG changes.  
Wake After Sleep Onset (WASO) are periods of wakefulness occurring after sleep onset, before 
final awakening (sleep offset).  
Total Sleep Time (TST) is the total time (minutes) spent asleep, from the start of sleep onset to 
sleep offset, subtracting any periods of wakefulness. TST includes stages N1, N2, N3, and REM 
sleep. Sleep Efficiency (SE) is calculated as TST divided by total time spent in bed, multiplied by 
100. Duration in sleep stages of non-rapid eye movement (NREM) sleep includes stages N1, N2, 
and N3, and is measured in minutes. The duration of sleep outside of those stages that is 
associated with specific EEG stages is REM sleep. 
Spectral Analysis. In addition to sleep staging, on the experimental nights topographical EEG 
power spectral density analysis associated with sleep stages will be calculated in the Delta (0.5-
Hz), Theta (4-7Hz), Alpha (7-11Hz), Sigma (12-15Hz), Beta-1 (15-20Hz), Beta-2 (20-35Hz) and 
Gamma (35-45Hz) bands, according to published methodsmethods139-147. 
Respiratory Sinus Arrhythmia. RSA during a paced breathing task will be collected and analyzed 
as described in prior Co-I Gross publications on the evening before, and morning after each sleep 
recording (baseline, end of treatment, and at follow-up). Two channels of respiration measured 
with inductive plethysmography bands will temporarily replace other non-essential electrodes in 
the montage above.  
 
8.1.6 NEUROIMAGING 
All imaging will be conducted on a single scanner at the Stanford Center for Cognitive and 
Neurobiological Imaging (CNI). 
8.1.6.1 PRIMARY FUNCTIONAL TASKS (APPROXIMATELY 34 MINUTES ON TASK) 
Emotional reactivity paradigm (faces; ~10 minutes on task)148-150. This task reliably activates the 
amygdala and is well suited to clinical patient studies62,151-155.  The task is described fully in 
Korgaonkar et al.156. In brief, stimuli were drawn from a standardized series of facial expressions 
of threat-related emotions (fear, anger), loss-related emotions (sadness) and reward-related 
emotions (happiness), along with neutral157. In both the supraliminal and subliminal conditions, a 
total of 240 stimuli are grouped in blocks of 8 faces for the same emotion, with each emotion block 
repeated 5 times and presented in a pseudorandom order. In the supraliminal condition, each face 
is presented for 500ms, with an interstimulus interval of 750ms. In the subliminal condition, faces 
are presented in a validated backward masking design to prevent conscious awareness148.  
Implicit Emotion regulation paradigm (faces; ~13 minutes on task). This task was designed to 
probe mPFC-modulated regulation and is described in full in Etkin et al.158. Participants are asked 

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to identify an expression of fear or happy, while ignoring an overlying word labeling the expression 
(“fear” or “happy”). The word either matches the facial expression (congruent) or conflicts with it 
(incongruent). Face stimuli are presented for 1s followed by a variable duration fixation (3-5s) for 
optimal signal estimation158. This emotional conflict induces reliable engagement of the 
vmPFC158,160,161. Poor threat regulation in this paradigm is observed in both anxiety disorders and 
MDD160,161.  
Emotion reactivity and regulation paradigm (scenes; ~11 minutes on task). This task is based on 
the psychological principles of weakening and appraising negative emotional states and has been 
utilized recently in several prior publications and is described fully in Fonzo et al. and Minkel et 
al.162,163. In short, participants are asked to “look” or “decrease” their emotional response to 30 
Negative and 15 neutral valance images taken from the IAPS163 Trials begin with a 2 second cue 
prompting them on whether they should “look” or “decrease” emotions to the subsequent 
emotional image. Either a negative or neutral image will then be presented for 7 seconds, followed 
by 4 second period where they are asked to rate their level of emotional negativity on a scale from 
1 (Not at all negative) to 5 (Very much negative). A 1-3s variable duration fixation screen preceded 
the onset of the next trial. Images are presented in a pseudorandom order such that no more than 
two of the same instruction or 4 negative stimuli could be presented consecutively. Of the negative 
images, 15 were paired with the instruction “look” and 15 were paired with the instruction to 
“Decrease.” All 15 neutral images are presented with the instruction “look.”  Prior to entering the 
scanner participants are given instructions on strategies for both the look and decrease conditions 
and are several practice images that are not included in the fMRI task162,163.    
8.1.6.2 SECONDARY FUNCTIONAL TASKS (APPROXIMATELY 35 MINUTES) 
Resting State (eyes open; 10-30 min). A series of stand-alone eyes-open resting state scans of 10-
30 min in duration separated into 2-6 five-minute runs will be acquired and analyzed using 
established methods from the HCP protocol165. Wakefulness will be monitored via eye tracking.  
Go-NoGo Task (5 min). This task measures impulsivity (for ‘Go’ responses) versus inhibition (for 
‘NoGo’ responses). Based on the color of the word ‘press’, the participant is instructed to either 
press or refrain from pressing the button. A green ‘press’ signifies the ‘Go’ response meaning the 
participant is instructed to press the button. A red ‘press’ signifies the ‘NoGo’ response meaning 
the participant is not supposed to press the button. Performance is based on reaction time and 
number of errors.  
 
8.1.6.3 MRI ACQUISITION  
Functional. fMRI images will be acquired during the above emotion paradigms using an echo 
planar imaging (EPI) MR sequence with these parameters: TR=2000ms, TE=27.5ms, matrix=64x64, 
FOV=24cm, flip angle=90. A 3D SPGR sequence is collected for normalization of functional images 
to standard space, as well as a field map for EPI unwarping.  
Structural. T1-weighted images will be acquired using an HCP-equivalent inversion recovery fast 
SPGR sequence with an inversion time of 450ms, a TR of 6.3ms, a TE of 2.8ms, and a flip angle of 
12°. T2-weighted images will be acquired with an HCP-equivalent 3D fast spin-echo sequence with 
a TE of 76ms and a TR of 2.5s. For the latter two sequences, the field of view will be 24cm with a 
320x320 matrix size and a slice thickness of 0.8mm (isotropic voxel size 0.8mm3).  
Diffusion-weighted: DTI was collected using single-shot, dual-spin-echo, echo-planar imaging 
sequence (84 unique directions; b = 1,250 s/ mm2; TR = 8,700 ms; TE = 8,700 ms; resolution = 2.0 
mm isotropic; 70 slices; scan duration = 13 min 29 s). Nine non-diffusion-weighted (b = 0 s/mm2) 

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volumes were additionally collected for anatomical localization and regis- tration purposes. 
8.1.6.4 PRE-PROCESSING AND DATA EXTRACTION. 
Standard pre-processing methods in SPM8 used in PI Goldstein-Piekarski and Co-I Williams prior 
publications will be implemented in Matlab (Mathworks, Inc., Natick, MA). These include 
realignment, slice timing correction, spatial normalization to the MNI template165 and smoothing 
at 8mm FWHM. First-level models: For each participant, trial-related activity will be assessed by 
convolving a vector of trial/block onsets with a canonical hemodynamic response function in the 
context of a GLM166 in each paradigm. Six movement-related covariates from realignment (three 
rigid-body translations/three rotations) will be used as regressors of no interest in the design 
matrix for modeling movement for the tasks. Connectivity between the mPFC-Amygdala  will be 
assessed using PPI analyses86 with the amygdala as the seed. Region of interest (ROI) analyses will 
be performed using established methods168, to identify BOLD-dependent signal change in the 
regions of interest for each network. Beta values for each participant and ROI will be extracted for 
regression analyses.  
 
8.1.7 GENETICS 
N/A 
 
8.2 
SAFETY ASSESSMENTS 
 
8.2.1  PHYSICAL EXAMINATION 
N/A 
 
8.2.1 QUESTIONNAIRES 
Acute/Unstable Chronic Illness Is a self-administered checklist designed to reveal uncontrolled or 
unstable illnesses during screening. The checklist evaluates for uncontrolled diabetes, thyroid disease, 
kidney, prostate, or bladder conditions, congestive heart failure, angina, sever cardiac illness, stroke, 
cancer, asthma, emphysema, respiratory disease, chronic pain conditions such as fibromyalgia, and 
neurological disorders such as Parkinson’s disease, and unstable epilepsy. 
The Columbia Suicide Severity Rating Scale is an assessment tool the evaluates suicidal ideation and 
behavior. Individuals are considered high risk if they endorse a 4 and will be evaluated by study PI, Co-I 
clinicians, and DSMB for inclusion  in this study. If individuals are considered low or moderate risk, they 
will be monitored over the following weeks. If individuals are considered to be of high and imminent 
risk, the researcher will help the participant seek immediate clinical care, either through his/her doctor 
or, if the doctor is not available, through local emergency services. 
BDI-II Suicide item during treatment is a 21-item self-administered survey which assesses depression 
symptoms in the past two weeks. Item 9 of the BDI assesses suicidal thoughts and wishes. If the 
participant answers anything other than “0-I don’t have thoughts of killing myself,” study staff will ask 
follow-up questions and notify the clinician.   
Beck Scale for Suicidal Ideation. The Beck Scale for Suicidal Ideation is an evaluation of suicidal 
thinking that helps identify individuals at risk. It also helps measure a broad spectrum of attitudes and 

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behaviors. If the participant answers anything other than “0-I don’t have thoughts of killing myself,” 
study staff will ask follow-up questions and notify the clinician.   
  
 
 
 
8.2.2 IMAGING 
See section Reporting Events to Participants 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
An Adverse Event (AE) is any untoward medical occurrence, including any abnormal sign, symptom, 
or disease temporally associated with study participation, whether or not considered related to 
participation in the research.   
 An AE is deemed to be associated with the use of the study device if there is “a reasonable 
possibility that the experience may have been caused by the device.”   
 Chronic problems which are unchanged from baseline are not considered AEs.  However, 
worsening of an ongoing condition would be considered an AE.  
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
A Serious Adverse Event (SAE) is an adverse event that  
 results in death  
 is life-threatening, or places the participant at immediate risk of death from the event as it 
occurred 
 requires or prolongs hospitalization 
 leads to persistent or significant disability or incapacity  
 Is another condition which investigators judge to represent significant hazards. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 
SEVERITY OF EVENT 
 
The severity of events reported on the “Adverse Events” log will be determined by the site 
physician as: 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  

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• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Of note, the term “severe” does not necessarily equate 
to “serious”. 
• 
Life threatening or disabling – life-threatening or incapacitating.   
 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All adverse events (AEs) will have their relationship to study procedures, including the 
intervention, assessed by an appropriately-trained clinician based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study procedures 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study procedures should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study procedures, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of study procedures). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study procedures administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study procedures) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Definitely unrelated – The AE is completely independent of study procedures 
administration, and/or evidence exists that the event is definitely related to another 
etiology. There must be an alternative, definitive etiology documented by the clinician. 
 
8.3.3.3 
EXPECTEDNESS  
 

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A clinician with appropriate expertise in sleep disorders, gerontology, and dementia will be 
responsible for determining whether an adverse event (AE) is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study procedures. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to 
make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study will 
be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
Trained study personnel will record events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the end of treatment visit (visit 9).  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
All adverse events will be reported annually or more often to the DSMB, Stanford IRB, and NIMH staff.   
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
In consultation with the PI, a trained member of the study team will be responsible for conducting an evaluation 
of a serious adverse event and shall report the results of such evaluation to the DSMB and NIMH Program 
Official as soon as possible, but in no event later than 10 working days after the investigator first learns of the 
event. 

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The PI and research team will report SAEs to the local IRB per Stanford University’s HRPP Policy Guidance 
“Events and Information that Require Prompt Reporting to the IRB“ GUI-P13 1/3 (see Appendix A). 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Incidental MRI findings. In our participant information and consent forms we will explicitly state that the 
scans performed in this study are for specific research purposes and are not optimized to find medical 
abnormalities. Before participation we will make sure participants have been informed of, understood and 
consented to the following: 
1. All research MRI and fMRI scanning protocols are carried out for scientific purposes and are not 
optimized to make clinical diagnoses, thus they do not qualify as clinical diagnostic scans. 
2. The investigators and personnel on this project are not trained to perform medical diagnosis on MRI 
scans. The investigators are not responsible for failure to find existing abnormalities in the MRI scans 
acquired with research protocols.  
3. Point 2 notwithstanding, there is a small possibility that during the processing of participants’ scans 
for research purposes, features of the brain that can be considered out of the normal range might be 
observed. In case such a potential abnormality is observed (i.e. incidental finding), we will follow the 
established management protocol for incidental findings, as outlined in collaboration with our 
Stanford imaging facility at CNI. This protocol is as follow:  
i. In the event of a potential incidental finding, research scans are referred to an appropriately 
qualified individual (neuroradiologist) designated by the CNI Board, for further review. The 
reviewer will determine if the potential abnormality merits further investigation and will 
inform the Principal Investigator of the action to be taken. 
ii. The CNI operations team promptly provides a DVD with the scans in question or in another 
way makes the images available to the reviewer to be read "as is". The reviewer is a doctor 
specializing in MRI will be asked to look at the images to see if any medical follow-up is 
needed.  
iii. If follow-up is recommended, the investigator will be informed by CNI. The investigator will 
then contact the participant with the appropriate information. Because the images are 
taken using research settings they will not be made available for clinical purposes. 
4. When participating in the experiment, the participant agrees with being informed about potential 
medical problems according to the above-described procedure. The participant is also informed that 
if such potential problem is reported to the participant, it is the participant’s responsibility to seek 
appropriate help from a qualified professional via their general physician. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
8.3.9 REPORTING OF PREGNANCY  
 
N/A 
 

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8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to include, 
in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 
1. Unanticipated problems (UPs) involving risks to participants or others  
Events (internal or external, deaths, life-threatening experiences, injuries, or other) occurring during 
the research study, which in the opinion of the Monitoring Entity or the PD meet all of the following 
criteria:  
a) Unexpected 
in terms of nature, severity, or frequency, given (a) the research procedures described in the 
protocol-related documents, and (b) the characteristics of the subject population being studied; 
AND 
b) Related to participation in the research or there is a reasonable possibility or likelihood that the 
incident, experience, or outcome may have been caused by the procedures involved in the 
research; 
AND 
c) Harmful 
the research places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
2. New Information that indicates a change to the risks or potential benefits of the research in terms of 
severity or frequency or impacts the participant’s willingness to participate (e.g., DSMB/DSMC Report, 
other safety information or publication, suspension or premature termination by the sponsor or 
investigator). 
3. Noncompliance: An action or activity in human subject research at variance with the approved IRB 
protocol, other requirements and determinations of the IRB, the HRPP Policy Manual and other 
applicable policies of Stanford University, SHC, LPCH, VAPAHCS (e.g., VHA Handbook 1200.5), Palo Alto 
Veterans Institute for Research (PAVIR) or relevant state or federal laws. 
             When the event is: 

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• 
Possibly serious  
 
Noncompliance that affects the rights or welfare of human subject research 
participants. 
• 
Possibly continuous  
 
A pattern of noncompliance that continues to occur after a report of noncompliance 
and a corrective action plan has been reviewed and approved by the IRB, after an 
investigator has been warned to correct errors or noncompliance, or a circumstance in 
which an investigator fails to cooperate with investigating or correcting non-compliance. 
4. Complaint unresolved by the research team. 
5. Incarceration when in the opinion of the PD it is in the best interest of the participant to remain in the 
study.  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
1. Hypothesis 1: enroll 70 participants and retain ≥85% at 11 weeks.  
2. Hypothesis 2: At least 60% of participants show an increase in emotional regulation as indicated by any one 
of the three: i) an increase in mPFC activation, ii) an increase in mPFC-amygdala connectivity, or iii) a decrease 
in amygdala activation relative to baseline, supporting that the targets can be modified in a majority of 
participants. 
9.2 
SAMPLE SIZE DETERMINATION 
The primary goals of Study 1 are to verify preliminary evidence of target engagement and to refine the measures 
selected to use in Study 2. To aid in defining meaningful effect sizes for early stage research, Sheiner and Julious 
and Patterson proposed the use of precision intervals of pre-specified width to guide sample size 
determination—an approach that Co-I Ma et al. have used in a prior NIH-funded pilot study. Julious83  offered 
a further adjustment to provide Assurance (in a role similar to Power) that a chosen standardized width contains 
the mean parameter. To obtain a precision interval with standardized half-width 0.50 (similar to a “medium” 
effect size) with Assurance of 95%, 44 participants are required. For the R61 phase we have planned more 
conservative sample size of 70 and will retain ≥ 80% (56 participants). This allows for occasional fMRI data 
collection failures (e.g., no shows and magnet leavers) and will provide more reliable estimates of neural target 
engagement, defined as the effect of CBT-I on changes in amygdala reactivity and amygdala-mPFC connectivity 
from baseline to 11 weeks. This will provide reliable estimates of target engagement (i.e., the treatment effect 
on amygdala activation and amygdala-mPFC connectivity). 
In addition to testing the Go criteria, the results of the analyses conducted in the R61 phase will be used to 
refine the list of measures included in the R33 phase. We will use regression models to evaluate which of the 
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in sleep. Those measures that yield a clinically meaningful effect as defined by R2=0.10 (medium effect size) in 
the R61 phase will be maintained in the R33 phase for confirmatory analyses. Using a conservative estimate, in 
order to detect effects in which changes in sleep explain at least 10% of the variance (i.e. R2 ≥ 0.10) with at least 
80% power, we will need 56 participants. This is feasible based on our planned retention strategy, limiting drop 
out to ≤20%. We will examine changes in depressive symptoms and suicidality trajectories as a function of 
treatment dose (defined as cumulative sessions of CBT-I) to determine whether target engagement may be 
occurring earlier in treatment in order to better optimize dose. Age, sex, and symptom severity will be included 
as covariates. 
 
 
 
9.3 
POPULATIONS FOR ANALYSES 
We will conduct both an intent-to-treat (ITT) analysis using the last observation carried forward and analysis 
based on completers only, to assess bias caused by dropouts. Emotional distress assessments during the weekly 
treatment sessions will aid in understanding reasons for dropout.  
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
This project will employ robust statistical methods for each aim to rigorously test our model. We will maintain 
meticulous version control in the analysis utilizing git and will make our analysis and design code available via 
github to aid in transparency and methodological reproducibility.   
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Statistical Analyses: We hypothesize that in this single-arm study treatment with CBT-I will lead to improvements 
in Emotion Regulation Network function. Specifically, we predict that sleep restoration will be associated with 
greater increases in mPFC reactivity and mPFC-Amygdala Connectivity, and with decreases in Amygdala reactivity. 
An extended analysis of covariance (ANCOVA) will be used to test the primary hypothesis of change in Emotion 
Regulation Network function from baseline to end of treatment. We will characterize the association between our 
primary measures of Emotion Regulation Network function and that of our proximal outcome (sleep disruption as 
defined by sleep-EEG derived sleep efficiency) using a regression framework with age and sex included as 
covariates. 
 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Statistical Analyses Related to Treatment Effects: We will examine the treatment effect on outcomes as 
measured by validated self-report questionnaires and sleep disruption measurements as well as the association 
of change in Emotion Regulation Network function with change in outcomes.  We will also analyze within-

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subject trajectories of BDI and CSSRS scores, as well as sleep variables derived from actigraphy and daily sleep 
logs as a function of treatment dose, defined as cumulative number of CBT-I sessions. 
 
Statistical Analyses Secondary Measures Related to Emotional Distress: Emotional distress secondary 
outcomes will be assessed using validated measures including Columbia Suicide Severity Rating Scale (CSSRS), 
World Health Organization quality of Life Assessment (WHOQoL-BRIEF), Patient Health Questionnaire (PHQ-9), 
and the Generalized Anxiety Disorder Scale (GAD-7). Secondary sleep disruption outcomes will include 
subjective experience of sleep disruption as indicated by the Insomnia Severity Index (ISI) and daily sleep logs, 
as well as sleep continuity and architecture variables derived from overnight sleep-EEG recording and 
actigraphy. Spectral analysis variables derived from the overnight sleep-EEG recording. We will also explore 
associations between emotion regulation related behaviors and physiology including behavior on the 
neuroimaging emotion regulation tasks (implicit threat priming, emotional conflict, and emotional response), 
measures of emotional reappraisal and suppression as assessed with the Emotion Regulation Questionnaire 
and the other domains, and Respiratory Sinus Arrhythmia (RSA). The statistical approach to analysis of the 
treatment effect on these outcomes will use ANCOVA, analogous to the analysis of target engagement (above). 
 
Some measures will be collected daily (e.g. actigraphy and sleep logs) and weekly (BAI, BDI, CSSRS) over the 
course of treatment. Our general approach is to apply mixed linear models, using the daily/weekly reports to 
construct an individual specific estimate (functionally the mean and coefficient of variation of daily 
measurements for each naturalistic measure over a week) for baseline and follow-up, and then testing the 
effect of time (thus testing the within-person change over time). Random intercepts and slopes (and their 
covariance) at the person level will be included in our models. Random intercepts will be used to account for 
the clustering of observations within individuals across time; random slopes for key within-person predictors 
(e.g. ‘time’ or pre to post in this case) will be included to allow within-person slopes to be stronger for some 
individuals and weaker for others. In cases where random slopes are observed, we will test for potential 
subgroups/moderation (e.g., by age, sex, etc.; although we note that the small sample size somewhat limits our 
statistical power for such moderation tests).  
 
 
Statistical Analyses Secondary Measures Related to Cohesive Factors of Dysfunction: Sparse unsupervised 
clustering and PCA analyses will be used to identify cohesive factors of dysfunction in a) targets of Emotion 
Regulation Network function, b) sleep disturbances, c) patterns of emotional distress, and d) behavioral 
measure of Emotion Regulation Network function at baseline. General linear models will be used to quantify 
the relationships within and between these factors. 
 
9.4.4 SAFETY ANALYSES 
 
N/A 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Intervention groups will be compared on baseline characteristics including demographics, objective and 
subjective sleep disturbances, cognitive impairment, depression, and anxiety. 
 
9.4.6 PLANNED INTERIM ANALYSES  

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There is no planned interim analysis for this project.  The DSMB or NIMH will determine if a planned interim 
analysis should be conducted.  If the DSMB requests a detailed safety review of SAEs or severe AEs by group, 
then based on that review, the DSMB or NIMH Officer will determine what steps will be taken.  
 
9.4.7 SUB-GROUP ANALYSES 
 
We will examine sex differences and associations with age in a priori subgroup analyses, but without requiring 
conventional statistical power.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Data will be stored in the long format with the end points in separate columns and participants repeated across 
rows specified by the time points.   
 
9.4.9 EXPLORATORY ANALYSES 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 

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10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANT 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to 
the participant and written documentation of informed consent will be completed prior to starting the 
study intervention.   
 
• Consent Procedures and Documentation 
Procedures for obtaining informed consent.  During the consenting process, each prospective 
participant will meet in a private interview room at the study site with the PI or trained study staff.  The 
information contained in the Informed Consent Form (ICF) is initially described orally to the prospective 
participant.  Care is taken to inform prospective participants repeatedly that participation is entirely 
voluntary and that they may withdraw at any time and for any reason.  Any questions will be answered.  
The prospective participant is then asked to read the consent form carefully.  The prospective 
participant is asked to summarize the consent form, including the discomforts, risks, and confidentiality 
sections.   
Enough time will be allowed for the potential participant and to make an informed decision, including 
time to discuss the study with the researchers and ask any questions they may have.  We estimate the 
consenting process will take between 30 minutes and one hour.  The potential participant may take the 
consent home to discuss with others, and return later to sign it if they desire and return at a later time 
to complete the study visit. 
Procedures for documenting informed consent.  Only after the prospective participant demonstrates 
by stating in their own words that they understand the purposes, risks, and potential benefits of the 
study and they are willing to volunteer, will the participant be asked to sign and date their respective 
consent forms.   
A copy of the ICFs will be given to each participant.  This fact will be documented in the participant’s 
record.  All original signed consent forms will be stored in the Study Consent Binder in a locked file 
when not in use.    
Provisions for vulnerable populations. We do not anticipate any participants to fall under provisions 
for vulnerable populations.  
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
The study may be discontinued at any time by the IRB, the NIMH, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected.  
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 

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Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, the 
safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is extended to the 
data being collected as part of this study. Data that could be used to identify a specific study participant will be 
held in strict confidence within the research team. No personally-identifiable information from the study will 
be released to any unauthorized third party without prior written approval of the sponsor/funding agency.  
 
Standard procedures for data collection will be employed to minimize the risk to participant confidentiality. An 
anonymous ID key will replace all details that identify participants before any use or transmission of data. Any 
details identifying participants will be held in confidence and stored within the secure database. The 
information obtained in the study will be treated in the strictest confidence and none of the participants in this 
study will be individually identifiable in any resulting publications or reports. All data files will be kept in 
password-protected computer files. All research activities will be conducted in as private setting as possible, 
and all confidential information gathered during the course of interviews and data collection will be entered 
into password-protected computers. Follow-up interactions will take place by private phone calls and emails to 
previously identified email addresses private to that participant. 
All scanning will take place in the MRI suite in the Center for Cognitive and Neurobiological Imaging (CNI) at 
Stanford, to which access is restricted except to study personnel. All data will be de-identified after acquisition. 
PHI will be maintained in the secure REDCap database and password-protected computers in the lab of Dr. 
Goldstein-Piekarski. Paper copies of PHI and questionnaire data will be kept in locked cabinets in Dr. Goldstein-
Piekarski’s lab. All computers, external hard disks, USB thumbs, tablet computer, smart phone etc. will be 
encrypted and password protected. Once acquired, data will be de-identified and given a generic indicator (e.g. 
IREST001). MRI scans, from which facial information may be reconstructed (and thus an identifier) will be de-
identified using conventional face stripping algorithms for MRI data. Audio/video recordings will be edited to 
obscure facial features and will be marked with a generic identifier. Access to de-identified data will be available 
to the study personnel and access will be controlled by the study lead investigator and protocol director (Dr. 
Goldstein-Piekarski). All research staff will undergo training from the lead investigator, including in the means 
through which confidentiality is maintained. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of the 
Institutional Review Board (IRB), regulatory agencies or representatives from companies or organizations 
supplying the product, may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored in the lab of Dr. Goldstein-Piekarski for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency 
requirements. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made available to 
the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to share data 
will include proper plans and safeguards for the protection of privacy, confidentiality, and security for data 
dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be traceable to a specific 

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study participant). Plans for archiving and long-term preservation of the data will be implemented, as 
appropriate.  
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), has issued 
a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, clinical or other 
human subjects research funded wholly or in part by the federal government.  Recipients of NIH funding for 
human subjects research are required to protect identifiable research information from forced disclosure per 
the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 
75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered by this Policy are 
required to establish and maintain effective internal controls (e.g., policies and procedures) that provide 
reasonable assurance that the award is managed in compliance with Federal statutes, regulations, and the 
terms and conditions of award. It is the NIH policy that investigators and others who have access to research 
records will not disclose identifying information except when the participant consents or in certain instances 
when federal, state, or local law or regulation requires disclosure. NIH expects investigators to inform research 
participants of the protections and the limits to protections provided by a Certificate issued by this Policy.] 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored on encrypted computers and in locked files within PI 
Goldstein-Piekarski’s lab at Stanford. After the study is completed, the de-identified, archived data will be 
transmitted to and stored at the NIMH data archive, for use by other researchers including those outside of the 
study. Permission to transmit data to the NIMH data archive will be included in the informed consent.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples may be stored in one of the National Institutes of Health (NIH) databases with the same goal 
as the sharing of data with the NIMH data archive. The NIH repository will also be provided with a code-link 
that will allow linking the biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological 
specimens stored for future research. However, withdrawal of consent with regard to biosample storage may 
not be possible after the study is completed.  
 
 
 
 
 
 
 
 

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10.1.5 KEY ROLES AND STUDY GOVERNANCE
Principal Investigator
Data Safety Monitoring Board
Andrea Goldstein-Piekarski, PhD
Stanford University School of Medicine
401 Quarry Rd.
Palo Alto, CA 94304
agoldpie@stanford.edu
Daniel Taylor, Ph.D. 
University of Arizona
Meredith Wallace, Ph.D. 
University of Pittsburgh School of Medicine
Yelena Blank, Ph.D.
Private Practice 
10.1.5.1
STUDY TEAM ORGANIZATIONAL STRUCTURE
The team is structured around a collaborative model. PI Goldstein-Piekarski will be the overall study PI 
and coordinate the data management and operations of the study. 
10.1.5.2 INVESTIGATORS AND RESEARCH STAFF
10.1.5.3 PI LEADERSHIP

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Andrea Goldstein-Piekarski, PhD will lead the team of investigators and staff and will direct the 
oversight and coordination of fiscal management, research administration, publications and data 
sharing, and integration of all resources needed for the project. In particular, she will (1) review and 
address issues that require judgment over the scientific direction and conduct of the protocol; (2) 
oversee decisions on any changes in research direction and therefore, have the authority to reallocate 
funds and resources to best meet the emerging needs of the project; (3) provide communication with 
in the organizational hierarchy to maintain alignment with operational priorities, and assist with 
addressing both scientific and implementation questions and barriers; and (4) ensure compliance with 
participant privacy and confidentiality regulations at all times. Decisions will be made through 
discussion and consensus building with all the co-investigators. Throughout the process, the PI and co-
investigators will remain respectful of the perspectives that each individual brings to the project and 
will collaborate diligently to ensure scientific rigor and transparency and optimize operational 
efficiency.  
 
10.1.5.4 RESEARCH STAFF AND POSTDOCTORAL FELLOWS 
 
intervention implementation, (2) recruitment, retention and data collection, and (3) data management 
and analysis. The Intervention Implementation staff includes a clinical psychologist who will provide 
treatment to the participants and monitor suicide risk. The clinical psychologist will interface with the 
Intervention Core including Drs Manber and Bernert. Dr. Bernert and Dr. Yesavage will serve as medical-
monitors for the study. The Recruitment, Retention and Data Collection staff are clinical research 
coordinators who will develop and implement the participant recruitment and retention protocol as 
well as the data collection procedures, forms and databases in the R61 phase. They will work with the 
Trial design and biostatistics core to refine the protocols and measures for use in the R33 phase.  The 
two postdoctoral fellows with expertise in neuroimaging and sleep research will also contribute to data 
collection and ensure ongoing quality of the incoming data.  The Data Management and Analysis staff 
will develop and maintain the data management system and protocols and perform data analyses under 
the guidance of PI Goldstein-Piekarski and the Trial design and Biostatistics Core.   
 
 
10.1.6 SAFETY OVERSIGHT 
 
DATA SAFETY MONITORING PLAN  
This safety monitoring protocol (Table 4) has been successfully employed in two former randomized controlled 
trials for suicide prevention funded to the Co-I [DOD: W81XWH-10-2-0178, NIH: K23MH093490], and is 
consistent with previous and in use procedures by the research team. All procedures will be closely supervised 
by this study’s PIs and on-site safety officers, Drs. Bernert and Yesavage. Suicide risk assessment will be 
conducted using empirically-established risk categorizations (minimal, mild, moderate, severe, imminent; Table 
5) to routinize clinical decision-making and emergency referral procedures for suicidal behaviors. 
TABLE 4: DATA AND SAFETY MONITORING PLAN (DSMP) 
 
Training of Personnel in Suicide Risk Assessment: 
1. 
All study personnel will complete extensive clinical training in suicide risk assessment practices, led by the PI, 
Safety monitors, and Co-I’s. This team will meet regularly to discuss suicide risk assessment, DSMP 
procedures, adequacy and assessment of training. Though all personnel will receive training, the CSSRS will 
only be administered only by Master’s level staff, clinical doctoral students, or trained clinicians (PIs/Co-Is, 
Study Clinicians). 
 

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Primary Assessment Measure 
2. 
A score > 4 on the CSSRS will prompt standardized suicide risk assessment and administration of The Suicide 
Checklist and Suicide Assessment Decision Tree (See Below). 
a. 
If risk is elevated but not imminent, established behavioral methods will be used to effectively manage 
risk on an outpatient basis. The PI/Safety Monitors will closely monitor decision-making and 
assessment, and all action taken will be clearly documented. 
b. 
If risk is imminent, participants will be referred for immediate hospitalization and emergency mental 
health services. The PI/Co-Is will closely monitor decision-making and assessment, and action taken 
will be documented. 
 
At Study Initiation: 
3. 
This study will follow warm transfer procedures previously used for triage to the National Suicide Prevention 
Crisis Line for referral and triage. Established in 2011, this was approved by Stanford University is has been 
previously used in DSMP protocols conducted by the research team. 
4. 
Participants will be required to provide contact information as part of informed consent procedures, including 
personal contact information (e.g., physical address, cell) and permission to call an identified next of kin or 
emergency contact in the case of an emergency. In the rare situation that: a participant is judged to be at 
imminent risk for suicide, is located offsite, and is unwilling/unable to seek out referred mental health services, 
next of kin notification will be utilized to coordinate emergency referral. 
5. 
Participants will be provided with emergency referral contact information and 24-hr resources (e.g., 1-800-273-
TALK, online chat and text; Crisis Text Line) for outpatient safety monitoring. Participants who endorse 
symptoms indicative of serious or imminent risk will be warm transferred to appropriate services. 
6. 
Best practices in suicide risk assessment and management procedures will be reviewed at the outset of the 
study with all participants, as a central component to the informed consent process. Notification of next of kin 
procedures, and permission to contact this individual in event of a no-show/elevation in risk/circumstances 
outlined in consent form, will be reviewed prior to enrollment, in addition to confidential/non-confidential referral 
resources available to the participant in the event of an elevation in symptoms. Emergency resources provision 
will be regularly provided at the outset of participation. 
7. 
Participants will be explicitly encouraged to contact the PI/Co-Is/Study Clinician if symptoms elevate between 
screening and intervention sessions via a 24/7 study pager. 
8. 
Participants will be referred to a supervising clinician if a participant experiences distress at any point following 
enrollment. This will prompt standardized suicide risk assessment according to established frameworks. 
 
Active/intervention phases of the study 
9. 
No shows will be vigorously pursued. 
10. Safety Checks will be conducted at all study visits and documented for future review. 
11. Safety planning will be conducted if risk is judged to be elevated, prompted by standardized risk assessment 
findings. Safety planning will be tailored to the individual and his or her level of risk. A safety plan will be 
outlined via construction and use of a Coping Card. Use of Coping Cards/Collaborative Assessment and 
Management of Suicidal Symptoms/Safety Planning Procedures are evidence-based for the management of 
suicidal symptoms in outpatient settings (Joiner et al., 1999; Brown & Stanley, 2008; Jobes 2006). These list 
internal and external coping strategies to be implemented, should the participant experience suicidal urges at 
any point in the study; they also list: local community emergency mental health contact numbers, 24-hour crisis 
hotlines, contact information for study personnel and on-call clinicians, contact information for an identified 
confidant that the individual may call, should he or she experience increased distress). Lethal means restriction 
may be a focus of a safety plan, if and when indicated. All safety and risk assessment interactions will be 
closely supervised by a licensed clinician, and thoroughly documented.  
12. 24-hr on-call clinical coverage teams will be assembled and in place throughout active treatment phases, 
consistent with previous IRB-approved clinical trials among high suicide risk participants 
(NCT01958541).Participants will be explicitly encouraged to contact the PI/Co-Is/Study Clinician if symptoms 
elevate between screening and intervention sessions. . 
13. Participants will be referred to a supervising clinician if a participant experiences distress at any point following 
enrollment. This will prompt standardized suicide risk assessment according to established frameworks. 
 
Active/intervention phases of the study 
14. No shows will be vigorously pursued. 
15. Safety Checks will be conducted at all study visits and documented for future review. 
16. Safety planning will be conducted if risk is judged to be elevated, prompted by standardized risk assessment 
findings. Safety planning will be tailored to the individual and his or her level of risk. A safety plan will be 
outlined via construction and use of a Coping Card. Use of Coping Cards/Collaborative Assessment and 
Management of Suicidal Symptoms/Safety Planning Procedures are evidence-based for the management of 
suicidal symptoms in outpatient settings (Joiner et al., 1999; Brown & Stanley, 2008; Jobes 2006). These list 
internal and external coping strategies to be implemented, should the participant experience suicidal urges at 
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hotlines, contact information for study personnel and on-call clinicians, contact information for an identified 
confidant that the individual may call, should he or she experience increased distress). Lethal means restriction 
may be a focus of a safety plan, if and when indicated. All safety and risk assessment interactions will be 
closely supervised by a licensed clinician, and thoroughly documented.  
17. On-call clinical coverage teams will be assembled and in place throughout active treatment phases. 
 
 

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This study will utilize a comprehensive, in-built infrastructure and set of standard operating procedures that 
support safe conduct of the current trial. Based on evidence-based best practices in standardized risk 
assessment and management, subjects at imminent risk will be referred for immediate hospitalization. 
Proposed procedures have been used in previous IRB-approved proposals by the research team, and DSMP 
protocols employed by Drs. Goldstein-Piekarski, Bernert, Williams, Manber, and Yesavage. If indicated by 
suicide risk assessment, safety monitoring will be used according to the protocol below, and treatment will be 
provided as an enhancement to treatment as usual (TAU). Procedures are consistent with past behavioral 
insomnia clinical trials among high risk participants. 
 
DATA SAFETY MONITORING BOARD 
As a further protection against risk, a DSMB will be formally constituted to: independently review, oversee, and 
monitor risk procedures for the proposed studies. DSMB construction will be closely guided by the PI’s 
supervision, and consultation with Investigators and Consultants. This DSMB will report to Stanford University 
IRB regarding study recruitment and adverse event (AE) reporting on at least annual basis. The DSMB will consist 
of individuals with the following expertise, nonaffiliated with the study: (1) An expert in sleep and mood 
disorders, (2) A biostatistician with expertise in clinical trials, and (3) A patient advocate. During the proposed 
intervention, participants will be instructed to report any intervention-emergent AEs or symptoms to study 
Personnel. These will be closely monitored and assessed on at-least weekly basis. DSMB and Stanford IRB will 
be immediately advised if a participant reports a serious emerging condition or AE—independent of cause or 
relation to the intervention. In the rare case that an AE warrants evaluation by the ombuds/patient advocate, 
DSMB consensus will have power to determine appropriateness of study continuation. Such decisions will be 
binding. 
 
Data Safety Monitoring Board Members:  
1. Daniel Taylor, Ph.D. Dr Taylor is a professor of Professor in the Department of Psychology at the University 
of Arizona. He is a certified behavior sleep medicine specialist and a dimplomat of the American Board of 
Sleep Medicine.  
2. Meredith Wallace, Ph.D. Dr. Wallace is an Associate Professor in the Department of Psychiatry at the 
University of Pittsburgh School of Medicine.  
3. Yelena Blank, Ph.D. Dr. Blank is a licensed clinical psychologist with a private practice in Mountain View, CA.  
 
Clinical Oversight and Credentials of Those Supervising DSMP Trainings: 
1. Rebecca Bernert, Ph.D. [Co-I, Co-Safety Monitor]. Dr. Bernert is an Assistant Professor in the Department of 
Psychiatry and Behavioral Sciences at Stanford University, and Director of the Suicide Prevention Research 
Laboratory. She has had >15 years of clinical experience evaluating and treating suicidal patients using 
empirically-supported assessment procedures and within clinical trials, including at Stanford, VA Palo Alto 
Health Care System (inpatient, outpatient units), and the Stanford Mood Disorders Center and Stanford Sleep 
Medicine Center. She has administered emergency psychiatric evaluations for involuntary and voluntary 
inpatient psychiatric hospitalizations among those severely and persistently mental ill; and has worked as a 
suicide risk assessment crisis monitor to silently rate suicide risk assessment practices among crisis workers at 
the National Suicide Prevention Lifeline (NSPL), and intervened if necessary (as part of a SAMHSA-funded multi-
national research collaborative to evaluate and improve suicide risk assessment practices among crisis workers 
at NSPL: PI Kalafat). She is a licensed psychologist, and has published on and contributed to VA/DOD clinical 
practice guidelines in the assessment and management of suicide risk, and ethical practices in suicide 
prevention. She has previously conducted NIH- and DOD-funded, IRB approved research in clinical trials 
involving high suicide risk participants. She created a DSMP model for suicide prevention clinical trials at 

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Stanford that will be utilized in the current study, and previously approved by the NIH Human Subjects 
Committee for sleep research among those at high risk for suicide. This protocol has since been used across 
multiple investigators, grants, and institutions for NIH-funded research protocols. DSMP protocols include 
operationalized procedures for the selection and training of study clinicians, on-call 
procedures for risk assessment/supervision of safety; personnel training certifications; coordination of an 
emergency safety monitoring protocol for referral, reporting, triage, and documentation; and adherence to 
University and Departmental policies for risk assessment and referral. She is licensed in the state of California 
(PSY27980) and medically credentialed by Stanford, and as a Stanford provider, is up-to-date on all HIPAA, IRB, 
and CITI trainings. She will work closely with the PI and collaborate with Dr. Yesavage to oversee safety 
procedures, and agrees to meet regularly with on behalf of safety considerations related to enrollment and trial 
conduct. 
2. Jerome Yesavage, M.D. [Co-I, Co-Safety Monitor]. Dr. Yesavage holds a joint appointment as a Professor of 
Psychiatry at Stanford University and is the Associate Chief of Staff for Mental Health and Chief of Psychiatry at 
the VAPAHCS. He has been PI and Co-I for multiple RCT psychotherapy and pharmacotherapy treatment trials, 
including those utilizing CBT-I and rTMS for depression. He also serves as the Director of the Stanford/VA 
Alzheimer’s Center, and is licensed as a psychiatrist in the state of California. As Co-I and Co-Safety Monitor, Dr. 
Yesavage will work closely with Dr. Bernert and the PI to oversee clinical safety issues on the proposed project. 
He will have planned, frequent meetings and communication with Dr. Bernert and the PI to together establish 
and review: (1) construction and assembly of a DSMB; (2) training and evaluation of training in suicide risk 
assessment and certification procedures upfront of study launch and participant recruitment and enrollment; 
and study-related trainings in DSMP and DSMB reporting (Note: this applies to ALL study personnel, even if they 
are not in direct contact with participants in treatment); (3) IRB and Human Subjects/HRPO approvals; (4) each 
participant’s screening, enrollment, stage of treatment, clinical status, and DSMP procedures; and (5) 
documentation of action taken if DSMP procedures are enacted. All procedures will be in accordance with DSMP 
procedures used in past clinical suicide prevention trials conducted by Co-Safety Monitor, Dr. Bernert. All 
protocols were previously federally-funded grants that were IRB approved and regularly renewed to support 
safe conduct of screening, recruitment, enrollment, and data monitoring procedures for behavioral insomnia 
treatment trials for depression and suicidal behaviors. 
3. Rachel Manber, Ph.D. [Co-I]. Dr. Manber is a professor of Psychiatry and behavioral Sciences and the director 
of the Sleep Health and Insomnia Program (SHIP) at Stanford University. She will serve as Co-I for this study and 
has 25 years of experience providing CBTi to adults, teens and children. She also has extensive experience in 
the conduct of federally funded randomized control treatment outcome studies assessing the efficacy of CBTi 
in various insomnia populations, including those with depression and anxiety. She has worked directly with the 
PI, and will be involved with training of study personnel in these treatment modalities. She will also will 
supervise the Intervention core and clinical psychologist in aspects related to treatment. 
4. Leanne Williams, Ph.D. [Co-I]. Dr. Williams is Professor of Psychiatry in the Department of Psychiatry and 
Behavioral Sciences at Stanford University, with joint appointment at the VA Palo Alto HCS, where she serves 
as Director of PTSD Education and Dissemination at MIRECC. She will serve as Co-I for this study, and has 
conducted multiple trials supporting feasibility and safety of the current trial. She directs the Personalized and 
Translational Neuroscience Laboratory (PanLab) Stanford, and has developed a clinical translational 
neuroscience taxonomy for anxiety and depression [NCT02220309]. In the past 15 years, she has established 
standardized protocols for brain imaging in biomarker intervention trials that will uniquely support the 
successful and safe conduct of this study. Dr. Williams has a history of leading and overseeing protocols, 
including large-scale clinical trials for mood disorders, including among high risk individuals and veterans, which 
are well-matched to the current study. She has worked directly with the PI, and has 
experience working with all members of the research team to support safe conduct of the current study. 
 

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Plans for monitoring the accuracy and integrity of the data: The data will be managed by the PI and all data will 
be stored on a secure server. The Study Coordinator will assist Dr. Goldstein-Piekarski by monitoring the 
accuracy and integrity of the data. This will be done by verifying that follow-ups are conducted within the target 
window, verifying that assessments are complete, and the data are entered promptly. The Study Coordinator 
will audit the research data entered against the source documents. S/he will coordinate IRB and R&D approvals 
and renewals, study documentation and preparations for audits under the direction of Dr. Goldstein-Piekarski. 
 
1.. Clinical Monitoring 
 
N/A 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Trained study staff will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well as a 
percentage of the completed consent documents.  This review will evaluate compliance with GCP, accuracy, 
and completeness.  Feedback will be provided to the study team to ensure proper consenting procedures are 
followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see Section 
10.1.8, Data Handling and Record Keeping) and will ultimately be entered into the study database.  To ensure 
accuracy site staff will compare a representative sample of source data against the database, targeting key data 
points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will implement 
corrective actions when the quantity or nature of deviations are deemed to be at a level of concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor/funding agency, and 
inspection by local and regulatory authorities. 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the PI. The 
PI will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 

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All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording 
data for each participant consented/enrolled in the study.  Data recorded in the electronic case report form 
(eCRF) derived from source documents will be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into REDCAP, a 21 CFR Part 11-compliant data capture system 
provided by the Stanford University School of Medicine. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents. 
10.1.8.1 STUDY RECORDS RETENTION  
 
Per the Stanford IRB and HIPPA, research records must be maintained for at least 6 years after study closure. 
No records will be destroyed without the written consent of the sponsor/funding agency, if applicable. It is the 
responsibility of the sponsor/funding agency to inform the investigator when these documents no longer need 
to be retained. 
 
10.1.9 PROTOCOL DEVIATIONS   
Protocol deviations will be captured using a Protocol Deviation Log.   
o Any serious protocol deviation (that meets the definition of an SAE or compromises the safety, 
welfare or rights of participants or others) will be reported to the ISM, NIMH Program Official, and 
IRB as soon as possible, not more than 10 days after the PI first learns of the deviation.  
o The report will describe what steps have been taken and what steps are planned as a result of the 
event. 
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY  
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical 
Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial 
will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  
Considerations for ensuring confidentiality of these shared data are described in Section 10.1.3. 
 

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In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-funded 
research that generates large-scale human or non-human genomic data, as well as the use of these data for 
subsequent research. Large-scale data include genome-wide association studies (GWAS), single nucleotide 
polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data. 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, 
is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the design and conduct of this trial. The study leadership in conjunction with the NIMH 
has established policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
 
 
10.2 ADDITIONAL CONSIDERATIO 
N/A 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
The list below includes abbreviations utilized in this template. However, this list should be customized for each 
protocol (i.e., abbreviations not used should be removed and new abbreviations used should be added to this 
list). Special terms are those terms used in a specific way in the protocol. For instance, if the protocol has 
therapist-participants and patient-participants, those terms could be included here for purposes of consistency 
and specificity.  
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 

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FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a description 
of the change and rationale. A Summary of Changes table for the current amendment is located in the Protocol 
Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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