A Randomized Controlled Trial Examining the Neurocognitive Benefits of a Nationally Available Weight Management Program
Phase: PHASE4
Conditions: Overweight and Obesity
Sponsor: University of Pennsylvania

  
 
 
A Randomized Controlled Trial Examining the Neurocognitive Benefits of a Nationally 
Available Weight Management Program 
 
 
Principal Investigator:  
Ariana M. Chao, Ph.D., CRNP  
University of Pennsylvania School of Nursing, Dept. of 
Biobehavioral Health Sciences 
University of Pennsylvania School of Medicine, Dept. of Psychiatry 
418 Curie Blvd, Room 323 
 
Philadelphia, PA 19104 
215-746-7183 
arichao@upenn.edu 
 
Co- Investigators: 
  
Thomas A. Wadden, Ph.D.  
 
 
 
 
Ruben C. Gur, PhD 
 
 
 
IRB Number:  
 
834404 
 
ClinicalTrials.gov Number NCT04202133 
 
Study Site:   
 
Hospital of the University of Pennsylvania; 
Center for Weight and Eating Disorders 
                      
 
University of Pennsylvania  
 
Initial Version: 
 
October 10, 2019, version 1.0 
 
Amended: 
 
 
February 5, 2020, version 2.0 
 
 
 
 
February 24, 2020, version 2.1 
 
 
 
 
May 11, 2020, version 3.0 
 
 
 
 
July 6, 2020, version 4.0 
 
  

Neurocognitive Benefits of WW 
 
 
Version 4.0 
2
Table of Contents 
 
Contents 
STUDY SUMMARY ........................................................................................................................ 4 
BACKGROUND AND STUDY RATIONALE ................................................................................. 5 
INTRODUCTION ............................................................................................................................. 5 
1.1 
BACKGROUND AND RELEVANT LITERATURE ...................................................................... 5 
2 
STUDY OBJECTIVES ............................................................................................................ 7 
2.1 
PRIMARY OBJECTIVES ...................................................................................................... 7 
2.2 
SECONDARY OBJECTIVES ................................................................................................. 8 
3 
STUDY ENDPOINTS ............................................................................................................... 8 
3.1.1 Primary Study Endpoints ............................................................................................ 8 
3.1.2 Secondary Study Endpoints ....................................................................................... 8 
4 
STUDY DESIGN ..................................................................................................................... 8 
4.1 
GENERAL DESIGN ............................................................................................................. 8 
5 
STUDY POPULATION AND DURATION OF PARTICIPATION .......................................... 9 
5.1 
TOTAL NUMBER OF SUBJECTS AND SITES ......................................................................... 9 
5.2 
INCLUSION CRITERIA ......................................................................................................... 9 
5.3 
EXCLUSION CRITERIA ....................................................................................................... 9 
5.4 
DURATION OF STUDY PARTICIPATION .............................................................................. 10 
5.5 
VULNERABLE POPULATIONS: ........................................................................................... 10 
6 
STUDY PROCEDURES ....................................................................................................... 10 
6.1 
SUBJECT RECRUITMENT ................................................................................................. 10 
6.2 
SCREENING PROCEDURES .............................................................................................. 10 
6.2.1 PHONE SCREENING ......................................................................................................... 10 
6.2.2 SCREENING VISIT ............................................................................................................ 11 
6.3 
FMRI ASSESSMENTS. ..................................................................................................... 12 
6.4 
COGNITIVE ASSESSMENTS .............................................................................................. 14 
WEEK 8 ASSESSMENT. ............................................................................................................... 14 
6.5 
POST-TREATMENT VISIT (WAIT-LIST GROUP ONLY) ........................................................ 14 
6.6 
RANDOMIZATION VISIT .................................................................................................... 14 
TABLE 1. SCHEDULE OF STUDY ASSESSMENTS AND TREATMENT VISITS ....................................... 1 
TABLE 2. SCHEDULE OF PROCEDURES .......................................................................................... 1 
7 
STUDY INTERVENTION........................................................................................................... 1 
TABLE 3. TOPIC INFORMATION FOR WW SESSIONS ....................................................................... 1 
7.1 
UNSCHEDULED VISITS ...................................................................................................... 1 
7.2 
SUBJECT WITHDRAWAL .................................................................................................... 1 
7.3 
SAFETY EVALUATIONS ...................................................................................................... 2 
8 
STATISTICAL PLAN .............................................................................................................. 1 
8.1 
SAMPLE SIZE AND POWER DETERMINATION ...................................................................... 1 
8.1.1 Baseline Data .............................................................................................................. 1 
8.1.2 Efficacy Analysis ......................................................................................................... 1 
8.2 
SUBJECT POPULATION(S) FOR ANALYSIS .......................................................................... 2 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
3
9 
SAFETY AND ADVERSE EVENTS ....................................................................................... 2 
9.1 
DEFINITIONS ..................................................................................................................... 2 
9.1.1 Adverse Event ............................................................................................................. 2 
9.1.2 Serious Adverse Event ............................................................................................... 2 
9.2 
RECORDING OF ADVERSE EVENTS .................................................................................... 2 
9.3 
RELATIONSHIP OF AE TO STUDY ....................................................................................... 3 
9.4 
OUTCOME CATEGORIES AND DEFINITIONS: ....................................................................... 3 
10 REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED 
PROBLEMS ................................................................................................................................... 3 
10.1.1 
Follow-up report ...................................................................................................... 3 
10.1.2 
Investigator reporting: notifying the study sponsor ................................................ 4 
10.2 
MEDICAL MONITORING ...................................................................................................... 4 
10.2.1 
Data and Safety Monitoring Plan ............................................................................ 4 
10.2.2 
DATA SAFETY MONITORING BOARD .............................................................................. 4 
11 STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING ....................... 4 
11.1 
CONFIDENTIALITY ............................................................................................................. 4 
12 PRIVACY ................................................................................................................................ 4 
13 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................... 4 
14 ETHICAL CONSIDERATIONS .............................................................................................. 5 
14.1 
RISKS ............................................................................................................................... 5 
14.2 
BENEFITS ......................................................................................................................... 7 
14.3 
RISK BENEFIT ASSESSMENT ............................................................................................. 7 
14.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ................................................. 8 
15 STUDY FINANCES ................................................................................................................ 8 
15.1 
CONFLICT OF INTEREST .................................................................................................... 8 
15.2 
SUBJECT STIPENDS OR PAYMENTS ................................................................................... 8 
16 REFERENCES ....................................................................................................................... 8 
 
 
 

Neurocognitive Benefits of WW 
 
 
Version 4.0 
4
Study Summary 
Title 
A Randomized Controlled Trial Examining the Neurocognitive Benefits 
of a Nationally Available Weight Management Program 
Short Title 
Neurocognitive Benefits of WW 
IRB Number 
834404 
Phase 
Phase 4 
Methodology 
Randomized, wait-list controlled, open label  
Study Duration 
1.5 years  
Study Center(s) 
Single-center 
Objectives 
To assess the effects of a commercially available weight loss program 
(WW, formerly Weight Watchers) on neural response to food cues and 
memory tasks, as well as on structural brain morphology. 
Number of 
Subjects 
60 
Main Inclusion and 
Exclusion Criteria 
Key Inclusion: BMI>30 kg/m2; female; ages 18-60 
 
Key Exclusion: Weight > 158.8 kg; pregnancy or lactation; current 
psychiatric disorder that significantly interferes with daily living; active 
suicidal ideation; presence of conditions that may interfere with 
magnetic resonance imaging; use of weight loss medications or other 
agents known to affect body weight or blood glucose in the past 3 
months; type 1 or 2 diabetes mellitus; visual, auditory, or other 
impairment affecting task performance 
Reference therapy 
Wait-list control group 
Statistical 
Methodology 
Mixed-effects linear models 
Safety Evaluations  
Adverse events  
Data and Safety 
Monitoring Plan  
Drs. Chao and the co-investigators will be responsible for monitoring 
the data quality and the ongoing safety of subjects. A data safety 
monitoring board will also monitor the data quality and ongoing safety 
of subjects. 
 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
5
BACKGROUND AND STUDY RATIONALE 
Introduction 
This study will be one of the first randomized controlled trials to assess whether weight loss 
induced through diet and physical activity can change neural responses to high- and low-calorie 
food images. In addition, it will evaluate whether weight loss can improve neural function when 
performing the N-back task, a measure of working memory. Findings will address notable gaps in 
the literature by testing whether a scalable weight loss intervention can help protect and improve 
neurocognitive functioning and brain health in individuals with obesity. This study will also provide 
important information about the effects of weight loss on neuroplasticity in brain regions crucial 
for memory and cognitive functioning, which will help to inform future interventions aimed at 
promoting brain health.  
 
This document is a clinical research protocol and the described study will be conducted in 
compliance with the protocol, Good Clinical Practice standards, associated federal regulations, 
and all applicable University research requirements. This study will be conducted in full 
accordance with all applicable University of Pennsylvania Research Policies and Procedures and 
all applicable Federal and state laws and regulations including 45 CFR 46, and Good Clinical 
Practice. All episodes of noncompliance will be documented. 
1.1 
Background and Relevant Literature  
Obesity, characterized by a body mass index (BMI)>30 kg/m2, is caused by overconsumption of 
calories relative to energy expenditure.1 The modern obesogenic environment, filled with cues to 
consume highly-palatable and energy-dense foods, is a major driver of overweight and obesity.2 
Obesity greatly increases the burden of chronic illnesses including Alzheimer’s disease and 
dementia.3-8 Even before the onset of these conditions, elevated body mass is linked with worse 
neurocognitive functioning such as poor inhibitory control, attention, and memory.9 The purpose 
of this proposal is to evaluate the potential benefits of weight loss on two neural processes that 
have been shown to be impaired among people with obesity: food cue responsiveness and 
memory. 
 
People with obesity have altered neural responses to environmental food cues, including when 
seeing pictures of food.10 The majority of studies have shown that people with obesity, relative to 
those without, have greater responsiveness to high-calorie food images in regions of the brain 
associated with reward (e.g., striatum, amygdala, insula, orbitofrontal cortex), attention 
(anterior cingulate cortex), and motor processes (precentral gyrus, cerebellum).10,11 Elevated 
reward-region responses to high-calorie food images and cues are associated with higher food 
cravings, more snack consumption, and future weight gain.10,12-16 This increase in neural 
responsiveness has been hypothesized to be due to learning processes, as well as changes in 
energy-balance hormones, such as ghrelin, leptin, insulin, amylin, and peptide YY, which can 
modulate the brain networks associated with food reward and control.17-19  
 
Another area of research has shown that individuals with obesity, relative to those of normal 
weight, have reduced performance on behavioral measures of memory,20 as well as worse brain 
health in neural structures and functions associated with memory.21 For example, relative to 
participants with normal weight, those with obesity have lower performance on measures of 
working memory (i.e., the ability to store and manage information on a transient basis) as 
assessed by tasks in which participants are asked to recall sequences of numbers.20 Compared 
to participants with normal weight, those with obesity have decreased global brain volume, and 
decreased volumes in the temporal lobe, dorsolateral prefrontal cortex, orbitofrontal cortex, and 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
6
hippocampus.21,22 Reduced hippocampal volume among people with obesity is evident as early 
as childhood.23 Relative to participants with normal weight, those with obesity have lower neural 
activation of the parietal cortex (an area associated with memory retrieval) during working memory 
tasks.24 These brain structures and functions are crucial for memory, as well as general executive 
functioning and self-regulatory processes necessary to achieve long-term goals.25,26  
 
Weight loss through diet, physical activity, and behavior modification is recommended for 
individuals with obesity. Benefits of weight loss include improvements in glycemia, triglycerides, 
high-density lipoprotein cholesterol, blood pressure, inflammation, and health-related quality of 
life.27-29 After weight loss, individuals report improvements in appetite including decreased 
hunger,30,31 food cravings,32,33 and preoccupation with food, and increased fullness.34 In addition, 
there is evidence that low-fat diets can help to decrease cravings for high-fat foods and to shift 
preferences to low-carbohydrate/high-protein foods.35 However, the effects of weight loss on 
neural processes related to food cue reactivity and memory are not clear.  
 
Acute caloric restriction appears to increase neural responses to food cues, especially high-
calorie foods. Food, especially high-calorie and energy-dense food, is more attractive and 
palatable when people are hungry.36 Compared to satiated conditions, acute caloric deprivation 
(typically fasting 8-24 hours) increases activation in neural regions that have been implicated in 
attention (anterior cingulate cortex), reward valuation (amygdala), memory (hippocampus), and 
homeostatic feeding (hypothalamus) in response to pictures of palatable foods versus non-food 
control images.37,38 Further, acute caloric deprivation selectively increases responsiveness in 
brain reward systems (i.e., the ventral striatum, amygdala, anterior insula, and medial and lateral 
orbitofrontal cortex) to highly palatable foods relative to low-calorie food images.39-41  
 
In contrast to acute caloric deprivation, moderate caloric restriction (i.e., a diet of 800-1500 
kcals/day) for 3 weeks to several months alters neural responsiveness to food, but in the opposite 
direction of acute restriction. Longer-term moderate caloric restriction, with weight loss of 
approximately 3.5-10% of initial weight, has been associated with decreased food-cue reactivity 
to high-calorie foods in brain regions regulating energy balance (e.g., hypothalamus)42, some 
regions of the dopaminergic reward system (e.g. orbitofrontal cortex42,43, anterior cingulate 
cortex42, amygdala42, caudate44,45), and regions that execute appetitive behavior (e.g. precentral 
gyrus).42,46 A small pilot trial also demonstrated that weight loss increased responsiveness to low-
calorie foods (e.g., apple, grilled chicken, salmon; mean of 2.1 kcals/gram) in reward regions of 
the brain (dorsal and ventral striatum).47  
 
Another body of research indicates that weight loss improves attention, executive functioning, and 
memory.48 A recent meta-analysis of six studies demonstrated that weight loss induced through 
dietary changes, caloric restriction, and physical activity, significantly improved behavioral indices 
of memory compared to control groups.48 Yet, few studies have assessed whether behavioral 
findings of memory changes with weight loss correspond with improved brain structure and 
function. Relative to control conditions, aerobic exercise increased left hippocampal volume,49 
possibly through prevention of decreased neurogenesis and improved angiogenesis. In rodents, 
switching from a high-fat diet to a low-fat diet helped to reverse impairments in memory.50 Few 
studies have assessed the effects of lifestyle interventions consisting of dietary, physical activity, 
and behavioral modification on memory-related neural changes. Of the studies that have been 
conducted, compared to control groups, lifestyle interventions demonstrated improvements in 
hippocampal function,51-53 as well as increased hippocampal volumes.51,52 However, many of 
these studies are limited by pre-posttest designs and small sample sizes. Little is known about 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
7
the impact of weight loss induced through lifestyle modification interventions (that include dietary 
and physical activity changes) on memory-related neural processes.  
 
Thus, current evidence suggests that weight loss programs that encourage moderate caloric 
restriction and increased physical activity may improve neural responses to food cues. 
Furthermore, decreased neural reward responsiveness to high-calorie food cues and increased 
responsiveness to low-calorie food cues may underlie improvements seen in self-reported and 
behavioral measures of appetite. Behavioral weight loss studies also suggest that weight loss 
induced through diet, physical activity, and lifestyle changes can improve brain structures and 
function associated with memory. However, this literature is limited by small sample sizes and the 
lack of randomized trials that have directly assessed these questions. The present study is 
significant because it will help to improve our understanding of neuronal correlates of weight loss 
interventions. A better understanding of brain mechanisms underlying weight loss can improve 
the efficacy of obesity prevention and treatment interventions. 
2 
Study Objectives 
The purpose of the present study is to conduct a randomized controlled trial (RCT) to assess the 
effects of a commercially available weight loss program (WW; formerly Weight Watchers) on 
neural response to food cues and memory tasks, as well as on structural brain morphology. 
Participants with obesity will be randomized to either 16 weeks of a group-based WW program 
(n=30) or a wait-list control (WLC; n=30). Both groups will have structural and blood oxygen level-
dependent (BOLD) functional magnetic resonance imaging (fMRI) scans at baseline and after the 
end of the intervention. Participants will complete the following fMRI tasks: 1) structural scans; 2) 
food cue task to measure reactivity to high and low-calorie food images;10 and 3) N-back task to 
measure working memory (i.e., the ability to temporarily hold information available for 
processing).54 In addition, participants will complete self-report and behavioral measures of eating 
behaviors, appetite, physical activity, mood, quality of life, attention and memory at baseline, and 
weeks 8 and 16 (and at the end of the intervention). 
2.1 
Primary Objectives 
Aim 1: To compare differences between the WW and WLC groups at the end of the intervention 
in changes in BOLD fMRI response to food cues. 
Hypothesis 1: We hypothesize that compared to the WLC, the WW group will have significantly 
greater declines in BOLD response to high-calorie foods in the reward regions of the brain (insula, 
orbitofrontal cortex, anterior cingulate cortex, nucleus accumbens) and significantly greater 
increases in BOLD response to low-calorie foods in these reward regions.   
 
Aim 2a: To compare differences between the WW and WLC groups at the end of the intervention 
in changes in self-reported and behavioral measures of appetite, and Aim 2b: to test whether 
changes in self-reported and behavioral measures of appetite are associated with changes in 
neural responsivity to high and low-calorie foods in each study arm. 
Hypothesis 2a: We hypothesize that at the end of the intervention the WW group, compared to 
the WLC group, will have significantly greater declines in self-reported reward-based eating, food 
cravings, hunger, and preference for high-calorie foods, and significantly greater increases in 
fullness after meals and preference for low-calorie food. Hypothesis 2b: We hypothesize that in 
the WW group, greater declines in BOLD responses to high-calorie foods will be associated with 
decreased (self-reported) wanting, liking, preference and craving of these foods, and that greater 
increases in BOLD response to low-calorie foods will be associated with increased wanting, liking, 
preference, and craving of low-calorie foods. 
 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
8
Aim 3: To evaluate whether WW, compared to WLC, increases hippocampal volume from 
baseline to the end of the intervention.  
Hypothesis 3: We hypothesize that compared to the WLC, WW will be associated with a 
significantly greater increase in the size of the hippocampus.  
 
Aim 4: To compare differences between the WW and WLC groups at the end of the intervention 
in changes in BOLD fMRI response to the N-back task.54  
Hypothesis 4: We hypothesize that during the working memory task, the WW group, relative to 
the WLC group, will have significantly greater increases in BOLD activation in the hippocampus, 
dorsolateral and midventrolateral prefrontal cortex, posterior parietal cortex, and premotor cortex. 
2.2 
Secondary Objectives 
Aim 5a: To compare differences between the WW and WLC groups at the end of the intervention 
in changes in N-back behavioral performance, and Aim 5b: to assess the associations between 
pre- to post-treatment behavioral changes in memory, and pre- to post-treatment neural changes 
on the N-back task within each study arm.  
Hypothesis 5a: We hypothesize that at the end of the intervention, the WW group, relative to the 
WLC group will have significantly shorter reaction times and improved accuracy on the N-back 
task (indicating significantly greater improvements in working memory). Hypothesis 5b: We 
hypothesize that in the WW group, greater improvements in BOLD response in the hippocampus, 
dorsolateral and midventrolateral prefrontal cortex, posterior parietal cortex, and premotor cortex 
during the N-back task will be associated with greater improvements in N-back reaction time and 
accuracy. 
3 
Study Endpoints  
3.1.1 Primary Study Endpoints 
The primary endpoints are baseline to end of intervention changes in BOLD fMRI response to 
food images and to the N-back task as well as baseline to end of intervention changes in 
hippocampal volume and appetite (i.e., reward-based eating, food cravings, hunger, preference 
for high- and low-calorie food, and fullness). 
3.1.2 Secondary Study Endpoints 
Secondary endpoints include baseline to end of intervention changes in N-back task behavioral 
performance; association between changes in changes in memory and baseline to week 16 
changes in N-back task performance; and baseline to end of intervention changes in weight, blood 
pressure, waist circumference, eating behavior, perceived nutrition environment, quality of life, 
self-regulation, physical activity, stress, inhibitory control, and resilience.  
4 
Study Design 
4.1 
General Design 
The proposed investigation is an open-label, RCT to assess changes in neural responses to food 
images and memory tasks in 60 participants with obesity who are randomized to a 16-week 
behavioral weight loss program (WW; n=30) versus a WLC group (n=30). Participants will be 
assessed at baseline and 16 weeks and at the end of the intervention, with the baseline and end 
of intervention assessments including structural and functional neuroimaging with BOLD fMRI. An 
additional assessment will occur at week 8 and include self-report measures only. Neither 
subjects nor investigators will be masked to treatment assignment.  

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
9
COVID-19 Changes. Due to the mandatory restrictions in research related to COVID-19, we 
have transitioned our in-person groups to group-based, remotely delivered sessions via Blue 
Jeans. We are also not able to conduct fMRI scans on participants and have extended weekly 
treatment for those people who are currently in the intervention arm (currently our first cohort of 
10 participants). Extending treatment will help participants in the intervention arm continue to lose 
weight, which is an important mechanism we believe will be related to the fMRI results. The 
treatment will continue as it has, with remotely-delivered, group-based, behavioral weight loss 
sessions. Those on the wait-list have also had an extended time on the wait-list until we are able 
to conduct in-person, group treatment in accordance with University Guidance. We will administer 
the questionnaires at week 16 as in the original protocol. However, we will re-administer these 
questionnaires at the end of the intervention, once we are able to conduct fMRI scans on 
participants. 
5 
Study Population and Duration of Participation  
5.1 Total Number of Subjects and Sites  
This is a single-site study. We will randomly assign 60 females with obesity to either WW or a 
WLC. 
5.2 
Inclusion Criteria 
• 
Ages 18-60 years 
• 
Female 
• 
BMI>30 kg/m2 
• 
Eligible female patients will be: 
• 
non-pregnant 
• 
non-lactating 
• 
surgically sterile or postmenopausal, or they will agree to continue to use an 
accepted method of birth control during the study  
Acceptable methods of birth control are: hormonal contraceptives; double barrier 
method (condom with spermicide or diaphragm with spermicide); intrauterine 
device; surgical sterility; abstinence; and/or postmenopausal status (defined as at 
least 2 years without menses).  
• 
Participants must: 
• 
understand and be willing to comply with all study-related procedures and agree 
to participate in the study by giving written informed consent 
5.3 
Exclusion Criteria 
• 
Weight>158.8 kg (350 lbs, due to scanner weight restrictions) 
• 
Serious medical risk such as type 1 or 2 diabetes, cancer, or recent cardiac event (e.g., 
heart attack, angioplasty) 
• 
Untreated thyroid disease or any changes (type or dose) in thyroid medication in the last 
6 months 
• 
Current psychiatric disorder that significantly interferes with daily living  
• 
Active suicidal ideation  
• 
Current substance use disorder (current or in remission < 1 year) 
• 
Presence or history of orthopedic circumstances, metallic inserts, pacemaker, 
claustrophobia, or other conditions that may interfere with magnetic resonance imaging  
• 
Participation in a structured weight loss program in the prior 6 months  
• 
Active WW member within the past 12 months 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
10 
• 
Use of medications known to induce significant weight loss/gain, including chronic use of 
oral steroids in the past 3 months 
• 
Psychiatric hospitalization within the past 6 months 
• 
Loss of >10 lbs of body weight within the past 3 months 
• 
History or plans for bariatric surgery 
• 
Visual, auditory, or other impairment affecting task performance  
• 
Epilepsy 
• 
Neurological trauma (e.g., concussion) 
• 
Inability to attend treatment and/or assessment visits 
• 
Participant from same household 
• 
Adherence to specialized diet regimes, such as vegetarian, macrobiotic 
• 
Lack of capacity to provide informed consent 
• 
Inability to walk 5 blocks comfortably or engage in some other form of aerobic activity 
(e.g., swimming) 
• 
Any serious or unstable medical or psychological condition that, in the opinion of the 
investigator, would compromise the patient’s safety or successful participation in the 
study 
5.4 
Duration of Study Participation 
The maximum amount of time subjects in the WW group will participate in the study is 45 weeks 
(screening which may be up to 4 weeks before baseline fMRI; baseline fMRI which may occur up 
to 4 weeks before start of intervention; 16 to 36-week intervention; final fMRI up to 1-week post 
intervention period). The maximum amount of time the WLC subjects will participate in the study 
is 61 weeks (screening which may be up to 4 weeks before baseline fMRI; baseline fMRI which 
may occur up to 4 weeks before start of wait-list; 16 to 36 weeks on wait-list; final fMRI up to 1 
week post wait-list period; 16 week intervention). 
5.5 
Vulnerable Populations:  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study.  
6 
Study Procedures 
6.1 
Subject Recruitment  
Subjects will be recruited using print, radio and online advertisements. We will recruit participants 
through local media advertisements and news shows/outlets, as well as Internet-based 
advertising outlets and flyers and brochures around our community.  We also will advertise using 
clinician referrals from clinics affiliated with the University of Pennsylvania Health System. We will 
be recruiting from the university-based website, iConnect, which allows access to their volunteer 
registry data of potential participants. We will use study condition terms such as obesity. Recruitment 
may also use Penn media services (e.g., communications) and social media (e.g., Facebook, Twitter; 
please see attached for information about Facebook recruitment). Social media recruitment will be 
limited to one-way advertisements. 
 
6.2 
Screening Procedures 
6.2.1 Phone screening 
Interested subjects will call in and be consented verbally, over the phone, by study staff to 
participate in the initial telephone screening. Study staff from the Center for Weight and Eating 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
11 
Disorders will describe the study, explain that the research is completely voluntary, and conduct 
a brief screening of candidates who express an interest in proceeding (e.g., BMI and MRI 
eligibility). We request a waiver of written documentation of consent for the telephone and 
questionnaire screen.  
 
Those who appear to meet eligibility criteria and remain interested in the trial will be scheduled 
for an in-person interview. The Weight and Lifestyle Inventory (WALI),25 an inventory that 
assesses general eating and lifestyle behaviors, and the Beck Depression Inventory-II (BDI-II),26 
will be forwarded to eligible subjects via REDCap following the phone screen and completed by 
them prior to their screening/informed consent visit. (All patients and subjects at our Center 
complete the WALI and BDI to facilitate their initial interview.) 
6.2.2 Screening visit 
Following the initial telephone screening assessment, eligible participants will attend a 2-hour 
intake visit at the Center for Weight and Eating Disorders at the University of Pennsylvania. The 
in-person interview will be conducted by study staff, who will obtain informed consent and 
evaluate subjects’ behavioral eligibility (i.e., willingness and appropriateness to participate). This 
will include our assessment of the applicant’s mood (as measured by interview and the BDI26) 
and suicidality (including history of suicidal ideation and behavior, as assessed at screening by 
interview and the Columbia-Suicide Severity Rating Scale55). Subjects who remain interested and 
pass this portion of the assessment will be asked about their medical history to determine medical 
eligibility. The following procedures will be completed at the screening visit: 
• 
Informed consent 
• 
Behavioral evaluations 
• 
Review of Weight and Lifestyle Inventory25 
• 
Height and weight to assess BMI 
• 
MRI-eligibility checklist 
• 
Routine medical history 
• 
Review of medications 
• 
Psychiatric exam using the Columbia Suicide Severity Rating Scale55 and Beck 
Depression Inventory-II26 
• 
Waist circumference 
• 
Blood pressure and heart rate 
• 
Urine pregnancy test (if unsure about pregnancy status) 
• 
Practice session of the N-back task to minimize the learning effects of the experiment 
• 
Questionnaires (emailed via REDCap or printed)  
o Edinburgh Handedness Inventory (Short Form)56 
o Reward-Based Eating Drive Scale (RED-13)57 
o Eating Inventory (EI) 58 
o Questionnaire on Weight and Eating Pattern-5 (QEWP-5)59 
o Food Cravings Questionnaire- Trait (FCQ-T) 60 
o Paffenbarger Physical Activity Questionnaire (PPAQ)61 
o Yale Food Addiction Scale 2.0 (YFAS)62 
o Power of Food Scale (PFS)63 
o Palatable Eating Motives-Revised (PEMS-R)64 
o Eating Disorder Examination Questionnaire (EDE-Q)65 
o Perceived Stress Scale (PSS)66 
o Perceived Nutrition Environment (NEMS-P)67 
o Brief Resilience Scale (BRS)68 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
12 
o Short Form-36 (SF-36)69 
o Impact of Weight on Quality of Life-Lite (IWQOL-Lite)70 
o Index of Self-Regulation (ISR)71 
o Behavioral Avoidance/Inhibition Scales (BAS/BIS)72 
 
After participants complete the screening procedures, provide their informed consent to 
participate, and are enrolled into the study, they will complete two study assessment visits that 
include fMRIs (one at baseline and one after 16-weeks) as well as a mid-point assessment at 
week 8 (that does not include an fMRI).  
6.3 
FMRI Assessments.  
Prior to randomization, participants will complete a baseline fMRI assessment that will occur up 
to 4 weeks before the intervention begins. They will complete another fMRI assessment between 
2 weeks before the end of the intervention (or up to 1 week after the study intervention is 
completed). The timeframe for the follow-up assessment was selected so participants in the WW 
group will be actively engaged in weight loss efforts at the time of the second scanning. 
Participants will be compensated $100 for each fMRI assessment visit.  
 
Planning for the Assessment Visit. Study assessment visits will be scheduled for the morning 
and last approximately 3 hours (60 minutes in the fMRI scanner and 120 minutes to complete 
questionnaires, behavioral tasks, and physical measurements). The visits will be held at the 
Hospital of the University of Pennsylvania. Participants will be asked to fast (including no caffeine 
or alcohol) for at least 8 hours prior to the appointment to increase the stimulus salience41 and 
create a more homogeneous hunger state across participants. Participants will be asked to 
remove all jewelry and metal objects at the visit. Participants who require vision correction will be 
instructed to wear contact lenses or will be provided with MRsafe glasses in their prescription 
strength.  
 
Imaging Procedures 
Pre-scan preparation. Visits on imaging days will begin in the morning at the Hospital of the 
University of Pennsylvania. Upon arriving, participants will be greeted by research staff who will 
review the MRI-eligibility checklist to ensure no changes have occurred that would render MRI 
unsafe or uncomfortable. The MRI technician will review this checklist. All participants will be 
asked about pregnancy status. For those who are unsure, a urine pregnancy will be completed 
prior to the scan. Those who attest to being pregnant or test positive will be withdrawn. 
Participants will be asked to wear clothing without metal or to change into a hospital gown and be 
weighed, without shoes, on a calibrated electronic scale. They will then complete a self-report 
measure of current mood (i.e., the Profile of Mood States73), Food Cravings Questionnaire- State 
(FCQ-S), and Eating Behaviors Questionnaire, and visual analog scales for stress, hunger, food 
cravings, and fatigue level. They also will be required to demonstrate understanding of the task 
and use of the response device prior to entering the scanner.  
 
Imaging equipment. We will use a clinically approved 3.0 Tesla Siemens Prisma scanner 
equipped with 64-channel head coil. BOLD fMRI sequences include automatic higher order 
shimming and both prospective and retrospective motion correction. Gradient performance allows 
4 mm isotropic voxels at TR=2 sec and 3 mm isotropic voxels at TR=3 sec (3T). The system uses 
a transmit/receive head coil.  
 
The research scanner is equipped with stimulus delivery and monitoring systems for fMRI 
research. This includes Sanyo SXGA 4200 lumens projectors with Sanyo Long Throw zoom lens 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
13 
for rear-view/rear projection onto Mylar screens. Video signals are carried into the magnet room 
using a Lightwave FiberLynx optical-fiber VGA connection. Both the projector and the FiberLynx 
units are housed in custom RF shield boxes with filtered power receptacles. Images are viewed 
through mirrors mounted on the head coils. Responses will be monitored using a color-coded 
keypad made of non-ferromagnetic components (FORP Current Design Inc., Philadelphia, PA) 
installed at the 3T system. The MRI scan has been designed to last 55 minutes. To ensure 
completion of all scans, each procedure will be timed and every effort will be made to keep as 
close to the designated schedule as possible. In respect of time and data quality, if necessary, 
scans will be skipped or re-run at the discretion of the research team.   
 
Protocol for structural MRI (5 minutes). A magnetization-prepared, rapid acquisition gradient 
echo (MPRAGE) image will be acquired for anatomic overlays of functional data and spatial 
normalization 
using 
the 
following 
parameters: 
TI/TR/TE=900/2200/4.67ms, 
flip=8°, 
matrix=256x192, FOV=240x180mm, slices=160, slice thickness=1mm.  
 
Protocol for BOLD fMRI (~10 minutes). Resting and Task fMRI data will be acquired using a 
whole-brain, single-shot, multi-slice, gradient-echo EPI sequence.  
 
FMRI Tasks. We will use two tasks to assess the impact of WW on neural activity to food-cues 
and to memory. Our tasks have been selected to target relevant cognitive and neural models of 
weight loss. The timing of the stimulus presentation will be synchronized with trigger pulses from 
the magnet in order to ensure precise temporal integration of stimulus presentation and fMRI data 
acquisition. These tasks will be presented in a fixed order with the N-back occurring first and food 
cue task occurring second.  
 
BOLD fMRI Task (N-back; ~15 minutes). The N-back task is one of the most extensively used 
measures of working memory and requires the storage and updating of information. During the 
task, participants will be presented with a sequence of images one-by-one.54 For each stimulus, they 
will need to indicate if the current stimulus is the same as the one presented in a previous set. We 
will use four different difficulty levels for this study, one in which participants are asked to recall a 
stimulus that occurred 0, 1, 2, and 3 back (i.e.,0-, 1-, 2- and 3-back). For example, during the 2-back 
task, the response would be “yes” if the stimulus currently presented matches the stimulus presented 
two earlier. A 0-back task will be used as a control condition, in which participants are asked to simply 
respond yes to the stimuli they are being shown. Increasing memory load is determined by the 
increase in the number of items the participant has to keep in mind. A slower reaction time and less 
accuracy are indicative of worse working memory. The stimuli and blocks are presented in a 
pseudorandom order. 
 
BOLD fMRI task (Food images; 15 minutes). The food images task will be composed of five 
blocks of high-calorie foods (e.g., bacon, ice cream, cake, burger, French fries, pizza), five blocks 
of low-calorie foods (e.g., apples, broccoli, banana, salmon, lentils), and five blocks of neutral 
images (e.g., office supplies). Participants will passively view the images and be asked to imagine 
how much they want the object right now. Pictures have been matched for complexity, brightness, 
and color composition. Stimuli are digital photographs of food items depicted in the ready-to-eat 
state (e.g., all packaging is removed) on identical backgrounds that are validated and are 
available in publicly available databases.74,75 Each block will be 30 seconds in duration and 
presented in pseudorandom order. Each block will contain five photographs of food (5 seconds) 
separated by 1-second inter-stimulus interval (fixation point). Food blocks will be followed by a 
30-second rest period. Following the fMRI, participants will be asked to rate the liking and 
desirability of the food images (e.g., “How much do you like this food?”), using visual analog 
scales. 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
14 
 
Task Assessments and Questionnaires. After the fMRI is completed, participants will complete 
questionnaires to assess response to the fMRI tasks and manipulations and treatment outcomes. 
To assess the response to the tasks using the food images, participants will be asked about their 
liking and wanting and palatability of the presented foods on visual analog scales. Participants 
will complete physical measurements and additional questions, if they have not been completed 
before their screening visit. 
6.4 
Cognitive Assessments 
After participants complete the questionnaires, they will be asked to complete two cognitive 
assessments. We will also use the Leeds Food Preference Questionnaire, a computerized 
procedure to assess liking, wanting, and relative preferences for high versus low-fat foods and 
sweet versus savory foods.76 The Leeds Food Preference Questionnaire assesses different 
components of food preference and food reward. Participants are presented with an array of 
pictures of individual food items common in the diet that are high or low in fat but similar in 
familiarity, protein content, sweet or non-sweet taste and palatability. The task takes 
approximately 10 minutes to complete. Cognitive function will be assessed with the NIH Toolbox 
Cognitive Function Battery which includes 7 tests covering different cognitive abilities including 
attention and executive functioning, episodic memory, working memory, language, and 
processing speed.77 The cognitive assessments will be administered in a private room at both 
fMRI scans as well as a week 8 visit. 
Week 8 Assessment.  
We will also conduct a mid-point assessment. During this visit we will obtain participants’ weight, 
cognitive assessments, and questionnaires as listed on Table 1 and Table 2. Given the 
restrictions with COVID, we will only use self-report weight and self-report questionnaires at the 
week 8 visit. 
6.5 
Wait-List Post-Treatment Visit (Wait-list Group Only)  
After individuals in the WLC group complete their second fMRI assessment, they will be offered 
the WW treatment. The WLC group will be asked to complete questionnaires as well as their 
height, weight, and behavioral measures at their end of intervention visit. 
6.6 
Randomization Visit 
 
Participants who meet all eligibility criteria assessed at the screening visit will be scheduled for a 
baseline fMRI assessment. The visit will occur within approximately 4 weeks of beginning 
treatment. They will be instructed to complete the self-reported outcomes either online (using a 
link e-mailed to them) or using paper-and-pencil questionnaires (for those who prefer this method) 
approximately 10 days before their fMRI scan. Their questionnaires will be reviewed for 
completeness at the fMRI visit, with any omissions or errors corrected. The randomization visit 
will include a weight, waist circumference, blood pressure, and heart rate, and completion of 
additional baseline assessments (as described in Table 2). Participants will then be randomly 
assigned to the two groups in equal numbers (i.e., 1:1 ratio). This will be accomplished using a 
computer-generated algorithm operated by faculty at the Center for Weight and Eating Disorders 
at the University of Pennsylvania (e.g., Dr. Jena Tronieri). Assignment will be made from randomly 
varied block sizes (2 or 4). This is an open-labelled randomized trial. Due to COVID-19, we have 
combined the randomization visit with the baseline fMRI visit. After they complete their fMRI visit, 
they will be randomized to a treatment group. 
 

Neurocognitive Benefits of WW 
 
 
Version 4.0 
1
Table 1. Schedule of Study Assessments and Treatment Visits 
 
  
Weeks 
  
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Screening 
X X X X X X X X                                                                       
FMRI 
Assessme
nt 
        X X X X X                           X X X X                                   
Cognitive, 
Behavioral
, and Self-
report 
Assessme
nts 
                                X                                                     
Randomiz
ation Visit 
            X X X                                                                     
WW 
Group 
Treatment 
                  X X X X X X X X X X X X X X X X                                     
WLC 
Group 
Treatment 
                                                    X X X X X X X X X X X X X X X X   
*WLC group only. For participants affected by COVID-19 and subsequent mandates necessary to help mitigate the transmission of the 
virus (e.g., stay-at-home orders), their fMRI assessments will occur at the end of the intervention. They will have questionnaire 
assessments administered at week 16 and then again at the end of the intervention when they can have their fMRI scan. The 
randomization visit will now be combined with the fMRI visit. 
 

Neurocognitive Benefits of WW 
 
 
Version 4.0 
1
Table 2. Schedule of Procedures 
Study Phase 
Screening 
Baseline 
FMRI 
Assessmenta,b 
Randomization 
Visitc 
Intervention 
Cognitive, 
Behavioural, 
and Self-
report 
Assessments 
Follow-up 
FMRI 
Assessment 
b 
Informed consent 
X 
 
 
 
 
 
Review inclusion/exclusion 
criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Blood pressure, heart rate 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
Waist circumference 
X 
X 
X 
 
X 
X 
Prior/concomitant medications 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Randomization  
 
 
X 
 
 
 
FMRI Tasks 
 
 
 
 
 
 
Structural scans 
 
X 
 
 
 
X 
Food cue task 
 
X 
 
 
 
X 
N-back task 
 
X 
 
 
 
X 
Behavioral Measures 
 
 
 
 
 
 
Leeds Food Preference 
Questionnaire (LFPQ) 
 
X 
 
 
X 
X 
National Institutes of Health 
Toolbox- Cognitive Function 
Battery 
 
X 
 
 
X 
X 
Questionnaires 
 
 
 
 
 
 
Weight and Lifestyle Inventory 
(WALI) 
X 
 
 
 
 
 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
2
Edinburgh Handedness Inventory 
(Short Form) 
X 
 
 
 
 
 
Beck Depression Inventory-II 
(BDI-II) 
X 
X 
 
 
X 
X 
Profile of Mood States (POMS)# 
 
X 
 
 
X 
X 
Food Cravings Questionnaire- 
State (FCQ-S)# 
 
X 
 
 
X 
X 
Eating Behaviors Questionnaire 
(Ratings of appetite, satiety, food 
preoccupation) # 
 
X 
 
 
X 
X 
Reward-Based Eating Drive 
Scale (RED-13) 
 
X 
 
 
X 
X 
Eating Inventory (EI) 
 
X 
 
 
X 
X 
Questionnaire on Weight and 
Eating Pattern-5 (QEWP-5) 
 
X 
 
 
X 
X 
Food Cravings Questionnaire- 
Trait (FCQ-T) 
 
X 
 
 
X 
X 
Paffenbarger Physical Activity 
Questionnaire (PPAQ) 
 
X 
 
 
X 
X 
Yale Food Addiction Scale 2.0 
(YFAS 2.0) 
 
X 
 
 
X 
X 
Power of Food Scale (PFS) 
 
X 
 
 
X 
X 
Palatable Eating Motives- 
Revised (PEMS-R) 
 
X 
 
 
X 
X 
Modified Eating Patterns 
Questionnaire (MEPQ) 
 
 
X 
 
X 
X 
Eating Disorder Examination 
Questionnaire (EDE-Q) 
 
 
X 
 
X 
X 
Perceived Stress Scale (PSS) 
 
 
X 
 
X 
X 
Perceived Nutrition Environment 
(NEMS-P) 
 
 
X 
 
X 
X 
Brief Resilience Scale (BRS) 
 
 
X 
 
X 
X 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
3
Short Form-36 (SF-36) 
 
 
X 
 
X 
X 
Impact of Weight on Quality of 
Life-Lite (IWQOL-Lite) 
 
 
X 
 
X 
X 
Index of Self-Regulation (ISR) 
 
 
X 
 
X 
X 
Behavioral 
Avoidance/Inhibition 
Scales (BAS/BIS) 
 
 
X 
 
X 
X 
Adherence Measures 
 
 
 
 
 
 
Sessions attended* 
 
 
 
X 
 
X 
Self-monitoring food records* 
 
 
 
X 
 
X 
Additional treatment sought for 
weight or eating 
 
 
 
X 
X 
X 
*Weekly measure. aQuestionnaries will be sent after the screening visit and before the fMRI. bQuestionnaires will be distributed 10 days 
before scheduled fMRI and participants will be asked to be complete them before the fMRI visit (except those marked with #, which will 
be completed at the day of the fMRI scan). cParticipants will be asked to complete these questionnaires at the randomization visit or 
via email if preferred. For participants affected by COVID-19 and subsequent mandates necessary to help mitigate the transmission of 
the virus (e.g., stay-at-home orders), their fMRI assessments will occur at the end of the intervention. They will have questionnaire 
assessments administered at week 16 and then again at the end of the intervention when they can have their fMRI scan. The 
randomization measures will be combined with the baseline fMRI visit. 
 

Neurocognitive Benefits of WW 
 
 
Version 4.0 
1
 
7 
Study Intervention 
 
WW Group Lifestyle Modification Program. The WW intervention will consist of weekly, group 
weight loss workshops (formerly meetings) for 16 or more weeks. Each workshop will be 
approximately 1 hour and include 8 to 12 participants. Participants will have access to both in-
person or web-based, group meetings as well as digital tools (e.g., self-monitoring of intake, 
activity, and weight). The meetings will be led by a trained coach and a guide. All group sessions 
will be conducted at the University of Pennsylvania’s Center for Weight and Eating Disorders, 
following the WW program. Due to the coronavirus pandemic, all non-essential visits at the 
University of Pennsylvania will be canceled starting March 16, 2020. As a result, each group 
workshop after Week 8 will be moved to a virtual video chat platform, BlueJeans. Participants 
have the option of calling in through video or audio. All participants will be sent standardized 
scales and will self-report their weight. Blood pressure will not be measured until the participants’ 
next in-person visit. The program uses a SmartPoints® System that encourages consumption of 
fruits, vegetables, lean proteins, and less sugar and unhealthy fats. Participants will have their 
weight, blood pressure, and heart rate measured at each session. Changes in medications and 
adverse events will be reported privately to research staff at clinic meetings. 
 
Wait-list control (WLC) group. Participants in the WLC group will be asked to stay weight stable 
and not to make changes in their eating and physical activity behaviors and not to seek treatment 
for weight or eating during the waiting period. They will be contacted between week 6-8 via phone 
by a research assistant to keep participants engaged, enhance retention and schedule their week 
8 assessment visit. We will use a structured script and ask participants about any additional 
treatments they may have sought during the study. All WLC participants will be offered the WW 
intervention (as described above) after they complete the second fMRI assessment at the end of 
treatment. 
7.1 
Unscheduled Visits 
Participants who miss a session will be contacted by their coach, guide, or study staff following 
the absence. An in-person or phone make up visit will be offered.  
7.2 
Subject Withdrawal  
 
Subjects may withdraw from the study at any time without impact to their care at the University of 
Pennsylvania healthcare system. They may also be discontinued from the study at the discretion 
of the Investigator for lack of adherence to intervention or study procedures or visit schedules, 
AEs, or due to subject pregnancy or intention of becoming pregnant.  The Investigator may also 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the clinical 
study.  
 
Lost to follow-up: In the case of subjects who do not return to the Center for study procedures 
and cannot be contacted, study personnel will make vigorous and repeated attempts (minimum 
of 3) to contact the subject. If all attempts to contact the subject fail, that subject will be considered 
to be lost to follow-up and discontinued from the study. 
 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
2
7.3 
Safety Evaluations 
Safety evaluations include adverse events (AEs) and assessments of blood pressure and heart 
rate. At weeks 8 and 16, we will check for possible complications of weight loss, and will also 
encourage participants to inform the study team sooner if applicable. At weeks 8 and 16, study 
subjects will be asked whether there has been any change in their health or medications. In the 
event of adverse mental health events, participants will be referred to the study’s psychologist or 
psychiatrist for further evaluation, if required. For all non-study-related medical events, 
participants will be referred to their own primary care provider.  
8 
Safety and Adverse Events 
8.1 
Definitions 
8.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events 
if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
8.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  All adverse events that do not meet any 
of the criteria for serious should be regarded as non-serious adverse events.  
8.2 
Recording of Adverse Events 
At each contact with subjects, study personnel will be responsive to reports of adverse events 
with specific questioning, and, as appropriate, by examination. The investigator will report all 
adverse events including serious adverse events (SAE) and suspected unexpected serious 
adverse reactions (SUSARs) (as defined below) to the Penn IRB. Information on all adverse 
events will be recorded immediately in the source document and reported immediately, and also 
in the appropriate adverse event module of the case report form (CRF). Information on study 
name, subject identification, event (i.e., diagnosis), and reporter identification (e.g., name) will be 
collected and recorded in the source document (as detailed below). All serious adverse events 
will be reported to the IRB within 24 hours.  

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
3
 
All events meeting the definition of an adverse event will be collected and reported from the first 
trial related activity after the subject has signed the informed consent and until the end of the post-
treatment follow-up period. Serious adverse events that are still ongoing at the end of the study 
period will be followed up until either resolved or stable.  Any serious adverse event that occurs 
after the study period and is considered to be possibly related to the study intervention or study 
participation will be recorded and reported immediately. 
8.3 
Relationship of AE to Study  
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
• Possible: A causal relationship is conceivable and cannot be dismissed 
• Unlikely: The event etiology is most likely not related to the study procedures 
The PI will evaluate all unexpected events and adverse reactions. 
8.4 
Outcome Categories and Definitions: 
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned 
to the level observed at the first trial related activity after the subject signed the informed 
consent 
• Recovering: The condition is improving and the subject is expected to recover from the event. 
This term should only be used when the subject has completed the trial 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
significant disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with 
sequelae should be rated as an SAE 
• Not recovered 
• Fatal 
• Unknown 
9 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
All events meeting the definition of an adverse event will be collected and reported from the first 
trial related activity after the subject has signed the informed consent and until the end of the post-
treatment follow-up period as stated in the protocol.  
At a minimum the following information will be reported: 
• 
Study identifier 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as 
serious 
• 
Investigator assessment of the association 
between the event and study intervention 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse 
device effects and subject complaints  will be recorded and reported with respect to institutional 
and federal policies as described in the Penn Manual. 
 
9.1.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes 
the investigator’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) should be submitted to 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
4
the IRB. The investigator is responsible for ensuring that all SAE are followed until either resolved 
or stable.  
9.1.2 Investigator reporting: notifying the study sponsor 
Study-related unanticipated problem posing risk to subjects or others, and any type of serious 
adverse event, will be reported to the study sponsor within 24 hours of the event.  To report such 
events, a Serious Adverse Event (SAE) form will be completed by the investigator and sent to the 
study sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file at the 
study site. Within the following 48 hours, the investigator will provide further information on the 
serious adverse event or the unanticipated problem in the form of a written narrative.  This should 
include a copy of the completed Serious Adverse Event form, and any other diagnostic information 
that will assist the understanding of the event.  Significant new information on ongoing serious 
adverse events should be provided promptly to the study sponsor. 
10 Study Administration, Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
All electronic PHI will be maintained by using an institutionally secured and managed network 
drive, institutionally secured and managed devices, and institutionally approved third-party 
computing environments.  Should PHI need to be transferred, it will be done so through the use 
of a Penn-approved encrypted portable drive or a Penn-approved secure encrypted file transfer 
solution. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects who have revoked authorization to collect or use PHI, attempts will 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
 
Where possible, data will be entered directly into our password protected database, REDCap. 
All data pertaining to the study will be saved on the Center for Weight and Eating Disorders’ 
password-protected server.  Paper copies of informed consent, questionnaires, interviews, lab 
results, and any correspondence will be kept in the case record in locked offices.   
11 Privacy 
Steps will be taken to protect subject privacy. Informed consent and study procedures will be 
conducted in a private room, and the collection of sensitive information will be limited to the 
minimum necessary to achieve the aims of the project. 
12 Study Monitoring, Auditing, and Inspecting 
 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
5
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
13 Ethical Considerations 
 
The principal investigator (PI) will initiate and enroll subjects only after receiving IRB approval of 
the protocol and the informed consent documents. All recruiting materials used in the study will 
have IRB approval. Progress reports regarding the study will be submitted to the IRB in 
accordance with institutional and regulatory guidelines.  
 
The study will be performed in compliance with the FDA Code of Federal Regulations for Good 
Clinical Practice (GCP). These procedures ensure the protection of the rights and the integrity of 
the subjects, adequate and correct conduct of all study procedures, adequate data collection, 
adequate documentation, and adequate data verification.  
 
Before being enrolled, subjects will be provided informed consent. The nature, scope, and 
possible consequences of the study will have been explained in a form understandable to them. 
A copy of the consent document will be given to the subject. The PI will retain the original signed 
consent document.   
 
Subject confidentiality will be maintained throughout the study according to applicable guidelines, 
regulations and IRB requirements. All study clinical data and reports of results will de-identify 
individual subjects. Subjects will be identified by initials, date of birth, gender and subject number 
only for use in data collection. Published data will provide subject numbers only if needed for 
clarity of presentation (e.g., in individual event listings).  
 
The study will be conducted in accordance with the Declaration of Helsinki. The study will be 
conducted in accordance with the ICH GCP guidelines. The investigators will comply with all 
applicable regulatory and legal requirements, ICH GCP guidelines, and the Declaration of Helsinki 
in obtaining and documenting the informed consent. 
13.1 Risks 
 
The risks to participants in this trial have been carefully considered and minimized to the extent 
possible. The known risk of the WW program and completing the study assessments are minimal. 
Every effort has been made to provide a study in which the safety of research participants is 
protected. 
 
Risks of Assessments, Behavioral Weight Loss Treatment, and Wait-list 
Some of the questions in the interview that assess history of psychological conditions may be of 
a personal nature. All such questions will be asked by trained study staff. Appropriate referrals 
will be given as necessary. 
 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
6
Participants in the WLC group will be contacted at week 8 via phone by a research assistant to 
keep participants engaged and enhance study retention. All wait-list participants will be provided 
with the 16-week intervention after they complete the end-of-study testing at week 16. Though 
we considered other designs, a wait-list control comparison was selected as it was deemed 
ethical, while also permitting a non-intervention comparison and maximizing power to detect 
differences between groups.  
 
Weight loss 
Risk of Gallstones: Rapid weight loss may increase the risk of gallstones.  Symptoms of gallstones 
include abdominal pain, nausea, vomiting, fever, and chills.  The risk of gallbladder disease will 
be reduced by limiting weight loss to no more than 3 pounds per week for 4 consecutive weeks.  
 
Risks of MRI 
Flying objects: The known risks associated with this study are minimal. Implanted medical devices 
and metallic foreign fragments inside a participant’s body may pose a risk if the participant were 
to enter the MRI magnet room. The greatest risk is a magnetic object flying through the air toward 
the magnet and hitting someone. To reduce this risk, we require that all people involved with the 
study remove all metal from their clothing and all metal objects from their pockets. No metal 
objects are allowed to be brought into the magnet room at any time. In addition, once participants 
are in the magnet, the door to the room will be closed so that no one inadvertently walks into the 
magnet room. 
Magnetic fields health risks: There is no known health risk associated with exposure to magnetic 
fields during an MRI. 
Discomfort. Some people become uncomfortable or claustrophobic (fearing the enclosed space) 
while inside the scanner. Fatigue, anxiety and discomfort are potential adverse effects associated 
with the fMRI study. There are minimal risks from the loud noise associated with the MRI scanner 
and from the discomfort of lying on a hard surface. We will attempt to minimize these risks by 
familiarizing participants with the personnel and setting, and by closely monitoring them during 
the study. In our experience, participants who are well informed of the purpose of the study and 
who are accompanied throughout the procedures by a responsible member of the research team 
tolerate the testing well and without complications. Tests are administered by trained and 
supervised personnel and participants are debriefed after each session. Exposure to radiation 
with magnetic resonance measurements is far less than that resulting from a single X-ray. 
Thousands of patients have been safely studied at the Hospital of the University of Pennsylvania 
using magnetic resonance techniques. However, some individuals become uncomfortable or 
claustrophobic while inside the magnet. Participants who are uncertain whether they can tolerate 
the scanning environment can complete a “mock” scan on similar equipment prior to the research 
scans.  If participants become uncomfortable during completion of study procedures, they may 
withdraw immediately from the study. 
 
Incidental findings: This MRI is not a clinical scan. It is possible that during the course of the 
research study, the research staff may notice an unexpected finding(s). In the event of abnormal 
findings are identified by study MRI personnel (e.g., technologists, physicists, image processing 
scientists), the PI (Dr. Chao), will inform Dr. John Detre. Dr. Detre has agreed to be included in 
this study to address safety issues and incidental findings for this study. The participant will be 
contacted and Center Staff will arrange for the images to be sent to participants and/or their 
physician. These possible finding(s) may or may not be significant and may lead to anxiety about 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
7
a person’s condition and to further work-up by a physician.  
 
Pregnancy: Although there are no known risks related to MRI on pregnant women or a fetus, there 
is a possibility of yet undiscovered pregnancy related risks. Since there is no possible benefit from 
participating in this protocol for a pregnant woman, we will exclude pregnant women. At fMRI 
scans, participants will be asked to attest to pregnancy status. Participants who are unsure or 
who believe that they may be pregnant will be given a urine pregnancy test. 
 
Computer tasks. There are no known risks associated with the computer tasks the participant will 
be asked to perform during the study. Participants could become tired when performing them. 
 
During MRI scans, participants have occasionally reported tingling or twitching sensations in their 
arms or legs. Further, because of the strong magnetic field, participants with pacemakers, certain 
metallic implants, or metal in the eye cannot participate in this study. These exclusions will be 
reviewed carefully with the research technician prior to scanning. Although there are no known 
risks of MRI on pregnant women or the fetus, there is a possibility of yet undiscovered pregnancy 
related risks.  
 
Loss of Confidentiality Risk 
Because information about participant’s identity will be collected and stored for research 
purposes, there is a chance that the information could be viewed by others not associated with 
the research team and therefore, there is a potential for loss of confidentiality. The study team will 
work to uphold the privacy of the participants in several ways. Communications made among 
study staff regarding participants will use ID numbers only and never include names or other 
personal information. All participant data and recordings will be kept in locked files. In all data 
sets, we will use ID numbers only. A separate dataset linking names with ID numbers will be 
accessible only by the primary study investigators.  
 
If unforeseen risks are seen, they will be reported to the Office of Research Integrity and 
Compliance.  
13.2 Benefits 
All participants who enroll in this study will receive the WW program including access to the in-
person workshops and digital tools. Based on results of previous studies, we expect participants 
to lose an average of approximately 5% of their initial weight during the 16-week treatment 
program and have improvements in their eating behaviors and physical activity. Weight losses of 
this size may be associated with improvements in medical conditions made worse by excess 
weight including pre-diabetes (high blood sugar), high blood pressure, and high triglyceride levels. 
Participants will undergo assessment and monitoring of several health factors including weight 
and blood pressure. These results will be made available to participants.  Despite all of these 
potential benefits, there is no guarantee that participants will lose weight or get any medical 
benefits from this study.  This study may also benefit society at large by providing information 
about the effectiveness of a behavioral weight loss program on brain changes related to food cue 
responsiveness and memory.  
13.3 Risk Benefit Assessment 
The benefits of this research to the subjects studied, and to society at large, far surpass the risks. 
We believe that this study poses minimal risk to participants, while providing potential benefit to 
women with obesity. The treatments and procedures used in this study have been shown to be 
relatively safe. Numerous clinical trials have demonstrated the safety of MRI scans and efficacy 
of WW for obesity. Research staff will monitor subjects closely during their participation. We 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
8
anticipate that after the WW treatment participants will have improvements in their eating, physical 
activity, and weight. Results of this study hold promise of significantly improving the management 
of obesity and its associated complications. 
13.4 Informed Consent Process / HIPAA Authorization  
 
Following the screening telephone call, trained clinical assessors will meet in person with all 
potential participants to describe the study, its requirements, and its likely risks and benefits. 
Participants will be provided a written copy of the Consent Form/HIPAA Authorization at this 
meeting and will be given an opportunity to read it and have all of their questions answered. 
Persons who wish to participate in the study will be asked to give their written consent at the time 
of consent discussion and will then continue with the screening visit. Participants will also be 
permitted to discuss the consent form and procedures and return the signed form and continue 
with the screening at a later date (within 2 weeks), if they prefer. Participants will be told that they 
can contact the Principal Investigator at any time if they have questions about the study. The 
study team member who reviews the consent document will emphasize that participation in the 
study is voluntary and that medical care will not be influenced by the participants decision to 
participate or not. The consent process will take place in a private office or exam room to help 
protect subject privacy. Subject comprehension of the nature of the study will be assessed using 
interactive conservation methods (e.g., asking the potential subject to paraphrase different points 
of discussion, asking open-ended questions, encouraging questions). 
13.4.1 Waiver of Written Documentation of Consent 
 
We are requesting a waiver of the requirement to obtain a signed consent form for the phone 
screening. The only record linking the subject and the research would be the consent document 
and the principal risk would be potential harm resulting from a breach of confidentiality. Each 
subject will be asked whether the subject wants documentation linking the subject with the 
research, and the subject's wishes will govern.  
14 Study Finances 
14.1 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research.  
14.2 Subject Stipends or Payments 
 
Participants will be compensated $100 for each fMRI scan, $10 to help with travel costs to each 
of the 16 study intervention visits, and $25 for the week 8 study visit.  The total compensation if 
all study visits are completed is $385. No extra compensation will be provided for changes due 
to COVID-19. 
15 References 
 
1. 
Schwartz MW, Seeley RJ, Zeltser LM, et al. Obesity pathogenesis: an Endocrine Society 
scientific statement. Endocrine reviews 2017;38:267-96. 
2. 
Ravussin E, Ryan DH. Three New Perspectives on the Perfect Storm: What's Behind the 
Obesity Epidemic? Obesity 2018;26:9-10. 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
9
3. 
Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk 
with obesity, diabetes, and related disorders. Biol Psychiatry 2010;67:505-12. 
4. 
Bocarsly ME, Fasolino M, Kane GA, et al. Obesity diminishes synaptic markers, alters 
microglial morphology, and impairs cognitive function. Proceedings of the National Academy of 
Sciences 2015;112:15731-6. 
5. 
Alford S, Patel D, Perakakis N, Mantzoros C. Obesity as a risk factor for Alzheimer's 
disease: weighing the evidence. Obes Rev 2018;19:269-80. 
6. 
Sindi S, Hagman G, Håkansson K, et al. Midlife work-related stress increases dementia 
risk in later life: The CAIDE 30-year study. Journals of Gerontology Series B: Psychological 
Sciences and Social Sciences 2016;72:1044-53. 
7. 
Alkadhi KA. Chronic psychosocial stress exposes Alzheimer's disease phenotype in a 
novel at-risk model. Front Biosci (Elite Ed) 2012;4:214-29. 
8. 
Albanese E, Launer LJ, Egger M, et al. Body mass index in midlife and dementia: 
Systematic review and meta-regression analysis of 589,649 men and women followed in 
longitudinal studies. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring 
2017;8:165-78. 
9. 
Prickett C, Brennan L, Stolwyk R. Examining the relationship between obesity and 
cognitive function: a systematic literature review. Obesity research & clinical practice 2015;9:93-
113. 
10. 
Pursey KM, Stanwell P, Callister RJ, Brain K, Collins CE, Burrows TL. Neural responses 
to visual food cues according to weight status: a systematic review of functional magnetic 
resonance imaging studies. Frontiers in nutrition 2014;1:7. 
11. 
Stoeckel LE, Weller RE, Cook III EW, Twieg DB, Knowlton RC, Cox JE. Widespread 
reward-system activation in obese women in response to pictures of high-calorie foods. 
Neuroimage 2008;41:636-47. 
12. 
Demos KE, Heatherton TF, Kelley WM. Individual differences in nucleus accumbens 
activity to food and sexual images predict weight gain and sexual behavior. Journal of 
Neuroscience 2012;32:5549-52. 
13. 
Yokum S, Ng J, Stice E. Attentional bias to food images associated with elevated weight 
and future weight gain: an fMRI study. Obesity 2011;19:1775-83. 
14. 
Moreno-Padilla M, Verdejo-Román J, Fernández-Serrano MJ, del Paso GAR, Verdejo-
García A. Increased food choice-evoked brain activation in adolescents with excess weight: 
Relationship with subjective craving and behavior. Appetite 2018;131:7-13. 
15. 
Lawrence NS, Hinton EC, Parkinson JA, Lawrence AD. Nucleus accumbens response to 
food cues predicts subsequent snack consumption in women and increased body mass index in 
those with reduced self-control. Neuroimage 2012;63:415-22. 
16. 
Pelchat ML, Johnson A, Chan R, Valdez J, Ragland JD. Images of desire: food-craving 
activation during fMRI. Neuroimage 2004;23:1486-93. 
17. 
Neseliler S, Hu W, Larcher K, et al. Neurocognitive and hormonal correlates of voluntary 
weight loss in humans. Cell metabolism 2019;29:39-49. e4. 
18. 
Farr OM, Chiang-shan RL, Mantzoros CS. Central nervous system regulation of eating: 
Insights from human brain imaging. Metabolism 2016;65:699-713. 
19. 
Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal 
adaptations to weight loss. New England Journal of Medicine 2011;365:1597-604. 
20. 
Yang Y, Shields GS, Guo C, Liu Y. Executive function performance in obesity and 
overweight individuals: A meta-analysis and review. Neuroscience & Biobehavioral Reviews 
2018;84:225-44. 
21. 
Cherbuin N, Sargent-Cox K, Fraser M, Sachdev P, Anstey K. Being overweight is 
associated with hippocampal atrophy: the PATH Through Life Study. International Journal of 
Obesity 2015;39:1509. 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
10 
22. 
Willette AA, Kapogiannis D. Does the brain shrink as the waist expands? Ageing research 
reviews 2015;20:86-97. 
23. 
Bauer C, Moreno B, González‐Santos L, Concha L, Barquera S, Barrios F. Child 
overweight and obesity are associated with reduced executive cognitive performance and brain 
alterations: a magnetic resonance imaging study in M exican children. Pediatric obesity 
2015;10:196-204. 
24. 
Gonzales MM, Tarumi T, Miles SC, Tanaka H, Shah F, Haley AP. Insulin sensitivity as a 
mediator of the relationship between BMI and working memory‐related brain activation. Obesity 
2010;18:2131-7. 
25. 
Simons JS, Spiers HJ. Prefrontal and medial temporal lobe interactions in long-term 
memory. Nature reviews neuroscience 2003;4:637. 
26. 
Hofmann W, Gschwendner T, Friese M, Wiers RW, Schmitt M. Working memory capacity 
and self-regulatory behavior: toward an individual differences perspective on behavior 
determination by automatic versus controlled processes. Journal of personality and social 
psychology 2008;95:962. 
27. 
Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving 
cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes 
Care 2011;34:1481-6. 
28. 
Nicklas BJ, Ambrosius W, Messier SP, et al. Diet-induced weight loss, exercise, and 
chronic inflammation in older, obese adults: a randomized controlled clinical trial. The American 
journal of clinical nutrition 2004;79:544-51. 
29. 
Group LAR. Impact of intensive lifestyle intervention on depression and health-related 
quality of life in type 2 diabetes: the Look AHEAD Trial. Diabetes care 2014;37:1544-53. 
30. 
Foster GD, Wadden TA, Peterson FJ, Letizia KA, Bartlett SJ, Conill AM. A controlled 
comparison of three very-low-calorie diets: effects on weight, body composition, and symptoms. 
The American journal of clinical nutrition 1992;55:811-7. 
31. 
Foster G, Wadden T, Swain R, Stunkard A, Platte P, Vogt R. The Eating Inventory in 
obese women: clinical correlates and relationship to weight loss. International journal of obesity 
1998;22:778. 
32. 
Chao AM, Wadden TA, Tronieri JS, et al. Effects of addictive-like eating behaviors on 
weight loss with behavioral obesity treatment. Journal of behavioral medicine 2019;42:246-55. 
33. 
Kahathuduwa CN, Binks M, Martin CK, Dawson JA. Extended calorie restriction 
suppresses overall and specific food cravings: a systematic review and a meta‐analysis. Obesity 
reviews 2017;18:1122-35. 
34. 
Andriessen C, Christensen P, Nielsen LV, et al. Weight loss decreases self-reported 
appetite and alters food preferences in overweight and obese adults: Observational data from the 
DiOGenes study. Appetite 2018;125:314-22. 
35. 
Martin CK, Rosenbaum D, Han H, et al. Change in food cravings, food preferences, and 
appetite during a low‐carbohydrate and low‐fat diet. Obesity 2011;19:1963-70. 
36. 
Cameron JD, Goldfield GS, Finlayson G, Blundell JE, Doucet É. Fasting for 24 hours 
heightens reward from food and food-related cues. PloS one 2014;9:e85970. 
37. 
Führer D, Zysset S, Stumvoll M. Brain activity in hunger and satiety: an exploratory visually 
stimulated FMRI study. Obesity 2008;16:945-50. 
38. 
LaBar KS, Gitelman DR, Parrish TB, Kim Y-H, Nobre AC, Mesulam M. Hunger selectively 
modulates corticolimbic activation to food stimuli in humans. Behavioral neuroscience 
2001;115:493. 
39. 
Goldstone AP, Prechtl de Hernandez CG, Beaver JD, et al. Fasting biases brain reward 
systems towards high‐calorie foods. European Journal of Neuroscience 2009;30:1625-35. 
40. 
Siep N, Roefs A, Roebroeck A, Havermans R, Bonte ML, Jansen A. Hunger is the best 
spice: an fMRI study of the effects of attention, hunger and calorie content on food reward 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
11 
processing in the amygdala and orbitofrontal cortex. Behavioural brain research 2009;198:149-
58. 
41. 
Stice E, Burger K, Yokum S. Caloric deprivation increases responsivity of attention and 
reward brain regions to intake, anticipated intake, and images of palatable foods. Neuroimage 
2013;67:322-30. 
42. 
Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J. Leptin reverses weight loss–
induced changes in regional neural activity responses to visual food stimuli. The Journal of clinical 
investigation 2008;118:2583-91. 
43. 
Bruce AS, Bruce JM, Ness AR, et al. A comparison of functional brain changes associated 
with surgical versus behavioral weight loss. Obesity 2014;22:337-43. 
44. 
Chen EY, Olino TM, Conklin CJ, et al. Genetic and neural predictors of behavioral weight 
loss treatment: a preliminary study. Obesity 2017;25:66-75. 
45. 
McDermott KD, Williams SE, Espeland MA, et al. Impact of Intensive Lifestyle Intervention 
on Neural Food Cue Reactivity: Action for Health in Diabetes Brain Ancillary Study. Obesity 2019. 
46. 
Kahathuduwa CN, Boyd LA, Davis T, O'Boyle M, Binks M. Brain regions involved in 
ingestive behavior and related psychological constructs in people undergoing calorie restriction. 
Appetite 2016;107:348-61. 
47. 
Deckersbach T, Das S, Urban L, et al. Pilot randomized trial demonstrating reversal of 
obesity-related abnormalities in reward system responsivity to food cues with a behavioral 
intervention. Nutrition & diabetes 2014;4:e129. 
48. 
Veronese N, Facchini S, Stubbs B, et al. Weight loss is associated with improvements in 
cognitive function among overweight and obese people: A systematic review and meta-analysis. 
Neuroscience & Biobehavioral Reviews 2017;72:87-94. 
49. 
Firth J, Stubbs B, Vancampfort D, et al. Effect of aerobic exercise on hippocampal volume 
in humans: a systematic review and meta-analysis. Neuroimage 2018;166:230-8. 
50. 
Hao S, Dey A, Yu X, Stranahan AM. Dietary obesity reversibly induces synaptic stripping 
by microglia and impairs hippocampal plasticity. Brain, behavior, and immunity 2016;51:230-9. 
51. 
Stomby A, Otten J, Ryberg M, Nyberg L, Olsson T, Boraxbekk C-J. A Paleolithic Diet with 
and without Combined Aerobic and Resistance Exercise Increases Functional Brain Responses 
and Hippocampal Volume in Subjects with Type 2 Diabetes. Frontiers in aging neuroscience 
2017;9:391. 
52. 
Prehn K, Jumpertz von Schwartzenberg R, Mai K, et al. Caloric restriction in older adults—
differential effects of weight loss and reduced weight on brain structure and function. Cerebral 
Cortex 2016;27:1765-78. 
53. 
Boraxbekk C-J, Stomby A, Ryberg M, et al. Diet-induced weight loss alters functional brain 
responses during an episodic memory task. Obesity facts 2015;8:261-72. 
54. 
Owen AM, McMillan KM, Laird AR, Bullmore E. N‐back working memory paradigm: A 
meta‐analysis of normative functional neuroimaging studies. Human brain mapping 2005;25:46-
59. 
55. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and adults. 
American journal of psychiatry 2011;168:1266-77. 
56. 
Veale JF. Edinburgh handedness inventory–short form: a revised version based on 
confirmatory factor analysis. Laterality: Asymmetries of Body, Brain and Cognition 2014;19:164-
77. 
57. 
Mason AE, Vainik U, Acree M, et al. Improving assessment of the spectrum of reward-
related eating: the RED-13. Frontiers in psychology 2017;8:795. 
58. 
Stunkard AJ, Messick S. The Three-Factor Eating Questionnaire to measure dietary 
restraint, disinhibition and hunger. Journal of Psychosomatic Research 1985;29:71-83. 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
12 
59. 
Yanovski SZ, Marcus MD, Wadden TA, Walsh BT. The questionnaire on eating and weight 
patterns-5 (QEWP-5): An updated screening instrument for binge eating disorder. The 
International journal of eating disorders 2015;48:259. 
60. 
Cepeda-Benito A, Gleaves DH, Williams TL, Erath SA. The development and validation 
of the state and trait food-cravings questionnaires. Behavior therapy 2000;31:151-73. 
61. 
Paffenbarger Jr RS, Hyde R, Wing AL, Hsieh C-c. Physical activity, all-cause mortality, 
and longevity of college alumni. New England journal of medicine 1986;314:605-13. 
62. 
Gearhardt AN, Corbin WR, Brownell KD. Development of the Yale Food Addiction Scale 
Version 2.0. Psychology of Addictive Behaviors 2016;30:113. 
63. 
Lowe MR, Butryn ML, Didie ER, et al. The Power of Food Scale. A new measure of the 
psychological influence of the food environment. Appetite 2009;53:114-8. 
64. 
Boggiano MM. Palatable Eating Motives Scale in a college population: Distribution of 
scores and scores associated with greater BMI and binge-eating. Eating behaviors 2016;21:95-
8. 
65. 
Fairburn CG, Beglin SJ. Assessment of eating disorders: Interview or self‐report 
questionnaire? International journal of eating disorders 1994;16:363-70. 
66. 
Cohen S, Kamarck T, Mermelstein R. Perceived stress scale. Measuring stress: A guide 
for health and social scientists 1994;10. 
67. 
Green SH, Glanz K. Development of the perceived nutrition environment measures 
survey. American journal of preventive medicine 2015;49:50-61. 
68. 
Smith BW, Dalen J, Wiggins K, Tooley E, Christopher P, Bernard J. The brief resilience 
scale: assessing the ability to bounce back. International journal of behavioral medicine 
2008;15:194-200. 
69. 
Maruish ME. User's manual for the SF-36v2 Health Survey: Quality Metric Incorporated; 
2011. 
70. 
Kolotkin RL, Crosby RD. Psychometric evaluation of the impact of weight on quality of life-
lite questionnaire (IWQOL-lite) in a community sample. Quality of Life Research 2002;11:157-71. 
71. 
Fleury J. The index of self-regulation: development and psychometric analysis. Journal of 
Nursing Measurement 1998. 
72. 
Carver CS, White TL. Behavioral inhibition, behavioral activation, and affective responses 
to impending reward and punishment: the BIS/BAS scales. Journal of personality and social 
psychology 1994;67:319. 
73. 
Shacham S. A shortened version of the Profile of Mood States. J Pers Assess 
1983;47:305-6. 
74. 
Blechert J, Meule A, Busch NA, Ohla K. Food-pics: an image database for experimental 
research on eating and appetite. Food cravings 2015:40. 
75. 
Foroni F, Pergola G, Argiris G, Rumiati RI. The FoodCast research image database 
(FRIDa). 2013. 
76. 
Finlayson G, Arlotti A, Dalton M, King N, Blundell JE. Implicit wanting and explicit liking 
are markers for trait binge eating. A susceptible phenotype for overeating. Appetite 2011;57:722-
8. 
77. 
Weintraub S, Dikmen SS, Heaton RK, et al. Cognition assessment using the NIH Toolbox. 
Neurology 2013;80:S54-S64. 
78. 
Simmons JP, Nelson LD, Simonsohn U. False-positive psychology: Undisclosed flexibility 
in data collection and analysis allows presenting anything as significant. Psychological science 
2011;22:1359-66. 
79. 
Thirion B, Pinel P, Mériaux S, Roche A, Dehaene S, Poline J-B. Analysis of a large fMRI 
cohort: Statistical and methodological issues for group analyses. Neuroimage 2007;35:105-20. 
80. 
Desmond JE, Glover GH. Estimating sample size in functional MRI (fMRI) neuroimaging 
studies: statistical power analyses. J Neurosci Methods 2002;118:115-28. 

Neurocognitive Benefits of WW 
 
 
Version: 4.0 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
13 
81. 
Geuter S, Qi G, Welsh RC, Wager TD, Lindquist MA. Effect size and power in fMRI group 
analysis. Biorxiv 2018:295048. 
82. 
Monti MM. Statistical analysis of fMRI time-series: a critical review of the GLM approach. 
Front Hum Neurosci 2011;5.