Effects of Cognitive Training on Everyday Cognitive and Brain Function in Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: Yale University

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CLINICAL STUDY PROTOCOL
Observational Study of Individual or Group Template
Effects of Cognitive Training on Everyday Cognitive and Brain Function in 
Parkinson’s Disease 
 Protocol Number
Protocol Version
09/13/2023 Version #8
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Protocol Number
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Synopsis
Purpose
Parkinson’s disease (PD) affects over six million individuals globally. With increasing 
life expectancy, this number is estimated to double by 2040. PD patients experience 
cognitive problems, especially executive dysfunction, even in the early stages of the 
disease affecting their everyday functioning. Currently, pharmacological treatment 
provides, at most, modest benefit for symptoms of PD-dementia and there is no effective 
treatment for milder cognitive problems. 
Cognitive training programs in PD have gained popularity with varying degrees of 
success for the cognitive domain that is treated. However, the benefits have not been 
generalizable, and more importantly, not transferred to real-life tasks. Therefore, there is 
an urgent unmet need to develop effective treatment strategies to help PD patients 
independently manage the cognitive demands of everyday life. 
Our previous work using guided motor and visual imagery training showed improved 
motor performance and increased functional connectivity in specific brain networks in PD 
patients. Grounded in this previous work, we now propose a phase 1 randomized clinical 
trial to determine the effectiveness of a 6-week mental imagery training program in 
improving cognitive functions during everyday tasks and to investigate the brain 
mechanisms of this training using functional magnetic resonance imaging (fMRI) and 
functional connectivity analyses in PD patients. 
Our mental imagery training differs from existing cognitive training programs in 
important ways: It will 1) focus on cognitive functional improvement in relevant real-world 
tasks, 2) foster the development of personalized and practical skills that can be applied 
flexibly to real-life situations, and 3) measure whether the training effects are transferred 
to other standard tests of executive function. 
PD patients (N=120) with mild-to-moderate disease, who do not have mild cognitive 
impairment according to the Movement Disorders Society Level II criteria will be randomly 
assigned in parallel to either the experimental (mental imagery, PD-MI) or control 
(psychoeducation, PD-Con) group. The PD-MI group will practice mental imagery of 
everyday tasks in a supervised manner and via homework, whereas the PD-Con group 
will receive psychoeducation on cognitive functioning and brain health in PD. 
The primary cognitive target engagement outcome will be the self-reported 
improvement on cognitive functioning during tasks of daily life. The primary 
neurobiological target engagement outcome will be the task-specific changes in 
coordinated brain network interactions during naturalistic fMRI tasks that will mimic real-
world demands. We will also examine whether the putative post-training changes in 
cognitive function and functional connectivity will be sustained over a 12-week period. 
Moreover, we will explore whether the functional connectivity changes will predict the 
cognitive outcomes at the 6- and 12-week timepoints. We will use mixed ANOVA tests to 
assess the short- and longer-term changes in outcomes before and after training.
Findings will provide critical early data for longer-term efficacy trials. If successful, 
mental imagery can be developed into a personalized neurocognitive rehabilitation 
program in PD. 
Primary Objective
The primary objective of this study is to determine whether mental imagery training for 
6 weeks will improve everyday cognitive functions and brain functional connectivity during 
naturalistic fMRI tasks in people with PD.  
Secondary Objective
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The secondary objective of this study is to determine whether the cognitive and 
imaging effects of mental imagery training will be sustained after a 12-week period in 
people with PD. 
Study Design
We will conduct a phase 1 clinical trial with two groups of PD patients randomly 
assigned in parallel. The experimental group (PD-MI) will receive mental imagery training 
and the control group (PD-Con) will receive psychoeducation on cognition and brain 
health. The mental imagery training will be delivered one-on-one and via audio-recorded 
scripts. Psychoeducation will be delivered in pre-recorded lecture format. Other research 
procedures will include neurological exams, standardized cognitive tests, surveys, and 
MRI scans. The immediate and sustained training effects on cognitive function and brain 
functional connectivity will be tested at 6- and 12-weeks, respectively. 
Study Date Range and Duration
  The expected length of the study is 6 years. 
Number of Study Sites 
   The Yale School of Medicine campus will be the only study site. Research procedures 
will take place at two sites: The Yale Magnetic Resonance Research Center (MRRC) and 
the Yale Center for Clinical Investigation (YCCI) Church Street Research Unit.
Primary Outcome Variables
1) Quality of life in Neurological Disorders (Neuro-QoL) Scores
Timeframe: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.  
Rationale: The Neuro-QoL is a set of self-report measures that assesses the health-
related quality of life of adults and children with neurological disorders. Neuro-QoL 
instruments were developed through a collaborative, multisite NINDS-sponsored research 
initiative to construct psychometrically-sound and clinically-relevant health-related quality 
of life measurement tools for individuals with neurological conditions including PD. The 
Neuro- QoL instruments enable within-disease as well as cross-disease comparisons and 
are intended for use in both neurology clinical trials and clinical practice. We will use the 
Neuro-Qol version 2 Cognitive Function item bank to assess post-training self-reported 
changes in cognitive functions.
Change in the Neuro-Qol version 2 Cognitive Function scores from T0 to T1 and across 
T2 will be the primary cognitive outcomes of this study. Significant increase in the 
Cognitive Function scores at T1 will be considered significant improvement in self-
reported cognitive function in everyday life. Significant increase in these scores across T2 
will be considered sustained improvement in self-reported cognitive function in everyday 
life.
2) Questionnaire on Mental Imagery (QMI) Vividness of Imagery Scale scores
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: The QMI is a measure of vividness of an individual’s multisensory and motor 
imagery on a scale of 1 to 7 (1: perfectly vivid image, 7: no image present at all). 
 
Change in the QMI scores from T0 to T1 and across T2 will serve as the manipulation 
check for the mental imagery intervention. Significant increase in these scores at T1 will 
be considered improved imagery vividness. Significant increase in these scores across T2 
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will be considered sustained improvement in imagery vividness. 
3) Task-specific whole-brain pairwise functional connectivity
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will calculate the whole-brain pairwise functional connectivity during mental 
imagery and video-watching of naturalistic goal-directed tasks in the MRI scanner for each 
subject. 
Change in task-specific pairwise functional connectivity from T0 to T1 and across T2 will 
be the primary imaging outcomes of the study. Significantly increased task-specific 
pairwise functional connectivity in major networks (e.g., default mode network during 
mental imagery and frontoparietal executive network during video-watching) at T1 will be 
considered improved task-specific functional reorganization of these networks. 
Significantly increased task-specific pairwise functional connectivity in major networks 
across T2 will be considered sustained improvement in task-specific functional 
reorganization of these networks.
Secondary and Exploratory Outcome Variables 
1) Composite executive function test scores (Secondary)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will calculate the composite z-scores of the executive function test scores 
(i.e., Stroop, F-A-S letter fluency, and Trail Making A-B tests) for all subjects. 
Change in composite executive function test scores from T0 to T1 and across T2 will be 
the secondary cognitive outcomes of the study. Significant increase in these scores at T1 
will be considered improved executive function. Significant increase in these scores 
across T2 will be considered sustained improvement in executive function.
2) Local and global functional connectivity-based graph measures (Secondary)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will calculate the local (i.e., clustering coefficient) and global (i.e., 
betweenness centrality) network graph measures during mental imagery and video-
watching tasks in the MRI scanner. These measures will provide information about the 
context-dependent changes in the functional organization of the brain networks. 
Change in graph measures from T0 to T1 and change in graph measures across T2 will 
be secondary imaging outcomes the study. Significantly increased task-specific clustering 
coefficient in major networks (e.g., default mode network during mental imagery and 
frontoparietal executive network during video-watching) and significantly increased 
context-dependent betweenness centrality between major network nodes (e.g., stronger 
between the default mode and frontoparietal networks during mental imagery) at T1 will 
be considered improved task-specific functional differentiation of these networks. 
Significant increases in the same graph measures across T2 will be considered sustained 
improvement in task-specific functional differentiation of these networks.
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3) Modified Six-Elements Test scores (Exploratory)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: The Modified Six-Elements Test is a measure of goal-directed planning and 
execution. 
Change in these test scores from T0 to T1 and across T2 will be the secondary cognitive 
outcomes of the study. Significant increase in these scores at T1 will be considered 
improved performance in goal-directed planning and execution. Significant increase in 
these scores across T2 will be considered sustained improvement of performance in goal-
directed planning and execution.
4) Global cognition scores (Exploratory) 
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: The Repeated Battery for the Assessment of Neuropsychological Status 
(RBANS) is a commonly used battery with alternate versions allowing repeated testing of 
the cognitive domains of attention, verbal and visual memory, language, and visuospatial 
functioning. 
Change in total RBANS scores from T0 to T1 and across T2 will be the exploratory 
cognitive outcomes of the study. Significant increase in these scores at T1 will be 
considered improved global cognition. Significant increase in these scores across T2 will 
be considered sustained improvement of global cognition.
5) Post-training brain-cognition relationship (Exploratory)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will examine whether the post-training changes in whole-brain pairwise 
functional connectivity and graph measures will predict the post-training differences in the 
cognitive function in each group at T1 and T2. 
Study Population
  The study population will be people with PD defined according to the Movement 
Disorders Society (MDS) diagnostic criteria with mild-to-moderate PD, who do not have 
mild cognitive impairment, aged 40 and above, and are physically independent.
Idiopathic PD is an adult-onset neurological disorder. In the United States, the incidence 
of idiopathic PD cases before the age of 40 is extremely low. Therefore, individuals with 
PD who are 40 years and older will be included and there will be no upper age limit for 
participation in the study. 
  There is no restriction for gender, race, or ethnicity. The approximate male-to-female 
ratio in PD is 1.5 to 1. This ratio will be reflected in the enrollment. We will seek a racially 
and ethnically diverse enrollment.
Subjects will be recruited through:
1.
The Yale Movement Disorders outpatient clinics
2.
The outpatient clinics in the new Yale PD Comprehensive Care Center
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3.
The local PD support groups and nonprofit organizations (e.g., American PD 
Association Connecticut Chapter, Beat PD Today exercise program) that provide 
educational and wellness programs for the greater PD community in Connecticut
4.
Neurology practices in Connecticut who care for patients with PD.
5.
JDAT recruitment services (EPIC/MyChart Alerts & mailing)
6.
Departmental/Center newsletters
7.
The YCCI recruitment database
8.
Recruitment letters
Number of Participants
There will be 120 subjects. 
Study Schedule
Verbal consent will be obtained for the initial screening visit over the phone or via email.  
Electronically signed informed consent will be obtained at the beginning of the Zoom 
video screening visit.
Time estimate for initial screening: 1 hour
There will be a total of 4 in-person visits: 
Visit 1: Baseline Clinical Evaluation. Subjects will undergo detailed clinical evaluations to 
determine disease severity and level of cognitive functioning.
Time Estimate: 3 hours 
Visit 2: Baseline Neuroimaging Experiments. Subjects will rate their mental imagery skills 
at baseline and perform fMRI tasks in the scanner. Subjects will also receive instructions 
on their respective training and homework assignments. 
Time Estimate: 2 hours 
Training: Subjects will receive their respective training 3 times per week for 4 weeks. On 
non-training days during the 4-week period and in the subsequent 2-week block, subjects 
will complete homework. 
Visit 3: 6-Week Post-Intervention Assessments. All subjects will return for repeat 
cognitive evaluations as in Visit 1, and mental imagery vividness rating and fMRI scans as 
in Visit 2. 
Time Estimate: 3 hours
Visit 4: 12-Week Post-Completion Assessments. All subjects will return for repeat 
cognitive evaluations and fMRI tasks. The same procedures as described in Visit 3 will be 
followed.
Time Estimate: 3 hours
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Protocol Revision History
Version Date
Summary of Substantial Changes
August 26, 
2022
Version #2

More information has been provided about the neuropsychological 
tests (Modified Six Elements, RBANS, Stroop, F-A-S, Trails A/B, and 
Wechsler Adult Reading).

Consent process in the initial screening visit has been clarified.

More details about the recruitment process have been provided.

Reporting of AEs has been changed to 5 days.

Partial HIPAA waiver for screening purposes has been requested.

Total payment has been reduced from $700 to $650 by eliminating 
payment for the initial screening visit. 
November 
15th, 2022
Version #3

The Epworth Sleepiness Scale, Beck Depression Inventory II, and 
Spielberger Trait Anxiety surveys have each been replaced with 
equivalents that are available in public domain without licensing 
restrictions: Scales for Outcomes in Parkinson’s Disease – Sleep 
(SCOPA-Sleep), Geriatric Depression Scale (GDS long form), and 
the Parkinson Anxiety Scale (PAS).

Executive dysfunction is common in people with Parkinson’s disease. 
Executive domain scores of up to 2 standard deviations below the 
normative data according to the MDS Level II criteria will be allowed 
to enroll people with PD with mild executive dysfunction in order to 
improve the generalizability of the study

For the sake of efficiency, MRI safety and medical history screening 
will take place during the initial phone call. If a subject fails the MRI 
safety screening or meets any of the exclusion criteria for medical 
history, they will not be enrolled. Subjects who are still eligible will be 
scheduled for a follow-up video-screening via the Zoom 
videoconferencing platform.

Paper study consent forms have been replaced by the use of 
REDCap to obtain electronic study consent. 

REDCap will be used instead of Qualtrics for the administration of 
online surveys and completion of online training and homework.

A REDCap study database will replace the use of Eliapps for data 
storage. 

The research team will record Zoom videoconference meetings to 
facilitate data collection of mental imagery content. Once data 
transcription is complete, the videos will be deleted.

The pre-recorded Powerpoint lectures assigned to the 
psychoeducational group now contain three multiple choice questions 
to assess comprehension of the content. 
January 25th, 
2023
Version #4

The protocol has been updated to reflect the use of recruitment 
services offered by JDAT (EPIC/MyChart Alerts & mailing services), 
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Departmental/Center newsletters, the YCCI recruitment database, 
and recruitment letters. 
June 15th, 
2023
Version #6 

6.13 Funding Source on page 50 has been updated: The study will be 
funded through Dr. Tinaz’s NINDS 1R01NS129540-01A1 grant.
August 9th, 
2023
Version #7

6.13 Funding Source on page 50 has been updated: The study will be 
funded through Dr. Tinaz’s NINDS 1R56NS129540-01A1 grant
September 
13th, 2023
Version #8

We have changed the eligibility cut-off on cognitive tests. To improve 
the generalizability of the study and include people with cognitive 
deficits in domains other than the executive domain, we will allow test 
scores of up to 2 standard deviations below the normative data in all 
cognitive domains in line with the MDS Level II criteria (see section 
4.3.2 on page 29).
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Statement of Compliance 
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to the Common Rule at 45CFR46 
(human subjects) and other applicable government regulations and Institutional research 
policies and procedures.
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Abbreviations
Abbreviation 
Explanation
EliApps
Google Workplace for Education
EPI
Echo Planar Imaging
FDR Correction
False Discovery Rate Correction 
fMRI
Functional Magnetic Resonance Imaging
FoV
Field of View 
gPPI
Generalized Psychophysiological 
Interaction
MCI
Mild Cognitive Impairment
MDS
Movement Disorder Society
MDS-UPDRS
MDS Unified Parkinson’s Disease Rating 
Scale 
MoCA
Montreal Cognitive Assessment
MPRAGE
Magnetization-prepared rapid gradient-echo
MRRC
The Yale Magnetic Resonance Research 
Center
Neuro-QoL
Quality of Life in Neurological Disorders 
PD 
Parkinson’s Disease 
PD-Con Group
Parkinson’s Disease Active Control Group 
(Receiving psychoeducation)
PD-MI Group
Parkinson’s Disease Mental Imagery Group 
(Experimental Group)
QMI
Questionnaire on Mental Imagery
RBANS
Repeatable Battery for the Assessment of 
Neuropsychological Status
SPSS
Statistical Package for Social Sciences
YCCI
Yale Center for Clinical Investigation
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Glossary of Terms
Glossary
Explanation
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Table of Contents
Preface....................................................................................................................................2
Synopsis ..................................................................................................................................3
Purpose................................................................................................................................3
Primary Objective.................................................................................................................3
Secondary Objective ............................................................................................................3
Study Design........................................................................................................................3
Study Date Range and Duration ..........................................................................................4
Number of Study Sites .........................................................................................................4
Primary Outcome Variables .................................................................................................4
Secondary and Exploratory Outcome Variables (if applicable)............................................4
Number of Participants.........................................................................................................5
Study Schedule ....................................................................................................................5
Protocol Revision History.....................................................................................................6
Statement of Compliance.........................................................................................................7
Abbreviations ...........................................................................................................................8
Glossary of Terms....................................................................................................................9
1
Background/Literature Review........................................................................................13
1.1
Background .............................................................................................................13
1.2
Prior Experience (if applicable)................................................................................13
2
Rationale/Significance ....................................................................................................14
2.1
Rationale and Study Significance............................................................................14
2.2
Purpose of Study/Potential Impact ..........................................................................14
2.3
Potential Risks and Benefits....................................................................................14
2.3.1
Potential Risks..................................................................................................14
2.3.2
Potential Benefits .............................................................................................15
3
Study Purpose and Objectives .......................................................................................15
3.1
Hypothesis...............................................................................................................15
3.2
Primary Objective ....................................................................................................15
3.3
Secondary Objective (if applicable).........................................................................15
4
Study Design ..................................................................................................................16
4.1.1
General Design Description .............................................................................16
4.1.2
Study Date Range and Duration ......................................................................16
4.1.3
Number of Study Sites .....................................................................................16
4.2
Outcome Variables..................................................................................................16
4.2.1
Primary Outcome Variables .............................................................................16
4.2.2
Secondary and Exploratory Outcome Variables (if applicable)........................16
4.3
Study Population .....................................................................................................16
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4.3.1
Number of Participants.....................................................................................17
4.3.2
Eligibility Criteria/Vulnerable Populations.........................................................17
5
Study Methods/Procedures .........................................................................................18
5.1
Study Procedures....................................................................................................18
5.1.1
Data Collection.................................................................................................18
5.1.2
Adverse Events Definition and Reporting.........................................................18
5.2
Study Schedule .......................................................................................................18
5.3
Informed Consent....................................................................................................19
5.3.1
Screening (if applicable)...................................................................................19
5.3.2
Recruitment, Enrollment and Retention (if applicable).....................................19
5.3.3
Study Visits (is applicable) ...............................................................................19
5.4
Statistical Method ....................................................................................................20
5.4.1
Statistical Design..............................................................................................20
5.4.2
Sample Size Considerations ............................................................................20
5.4.3
Planned Analyses.............................................................................................20
5.4.4
Analysis of Subject Characteristics (if applicable)............................................20
5.4.5
Interim Analysis (if applicable)..........................................................................20
5.4.6
Handling of Missing Data .................................................................................20
6
Trial Administration.........................................................................................................20
6.1
Ethical Considerations: Informed Consent/Assent and HIPAA Authorization .........21
6.2
 Institutional Review Board (IRB) Review................................................................22
6.3
Subject Confidentiality.............................................................................................22
6.4
Deviations/Unanticipated Problems.........................................................................23
6.5
Data Quality Assurance...........................................................................................25
6.6
Study Records.........................................................................................................25
6.7
Access to Source.....................................................................................................25
6.8
Data or Specimen Storage/Security ........................................................................25
6.9
Retention of Records...............................................................................................25
6.10
Study Monitoring......................................................................................................26
6.11
Study Modification ...................................................................................................26
6.12
Study Completion ....................................................................................................26
6.13
Funding Source .......................................................................................................26
6.14
Conflict of Interest Policy.........................................................................................26
6.15
Publication Plan.......................................................................................................27
Appendices ............................................................................................................................28
List of Tables..........................................................................................................................29
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1
Background/Literature Review
1.1
Background
Parkinson’s Disease (PD) is the fastest growing neurological disorder and affects over six 
million individuals globally. With increasing life expectancy, this number is estimated to double 
by 2040.1 Cognitive deficits are common in PD and associated with poor outcomes, reduced 
quality of life, and significant caregiver burden.2 PD patients frequently present with executive 
dysfunction causing problems in everyday life. Currently, there are no therapies to prevent 
cognitive decline in PD. Pharmacological treatment provides, at most, modest symptomatic 
benefit in PD dementia.3 Cognitive training programs in PD have gained popularity with varying 
degrees of success for the cognitive domain that is treated. However, the benefits have not 
been generalizable, and more importantly, not transferred to real-life tasks.2 Therefore, 
developing effective treatment strategies to help PD patients independently manage the 
cognitive demands of everyday life is critically important. Indeed, the PD community identified 
maintaining cognitive function as one of its major unmet needs.2
The proposed training protocol intends to meet this need and is inspired by our previous 
work using kinesthetic motor imagery training to improve kinesthetic awareness and motor 
function in PD patients.4 Here, we will use mental imagery to train subjects with PD to simulate 
the planning and implementation process of goal-directed tasks in everyday life. This training 
is expected to improve the cognitive functioning in everyday life and functional connectivity of 
brain networks that support these cognitive functions in people with PD.
Executive dysfunction in PD 
Executive functions are central, supramodal cognitive processes that control goal-directed 
behaviors comprised of multiple steps including goal formulation, self-initiation, plan 
execution, and processing of the outcome.5 These control processes also call on working 
memory as well as internal and external attentional resources.6,7 Even in the early stages of 
the disease, PD patients frequently present with executive dysfunction. Executive dysfunction 
may also be observed in people who are at risk of developing PD and cause problems in 
instrumental activities of daily living.8 Specifically, PD patients have deficits in internal control 
of attention, set shifting, planning, inhibition, conflict resolution, dual task performance, and 
decision making.9 Apathy and depression are also associated with executive dysfunction in 
PD.9 
Knowledge gap: Executive dysfunction in PD has been established using standard 
cognitive tests, but the functional deficits in everyday life associated with executive dysfunction 
have not been investigated systematically. We aim to fill this gap by assessing executive 
dysfunction and post-training changes thereof in PD patients in daily life.
Neural substrates of cognitive/executive dysfunction in PD
Altered resting-state functional connectivity within and between the cognitive networks 
including the default mode, frontoparietal, dorsal attention, and salience networks plays a role 
in cognitive impairment in PD.10 Reduced functional connectivity within the default mode 
network in PD patients with impaired cognition compared with those with normal cognition and 
healthy controls has been demonstrated.11-16 Weakening of the natural anti-correlation 
between the default mode and task positive networks11,17 and between the default mode and 
salience networks18 has also been reported in PD patients with impaired cognition. Reduced 
functional connectivity between11,19 and within the dorsal attention11,20,21 and frontoparietal 
executive control networks,16 and reduced degree in the salience network18 have been 
reported in PD patients with cognitive impairment. Moreover, functional connectivity profiles 
mainly of the frontal nodes distinguished PD patients with cognitive impairment from those 
with normal cognition.22 PD patients also exhibit different functional connectivity patterns 
depending on the type of their cognitive deficit. Dysexecutive deficits have been found to 
correlate with reduced functional connectivity in the sensorimotor network, and posterior 
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cortical deficits (visuospatial skills, memory) to correlate with reduced functional connectivity 
in the frontoparietal executive network and increased functional connectivity in the temporal 
network.15 Reduced cerebellar functional connectivity with occipital and frontal regions has 
also been demonstrated in PD patients with impaired cognition.23 
Executive functions are supported by the frontostriatal circuits and particularly vulnerable 
in PD.24-27 Functional MRI studies of executive dysfunction in PD have demonstrated abnormal 
activation in these circuits and aberrant activations in other brain regions depending on the 
medication status and task features.28 For example, hypodopaminergic state is usually 
associated with reduced activation in the prefrontal cortex and dorsal striatum during planning 
and working memory tasks in PD.27,29 Increased or decreased activation in the prefrontal 
cortex also depends on the basal ganglia involvement during the task.30 Aberrant and 
compensatory frontostriatal hyperactivation has also been observed and is usually associated 
with worse and preserved executive performance, respectively.31,32  
Knowledge gap: The neural substrates of executive functions in PD during tasks mimicking 
real-world situations have not been investigated. We will examine the baseline and post-
training interactions within and between the brain networks supporting goal-directed behavior 
in PD patients using naturalistic fMRI tasks.33,34
Cognitive training in PD
Cognitive training programs have gained popularity with varying degrees of success for 
the cognitive domain that is treated, but usually without generalizable real-life benefits.2 Most 
studies to date used structured paper-pencil tests,35 games,36 computerized tasks,37 or 
strategy training38 to target multiple cognitive domains for training in nondemented PD 
patients. Training periods, anywhere between 4-12 weeks, were usually administered in small 
groups at least once a week with some components administered in individual sessions, and 
usually combined with unsupervised practice (e.g., homework). In a meta-analysis of 
randomized clinical trials, cognitive training in nondemented PD patients was found to show a 
small but significant effect.39 Larger effect sizes were noted on processing speed,35 working 
memory,36 and executive functions,38 whereas effects on quality of life and instrumental 
activities of daily living were not significant.38 Most studies focused on the rehabilitation of 
frontal executive dysfunction in PD and the effects were heterogeneous mainly due to the 
variability of cognitive profiles of subjects, small sample sizes, and lack of control groups in 
some studies.40 A multi-pronged program in PD patients with mild cognitive impairment (MCI) 
demonstrated that the combination of cognitive, psychomotor, and real-world transfer training 
was superior to any of these components alone in promoting a more active life style and more 
confidence in activities of daily living. Importantly, cognitive training was found to be arduous 
at times and psychomotor training was preferred by the participants.41 Only a few 
neuroimaging studies investigated the brain changes in PD as a result of cognitive training. 
After three months of cognitive training,35 increased task-based activation within and increased 
resting-state functional connectivity between the temporal and prefrontal cortex were 
demonstrated in the PD training group compared with the PD control group.42 After an 18-
month follow-up period, the same PD group was found to retain the cognitive improvements 
and functional brain changes.43 
Cognitive training is a promising non-pharmacological approach and the Institute of 
Medicine has established criteria for cognitive training programs.44 The criteria include transfer 
to other laboratory tasks that measure the same cognitive construct as the training task, 
transfer of training to relevant real-world tasks, use of an active control group, determining the 
duration of post-training skill retention, and replicability across studies. 
Knowledge gap: Currently, the cognitive training programs in PD do not fulfill all of the 
Institute of Medicine criteria.2 Specific to the PD population, it has also been recommended to 
include subjects with homogeneous cognitive profiles, target executive/attention dysfunction, 
include supervised training, use a personalized approach, and include measures of 
(instrumental) activities of daily living.40 Our proposed mental imagery training program 
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provides a personalized approach targeting executive functioning in PD patients with the aim 
of improving everyday functioning in the setting of a randomized clinical trial. Moreover, our 
study will shed light on the brain mechanisms of training effects using fMRI. This is an early-
phase study, the training effects will be tested immediately and again at 12 weeks. 
1.2
Prior Experience 
 
Neurofeedback-guided kinesthetic motor imagery in PD
In a randomized clinical trial, we tested whether neurofeedback-guided kinesthetic motor 
imagery of complex movements and activities can improve motor performance and functional 
brain plasticity in PD patients with normal global cognition.4 The neurofeedback signal was 
based on the right insula-dorsomedial frontal cortex functional connectivity strength given the 
role of these structures in motivating intentional action.45 In the scanner, the experimental PD 
group was instructed to increase this neurofeedback signal using motor imagery, whereas the 
control PD group performed visual imagery of objects and scenes without neurofeedback. 
Both groups also practiced their respective imagery tasks daily for 4 weeks. 
Post-training, we did not find a significant increase in the neurofeedback signal in the motor 
imagery compared with the visual imagery group partially due to large between-subject 
variability. However, both groups showed significant improvement in their kinesthetic and 
visual motor imagery skills as well as in their performance of timed motor tasks. Notably, the 
motor improvement correlated with the increase in neurofeedback signal only in the motor 
imagery group. Moreover, both groups showed specific training effects in whole-brain 
functional connectivity with distinct neural circuits supporting kinesthetic motor imagery (insula 
and premotor cortex) and visual imagery (nodes in the ventral and dorsal visual streams) 
(Figure 1).4 
These results provide a manipulation check and validate that the training targeted the 
expected brain networks, and are also in line with previous reports of differential activation 
patterns during kinesthetic motor46,47 and visual imagery.48 Importantly, the results 
demonstrate that PD patients are capable of mental imagery, can improve their imagery skills 
with practice, and the practice effects can be captured in the functional reorganization of 
specific brain circuits subserving the corresponding imagery modes
Self-regulation and self-efficacy in PD
We also investigated the behavioral and neural corelates of self-regulation and self-
efficacy skills in community dwelling PD patients. Self-regulation and self-efficacy are 
metacognitive skills that enable people to mobilize the motivation and cognitive resources to 
exert control over events 49 and to guide their goal-directed activities over time and across 
changing circumstances.50 These skills correlated negatively with apathy scores and global 
disease severity in our PD cohort. Moreover, a resting-state functional connectivity analysis 
including the main nodes of the major networks (i.e., default mode, dorsal attention, salience, 
sensorimotor, visual, language, and cerebellar) revealed that stronger functional connectivity 
between the salience network nodes including the dorsal anterior cingulate cortex and anterior 
insula correlated positively with self-regulation and self-efficacy scores. The self-regulation 
scores also showed a significant negative correlation with the functional connectivity between 
the dorsal anterior cingulate cortex and left lateral parietal cortex, which is a major node of the 
default mode network (Figure. 2).51 These results suggest that attentional self-regulation and 
self-efficacy require a salience-detection mechanism in order to switch efficiently from a self-
referential to a goal-oriented mental state. This mechanism seems to be subserved by the 
coupling among the nodes of the salience network and decoupling of the salience from the 
default mode network.
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Figure 1
Fig. 1. Whole-brain imagery task-based functional connectivity changes post-training. 
Red: Stronger functional connectivity between nodes in the motor imagery group > visual 
imagery group. Blue: Stronger functional connectivity between nodes in the visual imagery 
group > motor imagery group. Cb: Cerebellum, dPCC: Dorsal posterior cingulate cortex, FG: 
Fusiform gyrus, FP: Frontal pole, IFGo: Inferior frontal gyrus, orbital part; Ins: Insula, ITG: 
Inferior temporal gyrus, MTG: Middle temporal gyrus, OFC: Orbitofrontal cortex, PHG: 
Parahippocampal gyrus, PMC: Premotor cortex, V2: Secondary visual cortex, VA: Visual 
association cortex (FDR-corrected p < 0.05, two-tailed). Nodes are based on the Shen Atlas.52 
Nodes and connections are displayed on the MNI brain template in the CONN Toolbox.53 
Figure 2
Fig. 2. The pairwise functional connections that show significant correlations with self-
efficacy and self-regulation scores (FDR-corrected, p < 0.05). The nodes and connections 
are displayed on the MNI brain template in the CONN Toolbox.53 dACC: Dorsal anterior 
cingulate cortex, rAI: Right anterior insula, lLatPar: Left lateral parietal. Red: Positive 
correlation. Blue: Negative correlation.
2
Rationale/Significance
2.1
Rationale and Study Significance 
Mental imagery as a cognitive-behavioral intervention
Mental Imagery refers to the mental re-creation of perceptual experience across sensory 
modalities, of past or future events and scenarios, and of motor acts with the potential to 
Self-Efficacy
Self-Regulation
dACC
dACC
rAI
rAI
lLatPar
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prepare the individual for action.54,55 Mental imagery has been used extensively as a 
performance-enhancing strategy in sports and skilled performance,56-58 as a mnemonic 
strategy,59-61 and in cognitive behavioral therapy for regulation of anxiety and depression 
symptoms.62,63
It is important to note that mental imagery is not about passively viewing mental pictures, 
but rather about actively and intentionally constructing a mental picture and subjectively 
experiencing it.64 The experiential and emotional aspects of mental imagery especially from a 
first-person perspective make imagery an efficient tool in therapy.65 Similarly, the embodied 
and experiential aspects of mental imagery have been found to improve self-efficacy (e.g., to 
overcome fear of falling in older adults) 66, increase motivation, and promote engagement in 
planned activities and healthy behaviors such as exercise.67-69 
Mental imagery also plays a fundamental role in episodic future thinking,70 which refers to 
the ability to imagine the future and critically depends on episodic memory and frontal-
executive systems.71 Episodic future thinking serves decision making, emotion regulation, 
intention formation, and planning.71 Nondemented PD patients were found to produce fewer 
spontaneous thoughts72 and fewer episodic details73 than controls when asked to imagine 
future events. The poorest performers in future thinking also had significant executive 
dysfunction.73 This suggests that future thinking taxes the executive resources in PD by 
requiring active monitoring and combining of various sub-tasks. Episodic specificity induction 
that trains people to produce specific episodic details (e.g., people, places, time, objects, 
actions) has been shown to boost the episodic details in remembered past and imagined future 
events in young and older healthy people.71
Relevance of mental imagery for cognitive improvement in the PD population
Our mental imagery training will target cognitive/executive functioning in the service of 
goal-directed tasks in everyday life of PD patients. Subjects will learn to mentally simulate the 
planning and implementation steps of these tasks. The training will emphasize the experiential 
vividness and episodic richness of the imagined situations, enable the subjects to mentally 
and affectively prepare for the planned actions, and learn to self-regulate attention and 
executive resources as their plans unfold in real life. The training will be personalized, and 
once acquired as a skill, can be used flexibly in all real-life situations. 
The study will also provide mechanistic insights into the neural correlates of cognitive 
functional difficulties of PD patients using naturalistic fMRI tasks. These correlates and the 
dynamic, context-dependent interactions among them will be the neurobiological targets of 
the mental imagery intervention. Moreover, we will examine whether the potential benefits of 
mental imagery training are sustained in the short term.
Our study has the potential to benefit people with PD directly. Cognitive problems create 
a significant burden on the individuals with PD, caregivers, and public health. Novel treatments 
are critically needed to alleviate the cognitive problems affecting everyday functioning of PD 
patients. If successful, mental imagery training can be incorporated into cognitive 
neurorehabilitation programs for patients with PD.  
2.2 Purpose of Study/Potential Impact 
The study aims to investigate the potential role of mental imagery training as a noninvasive 
and nonpharmacological intervention to improve 1) goal-directed cognitive functioning during 
tasks of daily living and 2) functional connectivity of cognitive brain networks in PD patients. 
The study has the potential for high-impact findings and direct clinical significance for 
patients with PD:
1) The mental imagery training will be personalized, so that PD patients can continue to 
use the skills and strategies they have acquired during training and apply them flexibly 
and autonomously to real-life situations. If successful, mental imagery training could 
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also be incorporated into cognitive rehabilitation programs for PD. 
2) The study will also provide mechanistic insights into the neural correlates of cognitive
function of PD patients using naturalistic fMRI tasks mimicking real-world demands. 
Research on the brain pathophysiology in PD, as a basis for novel treatment options, as 
well as investigation of the therapeutic potential of noninvasive and nonpharmacological 
interventions, such as mental imagery training, has the potential for improvement of the quality 
of life in a considerable proportion of the general older population. 
      Innovations in our study can be summarized as:
Innovations in experimental medicine approach
Our proposal builds on the basic tenets of the experimental medicine approach as laid out 
in the National Institutes of Health (NIH) Science of Behavior Change Program report.74
 • This study will, for the first time, use mental imagery as an intervention targeting executive 
functioning to improve performance in goal-directed tasks in everyday life (putative cognitive 
target engagement). 
• The proposed cognitive training program is unique in that it is directly linked to the 
naturalistic tasks of everyday living and promotes an implicit strategy (i.e., mental imagery) 
that can be personalized and flexibly applied to real-life situations. 
• Real-world behavior is complex and multidimensional. Naturalistic fMRI paradigms 
representing real-world demands lend stronger ecological validity to human neuroimaging 
experiments.33,34 This study will, for the first time, examine the specific interactions within and 
between core brain networks supporting goal-directed cognitive functioning in PD using 
mental imagery and video-watching of naturalistic tasks of daily life. We will determine the 
changes in the coordinated network interactions as a result of training and how they relate to 
the cognitive changes (putative neurobiological target engagement). 
• Knowledge gained from our empirically-grounded and mechanism-based approach will help 
us refine the mental imagery intervention and predict treatment response in PD.  
Innovations in clinical applications
• The proposed training has direct therapeutic implications, and if successful, can be 
developed into a personalized neurocognitive rehabilitation program in PD. 
• The program could also be customized to meet the needs of PD patients with MCI.
2.3
Potential Risks and Benefits
2.3.1 Potential Risks 
The proposed research plan involves screening for clinical history, MRI safety, and global 
cognitive impairment; online surveys; neurological and movement examination, cognitive 
evaluation, performance-based tests, training via videoconferencing, pre-recorded 
psychoeducation lectures, and daily homework (listening to imagery audio files and filling out 
online surveys for the experimental group and taking brief online quizzes for the control group); 
and MRI scans. The potential risks associated with individual study procedures are as follows: 
Immediate risks
Medication status 
Subjects who are on medications for PD (e.g., carbidopa/levodopa, dopamine receptor 
agonists) will always be tested and scanned early in the day while they are on their regular 
medication regimen. This will minimize the risk of occurrence of symptoms related to being off 
medication such as excessive slowness or stiffness, freezing of gait, balance problems or falls, 
and severe anxiety.  
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Videoconferences for screening and training
The online Zoom platform will be used for videoconferences. There is no medical risk 
associated with videoconferences. There is a potential confidentiality risk (e.g., hacking of the 
conferences or user cameras).
Online surveys and homework
Online surveys and quizzes created on the Yale REDCap online database and survey  
platform will be emailed to subjects individually. Subjects will also submit their homework via 
REDCap. There is no medical risk associated with the online surveys and homework. No 
personally identifiable information will be collected, therefore, the surveys and homework do 
not pose a confidentiality risk.
Clinical, cognitive, and behavioral evaluation 
The clinical evaluation including neurological and movement examination, paper-pencil 
tests for cognitive evaluation, and performance-based tests do not entail any medical risk. All 
of these evaluations will be performed in controlled laboratory settings. No personally 
identifiable information will be collected during these evaluations. 
MRI in 3 Tesla scanner 
Subjects are at risk for injury from the scanner, if they have metal objects in their bodies 
(e.g., pacemakers, aneurysm clips, metallic prostheses, implanted delivery pumps, cochlear 
implants, shrapnel fragments). Welders and metalworkers are also at risk for injury because 
of possible presence of small metal fragments in the eye, of which they may be unaware. 
Individuals with fear of confined spaces (i.e., claustrophobia) may become anxious during 
MRI. The scanner makes a thumping noise created by the radiofrequency waves necessary 
for forming the images. The noise can be loud enough to damage hearing. On rare occasions, 
some people might feel dizzy, get an upset stomach, have a metallic taste or feel tingling 
sensations or muscle twitches. These sensations usually go away quickly. Subjects might 
experience discomfort from lying flat on their back during scanning.
Long-range risks
We do not foresee any long-range risks associated with this study.
Risk Minimization
Informed consent and assent 
Verbal consent will be obtained for the screening visit over the phone or via email. 
Electronically signed informed consent will be obtained at the beginning of the video screening 
visit. A member of the research team authorized to obtain consent will give the subjects 
detailed information about the study and go over all aspects of the research. The purpose, 
research procedures, any risk that these procedures might entail, and any possible benefits 
will be discussed in detail in language appropriate for the individual’s level of understanding. 
Subjects will be encouraged to ask questions and given enough time to discuss any aspect of 
the study with the research team. Subsequently, they will have to demonstrate understanding 
of the study procedures and what is expected of them. Once subjects understand the study, 
they will be asked if they wish to participate. If they do, they will be asked to electronically sign 
the consent form. 
Capacity will be assessed directly in the course of attempting to obtain informed consent. 
When the member of the research team authorized to obtain consent has reviewed the study, 
they will ask the subject to explain the major elements of the study. Those elements are a) 
this is a research study (not routine treatment), b) participation is voluntary, c) study 
procedures, d) risks, e) benefits. Open-ended questions such as “Can you tell me the main 
things that you would do in this study? Can you tell me the main risks of the study?” will be 
used to assess understanding and appreciation of the facts. Subject will then be expected to 
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make a rational choice: “Considering the risks and benefits we have discussed, would you like 
to take part in this study?” Based on the subject’s responses the team member will make a 
final judgment about capacity for consent. If the subject has capacity and agrees to the study, 
they will sign the consent form.
Subject monitoring 
Subject’s participation will be terminated under the following conditions: 1) Subject 
develops a serious medical condition. 2) Subject is not compliant with protocol evaluations. 3) 
Subject requests withdrawal from the study. Subjects may choose to stop participating in the 
clinical, cognitive, behavioral, and MRI evaluations at any time. During the experiments, the 
principal investigator or other members of the research team will be present at all times and 
monitor the subjects for adverse events. Subjects will maintain their regular medication 
regimen throughout the experiments. MRI scanning will be terminated immediately upon 
subject’s request or if an adverse event occurs.
MRI-related risk management
Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-
rays, to take pictures and measure chemicals of different parts of the body. The United States 
Food and Drug Administration (FDA) has set guidelines for magnet strength and exposure to 
radio waves, and we carefully observe those guidelines. Subjects will be watched closely 
throughout the MR study. Some people may feel uncomfortable or anxious. If this happens, 
they may ask to stop the study at any time and we will take them out of the MR scanner. On 
rare occasions, some people might feel dizzy, get an upset stomach, have a metallic taste or 
feel tingling sensations or muscle twitches. These sensations usually go away quickly but 
subjects will be instructed to tell the research staff if they have them. There are some risks 
with an MR study for certain people. If subjects have a pacemaker or some metal objects 
inside their body, they may not be in this study because the strong magnets in the MR scanner 
might harm them. 
Another risk is the possibility of metal objects being pulled into the magnet and hitting 
them. To lower this risk, all people involved with the study must remove all metal from their 
clothing and all metal objects from their pockets. We also ask all people involved with the 
study to walk through a detector designed to detect metal objects. No metal can be brought 
into the magnet room at any time. Also, once the subject is in the magnet, the door to the room 
will be closed so that no one from outside accidentally goes near the magnet. 
Subjects will be asked to read and answer very carefully the questions on the MR Safety 
Questionnaire related to their personal safety. They will be asked to tell us any information 
they think might be important. Subjects will be informed that this MR study is for research 
purposes only and is not in any way a complete health care imaging examination. The scans 
performed in this study are not designed to find abnormalities. Subjects will also be informed 
that the principal investigator, the lab, the MR technologist, and the Magnetic Resonance 
Research Center are not qualified to interpret the MR scans and are not responsible for 
providing a health care evaluation of the images. If a worrisome finding is seen on the subject’s 
scan, a radiologist or another physician will be asked to review the relevant images. Based on 
his or her recommendation (if any), the principal investigator or consulting physician will 
contact the subject, inform them of the finding, and recommend that they seek medical advice 
as a precautionary measure. Subjects will be informed that the investigators, the consulting 
physician, the Magnetic Resonance Research Center, and Yale University are not responsible 
for any examination or treatment that they receive based on these findings. The images 
collected in this study are not a health care MR exam and for that reason, they will not be 
routinely made available for health care purposes. 
Safeguard for vulnerable populations
Women of childbearing potential will not be included, if they are pregnant or breastfeeding. 
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Women who are 50 years of age and older or who have absence of menses for two years will 
not receive pregnancy tests. All other women will receive urine pregnancy test within two 
weeks before the scheduled MRI session.
Confidentiality
The data will be collected specifically for this project. 
Hard copies of HIPAA identifiers, consent forms, clinical screening information, and MRI 
screening form will be kept in a locked filing cabinet.  
The data will not contain personally identifiable information and will be labeled using a 
coding system. The data labels will contain the subject code, date and time of recording, and 
mode and condition of recording. Only the principal investigator, Dr. Tinaz, will have access 
to the centrally and electronically stored and password-protected subject identification list to 
decode data files. 
Case report forms for each subject will be used to enter clinical evaluation results, and 
scores of paper-pencil tests, online surveys, and performance-based tests. All of this 
information will then be entered into a password-protected electronic database, which will be 
stored in a group-owned (Tinaz Lab) shared space on a Yale REDCap database. This is a 
secure web application for building and managing online surveys and databases. It is 
specifically geared to support online or offline data capture for research studies and 
operations. Case report forms, individual data files, and the electronic database will not contain 
personally identifiable information and will be labeled using a coding system. The data labels 
will contain the subject code, date and time of recording, and mode and condition of recording. 
Only the principal investigator, Dr. Tinaz, will have access to the centrally and electronically 
stored and password-protected subject identification list to decode data files. The data will be 
collected specifically for this project. 
The username- and password-protected Yale REDCap platform will be used for the online 
surveys. Subjects will be emailed the survey links individually. Each survey will be linked to a 
record ID labelled according to the subject’s unique study code. 
Imaging data will be transferred securely to workstations for analysis and stored on HIPAA-
compliant secure central storage servers (“Storage@Yale”) provided by the Yale IT 
Department for a monthly fee. All team members will use encrypted research computers. 
As a covered entity, Yale School of Medicine provides HIPAA Zoom accounts. The HIPAA-
compliant and password-protected Zoom conferences will be conducted using an encrypted 
computer connected to the Yale secure network. The HIPAA Zoom has different features than 
the regular Zoom: 1) The ability to export, copy/paste or save chats is disabled. 2) Screen 
capturing and sending images are also disabled. 3) All messages are encrypted. 4) Cloud 
recording is disabled. Recordings are saved locally. To ensure security, each time a different 
invitation link with a unique meeting ID and password will be emailed to the subjects 
individually. As soon as the subject joins, the meeting will be locked to prevent others from 
joining. Meetings will be recorded by the research team to facilitate the collection of mental 
imagery content. Once the data has been transcribed, the videos will be deleted. Subjects will 
be permitted to record the meetings as well.  Zoom software will be updated regularly to ensure 
that new security features are incorporated.
Due to the Covid-19 pandemic, the Yale Human Research Protection Program prepared 
an online Remote Research Visit Source Document for remote research visits conducted 
using Zoom or telephone in accordance with the ICH Good Clinical Practice standards of 
ALCOA-C [Attributable, Legible, Contemporaneous, Original, Accurate and Complete]. The 
document includes detailed information that needs to be entered (protocol number, PI, subject 
code, visit type/number/date, name of staff conducting the remote visit, documentation of the 
consent process, type of protocol assessment (e.g., demographics, medical history, 
questionnaires, etc.), details of intervention, and side effects). After each telephone encounter 
and Zoom visit this online document will be filled out and maintained with subjects’ research 
records. 
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Upon completion of the study, study binders will be stored in a locked facility for the amount 
of time required by law. After this time, the study binders will be destroyed by shredding. The 
electronic database that contains the information in case report forms will stay on the 
password-protected research computer until the study closes. The link to personal information 
will be kept until the end of the study, after which time the link will be destroyed and the data 
will become anonymous. The data will be kept in this anonymous form indefinitely.
The principal investigator, research staff, and representatives from the Yale Human 
Research Protection Program and Yale Human Investigation Committee (for auditing 
purposes) will have access to the protected health information.
Safeguard procedure in the case of adverse events
Human subjects research will be conducted according to Yale University IRB guidelines 
for human subject protection in the setting of the Yale School of Medicine campus including 
the Yale MRRC and Yale Center for Clinical Investigation outpatient facilities, where – in 
addition to the medically credentialed principal investigator, Dr. Tinaz– physicians, nurses and 
code teams are on call to assist in any kind of unforeseen medical emergency.
Adverse events will be reported in accordance with federal and Yale University IRB rules. 
For each adverse event, the principal investigator, Dr. Tinaz, will record the onset, end, 
intensity, required treatment, outcome, seriousness, and action taken. Serious or unexpected 
adverse events will be reported immediately to the Yale University IRB, and in writing within 5 
days if life-threatening, and within 15 days otherwise. Expected or non-serious adverse events 
will be reported at the time of continuing review.
Risk-benefit assessment
This study poses not more than minimal risk and has the potential for high-impact findings 
and direct clinical significance for patients with PD. Therefore, we think that the risk-benefit 
ratio for this study is reasonable given the potential benefits. 
2.3.2
Potential Benefits
Immediate potential benefits 
Subjects with PD in the experimental group will most likely experience a direct benefit 
from the mental imagery intervention in terms of improvement in cognitive functioning in 
everyday life. Similarly, subjects with PD in the active control group will most likely experience 
a direct benefit from psychoeducation in terms of gathering information about cognitive 
problems experienced in PD and management and coping strategies. 
Long-Range Potential benefits
The knowledge gained from this study will facilitate the design and implementation of a 
phase 2 clinical trial. Ultimately, it is highly likely that mental imagery training will be 
incorporated into cognitive rehabilitation programs and will lead to improvements in the 
treatment of cognitive problems of individuals with PD.
3
Study Purpose and Objectives
3.1
Hypotheses
We hypothesize that our 6-week mental imagery training protocol will improve goal-
directed cognitive functioning in everyday life of PD patients. Furthermore, we predict the 
effects of mental imagery will increase task-specific whole-brain functional connectivity and 
improved differentiation of core brain networks. We hypothesize that the training effects on A) 
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goal-directed cognitive functioning and B) functional network re-organization will be sustained 
over the course of 12 weeks post-intervention in the PD-MI group, but not in the PD-Con 
group. 
Lastly, we hypothesize that the putative task-specific within- and between-network 
functional connectivity changes in the PD-MI group at the 6- and 12- week timepoints will 
predict the corresponding self-reported, performance-based, and executive function test 
outcomes.
3.2
Primary Objective 
The primary objective of this study is to determine whether mental imagery training will 
improve goal-directed cognitive functioning in everyday life and brain functional connectivity 
in patients with PD.  
3.3
Secondary Objective 
The secondary objective is to determine whether the behavioral and imaging effects (as 
outlined in the primary objective) of mental imagery training are sustained after a 12-week 
period in patients with PD. A final exploratory objective is to determine if there is a potential 
brain-cognition link to predict the corresponding cognitive functional outcomes. 
4
Study Design
4.1.1
General Design Description
We will conduct a phase 1 clinical trial with two groups randomly assigned in parallel. The 
experimental group (PD-MI) will receive mental imagery training and the control group (PD-
Con) will receive psychoeducation (see Figure 3). 
Within two weeks of obtaining consent and completing initial phone and online video-
screening, subjects will complete online surveys and arrive for an in-person visit to complete 
the screening process including the comprehensive evaluation of baseline cognitive 
functioning, performance-based tests, and neurological exam. At the end of this visit, eligible 
subjects will be randomized to two groups, PD-MI and PD-Con. 
Within two weeks of Visit 1, subjects will return for Visit 2 to assess baseline imagery skills 
and perform fMRI tasks in the scanner. Subjects in the PD-MI group will be interviewed in Visit 
2 to gather information about their daily activities and goals for imagery script development.
Following Visit 2, subjects will start their respective trainings for 6 weeks. The one-on-one 
training sessions will be delivered via videoconferencing.
We will guide the subjects in the PD-MI group using personalized scripts during one-on-
one mental imagery training 3 times a week for the first 4 weeks. We will also record the mental 
imagery scripts (each 5-10 min) for self-practice on none-training days in the first 4 weeks and 
for daily homework in the subsequent 2-week block. After each daily practice in the 2-week 
block, subjects will be asked to submit a detailed mental imagery diary via the Yale REDCap 
online survey platform. Subjects will also be called once a week in the 2-week block for check-
in.
The control group (PD-Con) will receive psychoeducation 3 times a week for 4 weeks 
regarding cognitive functioning and brain health in PD.  Subjects will receive private video links 
with pre-recorded PowerPoint lectures covering topics such as basic brain anatomy, 
neuroplasticity, attention-executive function, memory, speech-communication, hallucinations 
and delusions, sleep, diet, physical activity, mood disorders, stress, and social bonds. On no-
lecture days and in the subsequent 2-week block, subjects will receive online quizzes covering 
the lecture topics to be completed via Yale REDCap online survey platform. Subjects will also 
be called once a week in the 2-week block for check-in.
Upon completion of the 6-week training, all subjects will return for Visit 3 which will entail 
repeat cognitive evaluations and performance-based tests as in Visit 1, and mental imagery 
vividness rating and fMRI scans as in Visit 2. After Visit 3, subjects in the PD-MI group will be 
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encouraged to incorporate goal-directed mental imagery into their daily life and those in the 
PD-Con group will be encouraged to retain the psychoeducation material they learnt. 
Twelve weeks after Visit 3, all subjects will return for Visit 4 which will be the final visit and 
entail repeat evaluations of all cognitive and performance-based tasks and the fMRI tasks. 
The same procedures as described in Visit 3 will be followed.
Figure 3. Study Flow
Screening for:
-MRI safety
-Medical history
-Global cognition
-Functional abilities
Visit 1
-MDS-UPDRS
-Cognitive tests
-Performance-based tests
Randomization
PD-MI
PD-Con
Visit 2
-Mental imagery assessment
Scans:
-Mental imagery (x4)
-Video watching (x4)
Visit 3
-Mental imagery assessment
-Cognitive tests
-Performance-based tests
Scans:
-Mental imagery (x4)
-Video watching (x4) 
Visit 4
Same as in Visit 3, 12 wks later
Online Surveys
anxiety, depression, apathy, 
fatigue, sleepiness, quality of life
mental imagery training (4 wks)
 psychoeducation (4 wks)
mental imagery homework (2 wks) 
psychoeducation homework (2 wks)
4.1.2
Study Date Range and Duration
The expected length of the study is 6 years. See Table 1 below for the study timeline. 
Table 1. Study Timeline
Year 1
Data collection and analysis for primary objectives. Start data analysis for secondary objectives.
Year 2
Data collection and analysis for primary and secondary objectives. 
Year 3
Wrap up data analysis of primary objectives. Start writing manuscripts.
Year 4
Complete data collection. Wrap up data analysis for secondary objectives. Continue writing 
manuscripts.
Years 
5-6
Complete all statistical analyses. Present and publish findings. Propose mental imagery training 
manual. Refine the study procedures and start implementing the phase 2 trial.
4.1.3
Number of Study Sites
The Yale School of Medicine campus will be the only study site. Research procedures will 
take place at two sites: The Yale Magnetic Resonance Research Center (MRRC) and the Yale 
Center for Clinical Investigation (YCCI) Church Street Research Unit. The YCCI Research 
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Unit will be used as a backup for some of the longer clinical and psychometric evaluations 
(e.g., Visit 1).  
4.2
Outcome Variables
4.2.1
Primary Outcome Variables
1) Quality of life in Neurological Disorders (Neuro-QoL) Scores
Timeframe: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.  
Rationale: The Neuro-QoL is a set of self-report measures that assesses the health-related 
quality of life of adults and children with neurological disorders. Neuro-QoL instruments were 
developed through a collaborative, multisite NINDS-sponsored research initiative to construct 
psychometrically-sound and clinically-relevant health-related quality of life measurement tools 
for individuals with neurological conditions including PD. The Neuro- QoL instruments enable 
within-disease as well as cross-disease comparisons and are intended for use in both 
neurology clinical trials and clinical practice. We will use the Neuro-Qol version 2 Cognitive 
Function item bank to assess post-training self-reported changes in cognitive functions.
Change in the Neuro-Qol version 2 Cognitive Function scores from T0 to T1 and across T2 
will be the primary cognitive outcomes of this study. Significant increase in the Cognitive 
Function scores at T1 will be considered significant improvement in self-reported cognitive 
function in everyday life. Significant increase in these scores across T2 will be considered 
sustained improvement in self-reported cognitive function in everyday life.
2) Questionnaire on Mental Imagery (QMI) Vividness of Imagery Scale scores
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: The QMI is a measure of vividness of an individual’s multisensory and motor 
imagery on a scale of 1 to 7 (1: perfectly vivid image, 7: no image present at all).  
Change in the QMI scores from T0 to T1 and across T2 will serve as the manipulation check 
for the mental imagery intervention. Significant increase in these scores at T1 will be 
considered improved imagery vividness. Significant increase in these scores across T2 will be 
considered sustained improvement in imagery vividness. 
3) Task-specific whole-brain pairwise functional connectivity
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will calculate the whole-brain pairwise functional connectivity during mental 
imagery and video-watching of naturalistic goal-directed tasks in the MRI scanner for each 
subject. 
Change in task-specific pairwise functional connectivity from T0 to T1 and across T2 will be 
the primary imaging outcomes of the study. Significantly increased task-specific pairwise 
functional connectivity in major networks (e.g., default mode network during mental imagery 
and frontoparietal executive network during video-watching) at T1 will be considered improved 
task-specific functional reorganization of these networks. Significantly increased task-specific 
pairwise functional connectivity in major networks across T2 will be considered sustained 
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improvement in task-specific functional reorganization of these networks.
4.2.2
Secondary and Exploratory Outcome Variables 
1) Composite executive function test scores (Secondary)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will calculate the composite z-scores of the executive function test scores (i.e., 
Stroop, F-A-S letter fluency, and Trail Making A-B tests) for all subjects. 
Change in composite executive function test scores from T0 to T1 and across T2 will be the 
secondary cognitive outcomes of the study. Significant increase in these scores at T1 will be 
considered improved executive function. Significant increase in these scores across T2 will 
be considered sustained improvement in executive function.
2) Local and global functional connectivity-based graph measures (Secondary)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will calculate the local (i.e., clustering coefficient) and global (i.e., betweenness 
centrality) network graph measures during mental imagery and video-watching tasks in the 
MRI scanner. These measures will provide information about the context-dependent changes 
in the functional organization of the brain networks. 
Change in graph measures from T0 to T1 and change in graph measures across T2 will be 
secondary imaging outcomes the study. Significantly increased task-specific clustering 
coefficient in major networks (e.g., default mode network during mental imagery and 
frontoparietal executive network during video-watching) and significantly increased context-
dependent betweenness centrality between major network nodes (e.g., stronger between the 
default mode and frontoparietal networks during mental imagery) at T1 will be considered 
improved task-specific functional differentiation of these networks. Significant increases in the 
same graph measures across T2 will be considered sustained improvement in task-specific 
functional differentiation of these networks.
3) Modified Six-Elements Test scores (Exploratory)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: The Modified Six-Elements Test is a measure of goal-directed planning and 
execution.
Change in these test scores from T0 to T1 and across T2 will be the secondary cognitive 
outcomes of the study. Significant increase in these scores at T1 will be considered improved 
performance in goal-directed planning and execution. Significant increase in these scores 
across T2 will be considered sustained improvement of performance in goal-directed planning 
and execution.
4) Global cognition scores (Exploratory) 
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
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Rationale: The Repeated Battery for the Assessment of Neuropsychological Status (RBANS) 
is a commonly used battery with alternate versions allowing repeated testing of the cognitive 
domains of attention, verbal and visual memory, language, and visuospatial functioning. 
Change in total RBANS scores from T0 to T1 and across T2 will be the exploratory cognitive 
outcomes of the study. Significant increase in these scores at T1 will be considered improved 
global cognition. Significant increase in these scores across T2 will be considered sustained 
improvement of global cognition.
5) Post-training brain-cognition relationship (Exploratory)
Time frame: This measure will be collected at baseline (T0), immediately after 6 weeks of 
intervention (T1), and 12 weeks thereafter (T2) from all subjects.
Rationale: We will examine whether the post-training changes in whole-brain pairwise 
functional connectivity and graph measures will predict the post-training differences in the 
cognitive function in each group at T1 and T2. 
4.3
Study Population
The study population will be subjects with PD defined according to the Movement 
Disorders Society (MDS) diagnostic criteria with mild-to-moderate PD75, who do not have mild 
cognitive impairment76, aged 40 and above, and are physically independent.
Idiopathic PD is an adult-onset neurological disorder. In the United States, the incidence 
of idiopathic PD cases before the age of 40 is extremely low.77 Therefore, individuals with PD 
who are 40 years and older will be included, and there will be no upper age limit for 
participation in the study. 
There is no restriction for gender, race, or ethnicity. Parkinson’s disease affects more 
males than females with most studies reporting a male-to-female ratio ranging from 1.3 to 2.78 
We will aim to reflect a male-to-female ratio of 1.5 in subject selection. 
There is no restriction in participation regarding race or ethnicity. We will seek a racially 
and ethnically diverse enrollment. According to the United States Census Bureau, the 2020 
census demographic data in Connecticut showed the following distribution:79 White only 
66.4%, Black only 10.8%, Asian only 4.8%, Hispanic or Latino 17.3%. The percentage of other 
racial categories was very small. The numbers in the planned enrollment table were calculated 
based on these ratios. 
Subjects will be recruited through:
1.
The Yale Movement Disorders outpatient clinics
2.
The outpatient clinics in the new Yale PD Comprehensive Care Center
3.
The local PD support groups and nonprofit organizations (e.g., American PD 
Association Connecticut Chapter, Beat PD Today exercise program) that provide 
educational and wellness programs for the greater PD community in Connecticut
4.
Neurology practices in Connecticut who care for patients with PD. 
5.
JDAT recruitment services (EPIC/MyChart alerts & mailing)
6.
Department/Center newsletters
7.
The YCCI recruitment database
8.
Recruitment letters
Table 2. Planned Enrollment  
Not Hispanic or Latino
Hispanic or Latino
Total
F
M
F
M
American Indian/Alaska Native 
0
0
0
0
0
Asian
2
3
0
0
5
Native Hawaiian or other Pacific Islander
0
0
0
0
0
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Black or African American
5
8
1
1
15
White
32
47
9
12
100
More than one race
0
0
0
0
0
4.3.1
Number of Participants
We will enroll 120 individuals. Eligible subjects will be randomly assigned to either the PD-
MI (N=60) or PD-Con (N=60) group.
4.3.2
Eligibility Criteria/Vulnerable Populations
In order to be eligible for inclusion in the study, an individual must meet all of the following 
criteria: 

Subjects with a diagnosis of idiopathic PD defined according to the International 
Parkinson and Movement Disorder Society (MDS) Clinical Diagnostic Criteria for PD75

Age ≥ 40 years

Expected to be on a stable dopaminergic medication regimen throughout the study 
period
Any individual who meets any of the following criteria will be excluded from participation 
in this study: 

Age < 40 years

Non-English speaking

Pregnancy 

Breastfeeding

Excessive alcohol consumption (> 7 drinks per week for women, > 14 drinks per week 
for men) or illicit substance use

History of a neurological disorder such as a brain tumor, stroke, central nervous system 
infection, multiple sclerosis, movement disorder (other than PD), or seizures

History of schizophrenia, bipolar disorder, attention deficit disorder, or obsessive-
compulsive disorder 

History of head injury with loss of consciousness longer than a few minutes

Metallic surgical implants or traumatically implanted metallic foreign bodies

Inability to lie flat for about an hour in the MRI scanner

Discomfort being in small, enclosed spaces

Dementia at screening (Video-Montreal Cognitive Assessment score < 21/3080-82

Cognitive problems in activities of daily living suggestive of more than mild cognitive 
impairment (PD Cognitive Functional Rating Scale > 483)

Mild cognitive impairment according to the MDS Level II comprehensive assessment 
criteria (> 2 SD below the norm in two tests in a single cognitive domain or in one test 
in two separate cognitive domains). Note: The cutoff of 2 SD below the norm will apply 
to all domains including attention, verbal and visual memory, language, visuospatial 
skills, and executive functions.76 

Hoehn & Yahr stage > 3 (i.e., able to stand and walk, but not fully independent84)

Focal neurological findings on exam that suggest cerebral pathology other than that 
associated with parkinsonism

Motor symptoms that could potentially introduce too much motion artifact in the 
imaging data (e.g., MDS-Unified PD Rating Scale resting tremor score > 2 in limbs, 
head/chin tremor, or more than mild dyskinesia by history or exam85) 

Failure to adhere to training and homework requirements (i.e., less than 75% 
adherence to one-on-one sessions and less than 50% homework completion rate)
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
Failure to adhere to protocol 
Vulnerable Populations: 
Women of childbearing potential will not be included, if they are pregnant or 
breastfeeding. Women who are 50 years of age and older or who have absence of menses 
for two years will not receive pregnancy tests. All other women will receive urine pregnancy 
test in two weeks before the scheduled MRI session.
5
Study Methods/Procedures 
5.1
Study Procedures
All study procedures will be performed for research purposes. 
Recruitment: 
We will recruit individuals with PD directly through the Yale Movement Disorders outpatient 
clinics. The outpatient clinics in the new Yale PD Comprehensive Care Center will also be a 
source of recruitment. PD patients will be informed about the study during their visit at the 
clinics and provided with the study material. Interested patients will be contacted directly by 
the study team for initial screening.  
We will also attend meetings at the local PD support groups and nonprofit organizations 
(e.g., American PD Association Connecticut Chapter, Beat PD Today exercise program) that 
provide educational and wellness programs for the greater PD community in Connecticut to 
present the proposed study to potential subjects.    
Recruitment flyers will also be mailed to the providers at the neurology practices in 
Connecticut who care for patients with PD. Letters including study flyers will also be mailed to 
interested candidates.
In addition, the recruitment services at the YCCI will be used. Specifically, we will be 
utilizing the YCCI recruitment database. YCCI has an ever growing “Help us Discover” 
database of more than 14,000 individuals who have expressed interest in clinical research at 
Yale. Emails are sent periodically to the group to maintain engagement and research interest. 
Researchers and study teams have found the communications have increased interest and 
clinical trial recruitment after each YCCI email campaign.
We will also make use of the recruitment services offered by JDAT (EPIC/MyChart alerts 
& mailing) and Department/Center newsletters.
Consent 
Verbal consent will be obtained for the screening visit over the phone or via email. 
Electronically signed informed consent will be obtained at the beginning of the video screening 
visit. A member of the research team authorized to obtain consent will give the subjects 
detailed information about the study and go over all aspects of the research. The purpose, 
research procedures, any risk that these procedures might entail, and any possible benefits 
will be discussed in detail in language appropriate for the individual’s level of understanding. 
Subjects will be encouraged to ask questions and given enough time to discuss any aspect of 
the study with the research team. Subsequently, they will have to demonstrate understanding 
of the study procedures and what is expected of them. Once subjects understand the study, 
they will be asked if they wish to participate. If they do, they will be asked to electronically sign 
the consent form. 
Capacity will be assessed directly in the course of attempting to obtain informed consent. 
When the member of the research team authorized to obtain consent has reviewed the study, 
they will ask the subject to explain the major elements of the study. Those elements are a) 
this is a research study (not routine treatment), b) participation is voluntary, c) study 
procedures, d) risks, e) benefits. Open-ended questions such as “Can you tell me the main 
things that you would do in this study? Can you tell me the main risks of the study?” will be 
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used to assess understanding and appreciation of the facts. Subject will then be expected to 
make a rational choice: “Considering the risks and benefits we have discussed, would you like 
to take part in this study?” Based on the subject’s responses the team member will make a 
final judgment about capacity for consent. If the subject has capacity and agrees to the study, 
they will sign the consent form
Study Schedule
See also Figure 4 for study schedule and timeline. 
Initial Screening: After obtaining verbal consent, subjects will complete an initial phone call 
screening for MRI safety and medical history. If the subject fails the MRI safety screening or 
meets any of the exclusion criteria for medical history, they will be excluded from the study. 
Subjects who are still eligible will be scheduled for a follow-up video-screening via the Zoom 
videoconferencing platform. Consent process will take place at the beginning of this visit. 
Subjects will electronically sign the consent form via REDCap. The screening will be for 
demographic data, global cognition, and functional abilities. We will administer the MoCA to 
assess global cognition.80 We will use the PD Cognitive Functional Rating Scale for daily 
functional abilities.83 If a subject scores below the eligibility criteria of our screening, they will 
be excluded from the study and their data will not be used.
Figure 4. Study Timeline.
All subjects
• Movement exam
• Cognitive tests
• Performance-
based tasks
All subjects
• Mental imagery survey
fMRI Scans
• Mental imagery (x4)
• Video-watching (x4)
• MRI safety
• Medical history
• Global cognition
• Functional abilities
≤2 weeks
≤2 weeks
Training
4 weeks
12 weeks
Screening
Online surveys
Visit 1
Visit 3
Visit 4
Visit 2
Randomization
Homework
2 weeks
All subjects
• Cognitive tests
• Performance-based
tasks
• Mental imagery
survey
fMRI Scans
• Mental imagery (x4)
• Video-watching (x4)
All subjects
• Cognitive tests
• Performance-based
tasks
• Mental imagery
survey
fMRI Scans
• Mental imagery (x4)
• Video-watching (x4)
Mental Imagery
Group
Psychoeducation
Group
Respective Interventions
6 weeks
Online Surveys: To evaluate the contribution of nonmotor factors to cognitive functioning, the 
Geriatric Depression Scale,86 Parkinson Anxiety Scale,87 Starkstein Apathy scale,88 PD Quality 
of Life Questionnaire-39,89 Parkinson Fatigue Scale,90 and Scales for Outcomes in Parkinson’s 
Disease – Sleep91 via the Yale REDCap online survey platform to those who pass the initial 
screening. 
Visit 1: Baseline movement and cognitive evaluations to determine eligibility and baseline 
performance-based tasks: Visit 1 will be scheduled within two weeks after initial screening to 
complete the screening process. We will determine the disease severity with the MDS-Unified 
PD Rating Scale (MDS-UPDRS)85 that also includes  the Hoehn & Yahr staging.83 We will 
administer the Wechsler Test of Adult Reading92 to determine premorbid IQ, and perform a 
comprehensive cognitive evaluation to rule out MCI according to the MDS Level II criteria76 
using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)93 
and additional tests to assess frontal-executive functioning including the Stroop Test,94 letter 
fluency (F-A-S),95 and Trail Making Test parts A and B.96 The tests will be scored immediately 
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to determine eligibility. Eligible subjects will be randomized to two groups: PD-MI and PD-Con.
Brief description of the tests:
Weschler Test of Adult Reading: Is an assessment of intelligence that has participants 
pronounce 50 irregularly spelt words. The test typically takes 5-10 minutes to complete. 
RBANS: Assesses 5 domains of cognition, 1) immediate memory, 2) Visuospatial/
Constructional, 3) Language, 4) Attention, 5) Delayed Memory. Completion time is roughly 
30 minutes. 
Stroop test: Is a measure of attention that has the participant read through a list of words or 
naming colors as quickly as possible within 45 seconds. 
F-A-S verbal fluency test: Measures verbal fluency by having the participant verbally 
produce as many words as possible that begin with the letters F, A, and S, within a one-
minute timespan. 
Trail Making Tests A & B: Consist of 25 circles spread over a sheet of paper, the subject is 
tasked with connecting each circle by following a specific pattern in a 5-minute timespan. 
For all eligible subjects: We will administer the Neuro-QoL version 2 Cognitive Function 
survey to eligible subjects to assess self-reported cognitive functioning in everyday life.97 We 
will administer the Modified Six-Elements Test.98 The test consists of three tasks (simple 
arithmetic, written picture naming, dictation) each of which has two subtasks. The subject is 
required to attempt at least part of each of the six subtasks within 10 min, but without switching 
directly between subtasks within the same task category. The tests assess the ability to create 
and maintain goals and intentions, formulate a plan, organize behavior over time, and execute 
the plan at appropriate times.99 
For eligible subjects in the PD-MI group: We will perform a structured cognitive interview 
to determine the subject’s cognitive difficulties during everyday tasks. Information gathered 
from this interview will help with personalized mental imagery guidance. 
Visit 2: Baseline neuroimaging experiments: Visit 2 will be scheduled within two weeks 
following Visit 1. All subjects will complete the Questionnaire upon Mental Imagery (QMI) 
Vividness of Imagery Scale100 for evaluation of baseline imagery skills. All subjects will then 
perform fMRI tasks in the scanner. The mental imagery tasks will always be performed before 
the video-watching tasks to avoid possible carryover effects from the videos.
Mental imagery tasks: All subjects will receive instructions on how to perform mental imagery 
of goal-oriented daily tasks and practice guided imagery first outside the scanner. Subjects 
will then perform mental imagery of four different goal-oriented tasks in the scanner. We will 
keep the goals constant across subjects, but will not prescribe the specific steps or events. 
After each imagery run in the scanner, subjects will give an account of their imagery content 
which will be recorded.
Video-watching tasks: All subjects will also watch videos of four different everyday tasks (e.g., 
grocery shopping, preparing a meal) in the scanner. After each video-watching run in the 
scanner, subjects will answer questions about the content of the videos.
Scanning procedures: We will conduct the MRI experiments in a Siemens Prisma 3.0 Tesla 
human research magnet with a 64-channel head coil in the MRRC. First, T1-weighted high-
resolution MPRAGE anatomical images (voxel size: 1 x 1 x 1 mm) will be collected for an 
accurate localization of the fMRI data. Then, axial, T2*-weighted, echo planar functional 
images will be collected (voxel size: 3.5 x 3.5 x 4 mm, 36 slices, FoV: 224 mm, TR: 2000 ms, 
TE: 25 ms, flip angle: 90). There will be four mental imagery and four video-watching runs 
each lasting 4 min 18 s. During the mental imagery tasks, subjects will keep their eyes closed 
at all times and receive auditory instructions. During the video-watching runs, subjects will 
keep their eyes open and receive visual instructions. 
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Training period
Mental Imagery Training: Subjects in the PD-MI group will receive personalized training 
during one-on-one sessions 3 times a week for the first 4 weeks. Training will be offered via 
Zoom. Subjects will be guided to mentally simulate the planning and implementation of 
everyday tasks (e.g., going grocery shopping). The training sessions will last about 15-20 min. 
We will also record the mental imagery scripts for self-practice on no-training days in the first 
4 weeks and for daily homework practice in the subsequent 2-week block. After practice, 
subjects will be asked to submit a detailed daily mental imagery diary via the Yale REDCap 
online survey platform. We will structure this diary based on the key elements of mental 
imagery including the setting of the activity, components of the activity, contextual cues, 
episodic details, emotional experiences, and vividness and difficulty level of the mental 
imagery exercise. Subjects will also be called once a week in the last 2 weeks for check-in.  
Psychoeducation: Subjects in the PD-Con group will receive psychoeducation 3 times a 
week for 4 weeks regarding cognitive functioning and brain health in PD.  Subjects will 
receive private video links with pre-recorded PowerPoint lectures covering topics such as 
basic brain anatomy, neuroplasticity, attention-executive function, memory, speech-
communication, hallucinations and delusions, sleep, diet, physical activity, mood disorders, 
stress, and social bonds. The lectures will last about 15-20 min and will be accompanied by 
three multiple-choice questions to be completed via REDCap online survey platform to 
assess content comprehension. On no-lecture days in the first 4 weeks and in the 
subsequent 2-week block, subjects will receive quizzes covering the lecture topics to be 
completed via REDCap online survey platform. Subjects will also be called once a week in 
the last 2 weeks for check-in.  
Visit 3: Short-term outcome visit. Upon completion of the 6-week training, all subjects will 
return for repeat 1) mental imagery assessment using the QMI, 2) cognitive evaluation using 
a different form of the RBANS and the frontal-executive tests, 3) Neuro-QoL survey, 4) 
Modified Six-Element Test, and 5) fMRI scans while performing mental imagery and video-
watching of the same goal-directed daily tasks as in Visit 2. We will use modified versions of 
the videos to minimize learning effects. After Visit 3, subjects in the PD-MI group will be 
encouraged to incorporate goal-directed mental imagery into their daily life. Subjects in the 
PD-Con group will be encouraged to retain the psychoeducational information.
Visit 4: Long-term outcome visit. This will be the final visit. Twelve weeks after Visit 3, all 
subjects will return for repeat cognitive and imaging evaluations. The same procedures as 
described in Visit 3 will be followed. 
5.1.1
Data Collection 
The data will be collected specifically for this project. The information obtained in this study 
will be recorded in such a manner that the identity of the human subjects cannot be 
ascertained directly. The data will not contain personally identifiable information and will be 
labeled using a coding system. The data labels will contain the subject code, date and time of 
recording, and mode and condition of recording. Only the principal investigator, Sule Tinaz, 
will have access to the centrally and electronically stored and password-protected subject 
identification list to decode data files. All other study investigators will have access to the de-
identified data. All study investigators will use encrypted research computers.
Data Recording
Case report forms for each subject will be used to enter clinical evaluation results, and 
scores of paper-pencil tests, surveys, and performance-based tests. All of this information will 
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then be entered into a password-protected electronic database, which will be stored in a 
group-owned (Tinaz Lab) shared space on a Yale REDCap database. This is a is a secure 
web application for building and managing online surveys and databases. It is specifically 
geared to support online or offline data capture for research studies and operations.
Imaging data obtained at the MRRC will be transferred securely to workstations for 
analysis and stored on HIPAA-compliant secure central storage servers (“Storage@Yale”) 
provided by the Yale IT Department for a monthly fee. All team members will use encrypted 
research computers.
Sources of Data
Initial Screening: Data will be collected at meetings with the subjects via phone call and Zoom 
video platform. 

Demographic data (age, sex, ethnicity, level of education, etc.)

MRRC MRI safety questionnaire 

Medical history questionnaire 

MoCA test for global cognition

PD Cognitive Functional Rating Scale for daily functional abilities 
Online Surveys: These surveys will be administered via the Yale REDCap online survey 
platform to those who pass the initial screening. The selected surveys aim to evaluate the 
contribution of nonmotor factors (e.g., mood disorders, fatigue) to cognitive functioning. The 
survey data will be exported from REDCap.

Geriatric Depression Scale 

Parkinson Anxiety Scale 

Starkstein Apathy scale 

PD Quality of Life Questionnaire-39

Parkinson Fatigue Scale 

Scales for Outcomes in Parkinson’s Disease – Sleep  
Online Homework and Quizzes: These will administered via the Yale REDCap online survey 
platform. Responses will be exported from REDCap.

Quizzes on the psychoeducation material for the PD-Con group

Surveys on the content of mental imagery homework for the PD-MI group
Clinical and Cognitive Evaluations: 

MDS-UPDRS and Hoehn & Yahr to assess disease severity (Visit 1)

Wechsler Test of Adult Reading to determine premorbid IQ (Visit 1)

RBANS test and executive function tests (Stroop, letter fluency (F-A-S), and Trail 
Making Test parts A and B) for a comprehensive cognitive evaluation (Visits 1, 3, and 
4)

Neuro-QoL survey (primary cognitive outcome) to assess the impact of cognitive 
functioning on activities of daily living (Visits 1, 3, and 4)

Structured cognitive interview for the PD-MI group to determine subjects’ cognitive 
difficulties during everyday tasks (Visit 1)

QMI Vividness of Imagery Scale will serve as a manipulation check for the mental 
imagery intervention (Visits 2, 3, and 4)
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
Modified Six-Elements Test as a performance-based measure of goal-directed 
planning and execution (Visits 1, 3, and 4)
Case report forms for each subject will be used to enter clinical evaluation results, and 
scores of paper-pencil tests, online surveys, and performance-based tests. All of this 
information will then be entered into a password-protected electronic database, which will be 
stored in a group-owned (Tinaz Lab) shared space on a Yale REDCap database. 
Imaging Data:
Functional MRI data during mental imagery and video-watching tasks will be collected in 
a 3 Tesla human magnet at the MRRC (Visits 2, 3, and 4). The fMRI data will be used for 
functional connectivity analyses to evaluate the changes in whole-brain functional connectivity 
(primary imaging outcome) and other network measures as a result of the mental imagery 
intervention. 
Imaging data will be transferred securely to workstations for analysis and stored on HIPAA-
compliant secure central storage servers (“Storage@Yale”) provided by the Yale IT 
Department for a monthly fee. 
5.1.2
Adverse Events Definition and Reporting
An Adverse Event will be defined as any untoward or unfavorable occurrence in a human 
research subject (physical or psychological harm) temporally associated with the individual’s 
participation in the research (whether or not considered related to participation in the 
research).
Attribution of Adverse Events: 
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design by the principal investigator, Dr. Tinaz, according 
to the following categories: 
Definite: Adverse event is clearly related to investigational procedures
Probable: Adverse event is likely related to investigational procedures
Possible: Adverse event may be related to investigational procedures
Unlikely: Adverse event is likely not to be related to the investigational procedures 
Unrelated: Adverse event is clearly not related to investigational procedures 
Plan for Grading Adverse Events: 
The severity of adverse events noted during the study will be graded as mild, moderate, 
or serious.
Plan for Determining Seriousness of Adverse Events 
In addition to grading the adverse event, the principal investigator will determine whether 
the adverse event meets the criteria for a Serious Adverse Event (SAE). An adverse event is 
considered serious if it results in any of the following outcomes: 
1- Death
2-A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization;
3-A persistent or significant disability or incapacity;
4-A congenital anomaly or birth defect; OR
5-Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of the 
other outcomes listed in this definition. 
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An adverse event may be graded as severe but still not meet the criteria for a SAE. 
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. 
The principal investigator will consider the grade of the event as well as its “seriousness” when 
determining whether reporting to the IRB is necessary. 
Reporting of Adverse Events
Adverse events will be reported in accordance with federal and Yale University IRB rules. 
For each adverse event, the principal investigator, Dr. Tinaz, will record the onset, end, 
intensity, required treatment, outcome, seriousness, and action taken. Serious or unexpected 
adverse events will be reported to the Yale University IRB, within 5 days. Expected or non-
serious adverse events will be reported at the time of continuing review. 
We will submit information summarizing the number and frequency of adverse events 
experienced by participants in each group, regardless of whether or not they were anticipated 
or unanticipated. We will also provide the time frame for adverse event data collection and 
specify whether the collection approach for adverse events was systematic or non-systematic.
5.2
Study Schedule
See also Figure 4 for study schedule. 
Verbal consent will be obtained for the initial screening visit over the phone or via email 
when the potentially eligible subject is first contacted.  Electronically signed informed consent 
will be obtained at the beginning of the initial Zoom video screening visit via REDCap. 
Time estimate for initial screening: 1 hour
There will be a total of 4 in-person visits:
Visit 1: Baseline Clinical Evaluation. Subjects will undergo detailed clinical evaluations to 
determine disease severity and level of cognitive functioning.
Time Estimate: 3 hours 
Visit 2: Baseline Neuroimaging Experiments. Subjects will rate their mental imagery vividness 
at baseline and perform fMRI tasks in the scanner. Subjects will also receive instructions on 
their respective training and homework assignments. 
Time Estimate: 2 hours 
Training: Subjects will receive their respective training 3 times per week for 4 weeks. On non-
training days during the week and in the subsequent 2-week block, subjects will complete 
homework. 
Visit 3: 6-Week Post-Intervention Assessments. All subjects will return for repeat cognitive 
evaluations as in Visit 1, and mental imagery vividness rating and fMRI scans as in Visit 2. 
Time Estimate: 3 hours
Visit 4: 12-Week Post-Completion Assessments. All subjects will return for repeat cognitive 
evaluations and fMRI tasks. The same procedures as described in Visit 3 will be followed.
Time Estimate: 3 hours
5.3
Informed Consent
Consent forms describing in detail the study intervention, study procedures, and risks will be 
given to the participants and written documentation of informed consent will be required prior 
to starting intervention/administering study intervention. Consent form will be emailed to the 
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research participant. The authorized study member will obtain consent electronically at the 
start of the initial screening visit via Zoom. 
The written consent form is submitted with this protocol.
5.3.1
Screening 
The research assistant, Jared Cherry, will screen subjects over the phone for MRI safety 
and medical history. Eligible subjects will then be scheduled for a Zoom online video platform 
call to electronically sign the consent form via REDCap and undergo video-screening for 
demographic data, global cognition, and functional abilities. The initial screening will last 
approximately 1 hour.  
5.3.2
Recruitment, Enrollment and Retention 
Recruitment 
We will recruit individuals with PD directly through the Yale Movement Disorders 
outpatient clinics. The outpatient clinics in the new Yale PD Comprehensive Care Center will 
also be a source of recruitment. Potentially eligible PD patients will be informed about the 
study during their visit at the clinics and provided with the study flyer. Interested patients will 
be contacted directly by the study team for initial screening. More specifically, Dr. Tinaz and 
Dr. Vives-Rodriguez are both movement disorders neurologists who have a direct or indirect 
treatment relationship with PD patients in the Yale Movement Disorders Clinics. They (or the 
research assistant Jared Cherry) will inform the patients with whom they have a direct 
treatment relationship either during clinic visits or via phone. Dr. Tinaz and Dr. Vives-
Rodriguez will review the EPIC clinic visit progress notes of PD patients with whom they are 
not in a direct treatment relationship to determine eligibility (based on DOB, sex, past 
medical history, and movement exam scores). They will then ask the treating movement 
disorders neurologists in their practice to inform these potentially eligible PD patients about 
the study and ask them for permission to release contact information. 
We will also attend meetings at the local PD support groups and nonprofit organizations 
(e.g., American PD Association Connecticut Chapter, Beat PD Today exercise program) that 
provide educational and wellness programs for the greater PD community in Connecticut to 
present the proposed study to potential subjects.    
Recruitment flyers (see attached) will also be mailed to the providers at the neurology 
practices in Connecticut who care for patients with PD. Letters including study flyers will also 
be mailed to interested candidates who have agreed to be contacted by the study 
investigators. 
In addition, the recruitment services at the YCCI including the YCCI clinical trials website 
and the YCCI social media support will be used to advertise the study. The same language in 
the study flyer will be used for advertisements. We will also utilize the YCCI recruitment 
database. YCCI has an ever growing “Help us Discover” database of more than 14,000 
individuals who have expressed interest in clinical research at Yale. Emails are sent 
periodically to the group to maintain engagement and research interest. Researchers and 
study teams have found the communications have increased interest and clinical trial 
recruitment after each YCCI email campaign.
Lastly, we will also make use of the recruitment services offered by JDAT (EPIC/MyChart 
alerts & mailing) and Department/Center newsletters.
Enrollment
See Table 2. Planned Enrollment and explanations in Section 4.3. 
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Retention
We will ensure that the logistics of the study is straightforward in order to maximize subject 
compliance and retention. The Yale MRRC and YCCI are located in the Yale School of 
Medicine campus in close proximity to each other. No other research sites will be involved. 
We will email subjects the video link of a virtual tour of the MRRC and YCCI outpatient facility, 
so that they can familiarize themselves with the research sites (lobby, waiting area, behavioral 
testing rooms, scanner rooms, etc.) prior to their visit. Subjects will also be provided written 
directions and maps to the research site. Parking is always available in two garages near both 
research sites. Subjects who do not feel comfortable driving and have nobody else to drive 
them will be offered transportation. Subjects will be compensated for their participation and for 
travel expenses (e.g., parking, cab ride). 
The one-on-one mental imagery training for the experimental group and psychoeducation 
for the control group will be administered via the Zoom video platform and private video links, 
respectively, eliminating the burden of in-person visits on the subjects. The video visits will be 
scheduled at convenient times for the subjects. Several surveys will also be administered 
online via the Yale REDCap survey platform, which will provide the subjects with enough time 
and flexibility to fill them out. All subjects will also submit their homework via REDCap, which 
will allow us to monitor compliance in a timely fashion.
At the first screening visit, the study procedures, expectations, and the importance of their 
participation will be explained to subjects in detail and all questions will be answered. Plans 
to minimize risk and discomfort and to ensure safety and confidentiality will be discussed, and 
subjects will be encouraged to ask questions. At their first visit, subjects will receive a study 
folder containing brief descriptions of the study procedures, specific instructions for each 
research visit, calendar of research activities throughout the study period, and appointment 
cards. The subsequent visits will be scheduled considering the best availability of the subjects 
to avoid scheduling conflicts. Regular reminders for upcoming visits will be sent via email 
and/or phone. Subjects will be encouraged to contact the study team via email or phone 
anytime if they had questions, concerns, or requests. 
In our previous imagery study, the dropout rate was approximately 15%. This included 
subjects who did not complete the study and those who were not compliant with homework 
requirements. The dropout rate was not significantly different between the experimental and 
control groups. All others (a total of 44) successfully completed four research visits spanning 
6-8 weeks each of which lasting 2-3 hours. Subjects remained fully compliant and motivated 
throughout the study period. We expect a similar level of compliance and motivation, and not 
more than 15% dropout in the current study. We also considered specific factors regarding 
the control group in the current proposal that will help minimize the attrition rate. The control 
group will be actively engaged in psychoeducation tasks during video lectures and will 
complete homework (quizzes). Time spent with staff during research visits will also be 
matched between the experimental and control groups. We will explain to all subjects that their 
effort and compliance will play a major role in their success and potential benefit from the 
intervention. Therefore, we do not anticipate attrition problems related to subject motivation. 
In our sample size calculations, we have accounted for a 15% dropout rate between visits. 
If we experience a higher rate, we will identify the challenges of study participation and 
determine new or additional ways to facilitate retention (e.g., adjust the start time of visits, offer 
meals during long visits). 
In summary, we believe that the study design and logistics, as well as the resources for 
clinical research available at Yale will allow us to reach the recruitment and retention goals of 
the study within the proposed time frame.  
5.3.3
Study Visits 
Initial Phone Call Screening: 15 minutes 
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Obtain the following information and data: 

MRRC MRI safety questionnaire 

Medical history questionnaire 
Screening via Zoom: 45 Minutes
Obtain the following information and data: 

Electronically signed informed consent 

Demographic data (age, sex, ethnicity, level of education, etc.)

MoCA test 

PD Cognitive Functional Rating Scale 
Online Surveys: self-paced, total of 30 min

Geriatric Depression Scale

Parkinson Anxiety Scale

Starkstein Apathy scale 

PD Quality of Life Questionnaire-39

Parkinson Fatigue Scale 

Scales for Outcomes in Parkinson’s Disease – Sleep
 
There will be a total of 4 in-person visits:  
Visit 1. Baseline Clinical Evaluation: 3 hours
Within two weeks after the initial screening visit. 
Detailed clinical and cognitive evaluations including:

MDS-UPDRS and Hoehn & Yahr 

Wechsler Test of Adult Reading 

RBANS test and executive function tests (Stroop, letter fluency (F-A-S), and Trail 
Making Test parts A and B) 

Neuro-QoL survey 

Structured cognitive interview for the PD-MI group 

Modified Six-Elements Test 

Structured cognitive interview for the experimental PD-MI group
Visit 2. Baseline Neuroimaging Experiments: 2 hours
Within two weeks after Visit 1.

QMI Vividness of Imagery Scale 

Functional MRI scans during mental imagery tasks (x4) and video-watching tasks (x4)

Instructions on respective training and homework assignments. 
Training: Immediately after Visit 2. Mental imagery training and psychoeducation 3 times per 
week for 4 weeks. On non-training days during the week and in the subsequent 2-week block, 
subjects will complete homework. 
Visit 3. 6-Week Post-Intervention Assessments: 3 hours. All subjects will return for repeat 
cognitive evaluations as in Visit 1, and mental imagery vividness rating and fMRI scans as in 
Visit 2. 
Visit 4. 12-Week Post-Completion Assessments: 3 hours. All subjects will return for repeat 
cognitive evaluations and fMRI tasks. The same procedures as described in Visit 3 will be 
followed.
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5.4
Statistical Method
5.4.1
Statistical Design  
This is a phase 1 randomized clinical trial aiming to enroll 120 subjects with Parkinson’s 
disease (PD) assigned in parallel to the experimental PD-MI (N=60) and active control PD-
Con (N=60) groups. The units of observation are the subjects in these groups. Subjects will 
be enrolled continuously and randomized to two groups using the “minimization” method.101 
After truly randomly allocating the first 10 subjects, each subsequent subject will be allocated 
to either group considering the factors age, gender, and disease stage. This method will allow 
us to minimize the imbalance between the groups in terms of demographic and clinical 
characteristics while at the same time preserving the randomness of group allocation.
We will use independent-sample t-tests and nonparametric Mann-Whitney U tests to 
compare subjects characteristics between the PD-MI and PD-Con groups. 
We will use mixed ANOVA tests with interaction terms to assess the short- and longer-
term changes in cognitive and imaging outcomes before and after training. 
Our overall statistical approach is designed to address the outcomes of four different aims:
AIM 1: To determine the effects of mental imagery training on goal-directed everyday 
cognitive functioning in PD 
Primary outcome: Change in Neuro-QoL version 2 Cognitive Function scores.97
Manipulation check:  Change in QMI Vividness of Imagery Scale scores.100
Neuro-QoL version 2 Cognitive Function scores (Visit 1) and QMI scores (Visit 2) obtained at 
baseline and immediately upon conclusion of the 6-week intervention (Visit 3) will be 
compared between the PD-MI and PD-Con groups using a 2x2 mixed ANOVA with an 
interaction term (dependent variables: test scores, between-subject factor: group, within-
subject factor: time with two levels, i.e., baseline and post-training, interaction: group-by-time) 
(p < 0.05, two-tailed). 
Secondary outcomes: Change in composite z-scores obtained from the executive function 
tests.
We will calculate a composite z-score from the executive function test scores (i.e., Stroop,94 
F-A-S letter fluency,95, and Trail Making A-B tests96) for all subjects. 
Composite executive function test z-scores obtained at baseline (Visit 1) and immediately 
upon conclusion of the 6-week intervention (Visit 3) will be compared between the PD-MI and 
PD-Con groups using a 2x2 mixed ANOVA with an interaction term (dependent variables: test 
scores, between-subject factor: group, within-subject factor: time with two levels, i.e., baseline 
and post-training, interaction: group-by-time) (p < 0.05, two-tailed). 
Exploratory outcomes: 1) Change in RBANS scores,93 2) and change in The Modified Six-
Element Test scores.98  
The RBANS and Modified Six-Element Test scores obtained at baseline (Visit 1) and 
immediately upon conclusion of the 6-week intervention (Visit 3) will be compared between 
the PD-MI and PD-Con groups using a 2x2 mixed ANOVA with an interaction term (dependent 
variables: test scores, between-subject factor: group, within-subject factor: time with two 
levels, i.e., baseline and post-training, interaction: group-by-time) (p < 0.05, two-tailed). 
AIM 2: To determine the brain effects of mental imagery training in PD.
Primary outcome: Change in task-specific whole-brain pairwise functional connectivity.
We will generate group-level, task-specific, pairwise functional connectivity maps for the 
mental imagery and video-watching tasks using the CONN Toolbox.53 These maps at baseline 
(Visit 2) and immediately upon conclusion of the 6-week intervention (Visit 3) will be compared 
between the PD-MI and PD-Con groups using a 2x2 mixed ANOVA with an interaction term 
(dependent variables: whole-brain pairwise functional connectivity maps, between-subject 
factor: group, within-subject factor: time with two levels, i.e., baseline and post-training, 
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interaction: group-by-time). We will use the false discovery rate (FDR)-correction for multiple 
comparisons (p < 0.05, two-tailed).102
Secondary outcomes: Change in task-specific graph-based local and global network 
measures.
Based on the pairwise functional connectivity maps, we will compute the clustering coefficient 
and betweenness centrality representing local and global graph measures, respectively, using 
the CONN Toolbox.53 These graph measures associated with the mental imagery and video-
watching tasks performed at baseline (Visit 2) and immediately upon conclusion of the 6-week 
intervention (Visit 3) will be compared between the PD-MI and PD-Con groups using a 2x2 
mixed ANOVA with an interaction term (dependent variables: graph measures, between-
subject factor: group, within-subject factor: time with two levels, i.e., baseline and post-training, 
interaction: group-by-time). We will use the FDR-correction for multiple comparisons (p < 0.05, 
two-tailed).102
Behavioral scanning data: We will add up the number of key elements of the recorded mental 
imagery descriptions for each scan (e.g., entities, sensory descriptions, spatial/temporal 
references, thoughts, actions, emotions, task components) and average them across scans 
to obtain an average imagery content score per subject. We will also average the number of 
correct answers to content-related questions after video-watching scans to obtain an average 
accuracy score per subject.  The average mental imagery content and video-watching 
accuracy scores performed at baseline (Visit 2) and immediately upon conclusion of the 6-
week intervention (Visit 3) will be compared between the two groups using a 2x2 mixed 
ANOVA with an interaction term (dependent variables: average scores, between-subject 
factor: group, within-subject factor: time with two levels, i.e., baseline and post-training, 
interaction: group-by-time) (p < 0.05, two-tailed). 
AIM 3: To determine whether the cognitive and brain effects of mental imagery training 
in PD are sustained
The primary, secondary and exploratory outcomes as outlined in Aims 1 and 2 will also apply 
to Aim 3. All cognitive and functional MRI tasks will be repeated 12 weeks after the completion 
of the training program (Visit 4). These results will then be compared with those obtained at 
baseline and 6-week post-intervention using a 3x2 mixed ANOVA with an interaction term 
(dependent variables: cognitive test scores and functional connectivity and graph measures, 
between-subject factor: group, within-subject factor: time with three levels, i.e., baseline, 6-
weeks post-intervention, and 12-weeks post-completion, interaction: group-by-time) (p < 0.05, 
two-tailed). A significant interaction will be followed by post hoc simple effects tests to 
determine the level(s) of interaction. 
AIM 4: To explore the brain-cognition link associated with mental imagery training in 
PD
Exploratory Aim: We will examine the post-training brain-cognition relationship at the 6-week 
and 12-week timepoints in each group. We will test whether the post-training changes in task-
specific whole-brain pairwise functional connectivity and graph measurements will predict the 
post-training differences in the Neuro-QoL Cognitive Function and composite executive test 
scores in each group. 
Exploratory outcomes: This brain-behavior relationship at 6 weeks will be the exploratory 
outcome of Aim 2 and that at 12 weeks will be the exploratory outcome of Aim 3.
5.4.2
Sample Size Considerations
We calculated the sample size based on the primary cognitive outcome, i.e., Neuro-QoL 
version 2 Cognitive Function scores. The Neuro-QoL Cognitive Function validation study with 
120 PD patients who had mild disease (Hoehn & Yahr stage 2) showed mean ± SD = 50.46 ± 
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7.25.97 A change of 2-6 T-scores have been considered a minimally important change in 
patient-reported outcome measures.103
 We estimated the sample size based on the assumption that there will be an average of 
4 T-score improvement after mental imagery training using the G*Power 3.1 software104,105 
The repeated-measures ANOVA between-subject factor model with two groups and two 
measurements, with an effect size of f=0.266 (corresponding to a moderate effect size 
d=0.53), alpha 0.05, and power 0.80 yielded a total sample size of 86 (43 in each group). With 
an estimated 15% drop out (86/0.85 ≈ 101) during the 6-week intervention period and another 
15% drop out (101/0.85 ≈ 120) in the subsequent 12-week period, we plan to recruit 120 
subjects in total. 
In our previous work with PD patients using motor (N=22) and visual (N=22) imagery 
training, we showed robust task-specific pairwise functional connectivity changes post-training 
especially in the respective motor and visual networks.4 Therefore, we think this sample size 
will also be adequate for the primary imaging outcome.
5.4.3
Planned Analyses
Analysis of executive function and performance-based tests
We will obtain a composite executive function score by averaging the z-transformed 
individual scores on the Stroop, letter fluency (F-A-S), and Trail Making A-B tests.94-96 A total 
score will be calculated for the RBANS. We will calculate the Modified Six-Element Test score 
as the number of subtasks attempted minus the number of violations of the task switching 
rules.98 
Analysis of behavioral data during scanning
We will adopt the qualitative analysis approach used in our previous study.4 We will add 
up the number of key elements of the recorded mental imagery descriptions for each scan 
(e.g., entities, sensory descriptions, spatial/temporal references, thoughts, actions, emotions, 
task components) and average them across scans to obtain an average imagery content score 
per subject. We will also average the number of correct answers to content-related questions 
after video-watching scans to obtain an average accuracy score per subject. These scores 
will then be used in statistical analyses.  
Preprocessing of fMRI data
We will use the CONN toolbox for all fMRI data analysis steps.53 Removal of the first four 
scans to reach magnetization steady state, motion correction, outlier detection, coregistration 
of functional scans with the anatomical scan, normalization to the standard MNI template, and 
smoothing with an 8-mm kernel to account for inter-individual anatomical variability will be 
performed. De-noising steps will include the elimination of signal originating from the white 
matter and cerebrospinal fluid, regression of motion artifacts and outliers from the time series, 
linear detrending, and high-pass filtering (0.008 < f < Inf). 
Pairwise functional connectivity analysis
To compare the task-specific whole-brain functional connectivity changes between the 
groups, we will perform pairwise functional connectivity analyses using the generalized 
psychophysiological interaction (gPPI) model. We will first convolve the 3-min task blocks in 
each mental imagery and video-watching run with the canonical hemodynamic response 
function. We will use the functionally defined cortical and subcortical nodes (N=268) of the 
whole-brain Shen atlas.52 For each subject, we will extract the average blood oxygenation 
level-dependent signal time courses calculated via the gPPI model from these nodes and 
correlate them with each other using Pearson correlations. The r values will correspond to the 
functional connectivity strength between node pairs. We will Fisher z-transform the r values 
and obtain group-level functional connectivity maps for statistical analyses.
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Graph analysis
To compare the task-specific changes in local and global network properties between the 
groups, we will perform graph analyses on the pairwise functional connectivity data. 
Specifically, we will compute the 1) clustering coefficient, which shows the connectivity 
strength between neighboring nodes and is a measure of local network efficiency, and 2) 
betweenness centrality, which shows how well-connected a particular node is with all other 
nodes and is a measure of that node’s potential as an integrative hub.106 These graph 
measures will then be used in statistical analyses.
Sex as a biological variable
Sex differences in normal cognitive aging have been reported.107 Reports on sex 
differences in PD-related cognitive decline have been variable. Sex differences in cognition in 
de novo PD patients have been found to be similar to those in normal aging.108 On the other 
hand, male sex was found to be associated with PD-MCI,109 and poorer performance in male 
vs female PD patients in executive functioning and processing speed have been 
demonstrated.110 In our study, both groups will be sex-matched and we will use sex as a 
covariate in separate analytical models to examine the potential sex-related differences in 
training response.
5.4.4
Analysis of Subject Characteristics 
We will perform independent-sample t-tests to compare the normally distributed 
continuous baseline data (e.g., MoCA, MDS-UPDRS) and nonparametric Mann-Whitney U 
tests to compare the discrete baseline data (e.g., symptom onset side, Hoehn & Yahr score) 
and non-normally distributed continuous data between the PD-MI and PD-Con groups (p < 
0.05, two-tailed) using the statistical software package SPSS (IBM SPSS Statistics version 
28). If the nonmotor survey data (e.g., mood, fatigue) differ significantly between the groups, 
we will use them as covariates in the mixed ANOVA tests explained above. 
5.4.5
Interim Analysis 
N/A
5.4.6
Handling of Missing Data
We assume that the missing data will be missing at random. If the proportion of missing 
data is not more than 5%, we will ignore the missing data and perform complete case analyses. 
Otherwise, we will use multiple imputation to replace the missing data at follow-up for the 
primary cognitive outcome. Regardless of the proportion of missing data, we will constrain the 
voxelwise imaging analyses to complete cases because to our knowledge, there is no 
validated method to correct for missing data in such analyses.     
6
Trial Administration 
6.1
Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
Possible Deception
There is no possibility for deception. 
Payment
Subjects will be compensated for their participation and for travel expenses (e.g., parking, 
cab ride). The in-person visits are lengthy and training sessions require daily time commitment. 
Therefore, we think it is important to reimburse subjects for their time.
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Each in-person visit $100 (x4)
Each completed training week $50 (x4)
Total for parking $50
Discovery of Previous Unknown Conditions
If a worrisome finding is seen on the subjects imaging scan, a radiologist or another 
physician will be asked to review the relevant images. Based on his or her recommendation 
(if any), the principal investigator or consulting physician will contact the subject, inform the 
subject of the finding, and recommend that they seek medical advice as a precautionary 
measure. 
Permanent Medical Records
No information will be added to the subject’s permanent medical records. 
Consent 
Consent forms will be Yale IRB-approved and the participant will be asked to read and 
review the document. A member of the research team authorized to obtain consent will explain 
the research study to the participant and answer any questions that may arise. This 
conversation will take place in a private environment via Zoom.
Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants will have the opportunity to discuss the study with 
their family or surrogates, or think about it prior to agreeing to participate. The participant will 
sign the informed consent document prior to any procedures being done specifically for the 
study. Participants will be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. A copy of the informed consent document will 
be given to the participants for their records. 
The purpose, research procedures, any risk that these procedures might entail, and any 
possible benefits will be discussed in detail in language appropriate for the individual’s level 
of understanding. Subjects will be encouraged to ask questions and given enough time to 
discuss any aspect of the study with the research team. Subsequently, they will have to 
demonstrate understanding of the study procedures and what is expected of them. Once 
subjects understand the study, they will be asked if they wish to participate. If they do, they 
will be asked to electronically sign the consent form at the Zoom video-call screening visit. 
Evaluation of Subject’s Capacity to Provide Consent 
Capacity will be assessed directly in the course of attempting to obtain informed consent. 
When the member of the research team authorized to obtain consent has reviewed the study, 
they will ask the subject to explain the major elements of the study. Those elements are a) 
this is a research study (not routine treatment), b) participation is voluntary, c) study 
procedures, d) risks, e) benefits. Open-ended questions such as “Can you tell me the main 
things that you would do in this study? Can you tell me the main risks of the study?” will be 
used to assess understanding and appreciation of the facts. Subject will then be expected to 
make a rational choice: “Considering the risks and benefits we have discussed, would you like 
to take part in this study?” Based on the subject’s responses the team member will make a 
final judgment about capacity for consent. If the subject has capacity and agrees to the study, 
they will sign the consent form.
Subject Coercion 
The voluntary nature of the study will be stressed and reiterated throughout conversations 
with potential participant during the consent process. It will be made clear that the individual’s 
refusal to participate will in no way affect the care which they are entitled to. 
Sensitive Data and Privacy 
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Hard copies of HIPAA identifiers, consent forms, clinical screening information, and MRI 
screening form will be kept in a locked filing cabinet. 
Study data will not contain personally identifiable information and will be labeled using a 
coding system. The data labels will contain the subject code, date and time of recording, and 
mode and condition of recording. Only the principal investigator, Dr. Tinaz, will have access 
to the centrally and electronically stored and password-protected subject identification list to 
decode data files. 
De-identified data will be stored on username- and password-protected servers provided 
by the Yale University and managed by the Yale IT Department. 
Upon completion of the study, study binders will be stored in a locked facility for the amount 
of time required by law. After this time, the study binders will be destroyed by shredding. The 
electronic databases will stay on the password-protected research computers until the study 
closes. The link to personal information will be kept until the end of the study, after which time 
the link will be destroyed and the data will become anonymous. The data will be kept in this 
anonymous form indefinitely.
 
6.2
 Institutional Review Board (IRB) Review
This will be a phase 1 randomized clinical trial.
Modifications and Updates
The protocol will be submitted to the IRB for review and approval. No research activity will 
commence until IRB approval received. Any change to the protocol or study team will require 
an approved IRB amendment before implementation. The IRB will determine whether 
informed consent and HIPAA authorization are required.
A study closure report will be submitted to the IRB after all research activities have been 
completed.
Unanticipated Problems
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs), including 
adverse events, are not anticipated. In the unlikely event that such events occur, they will be 
reported in accordance with federal and Yale University IRB rules. 
Reportable Events (which are events that are serious or life-threatening and unanticipated 
(or anticipated but occurring with a greater frequency than expected) and possibly, probably, 
or definitely related) or UPIRSOs that may require a temporary or permanent interruption of 
study activities will be reported immediately, followed by a written report within 5 calendar days 
of Dr. Tinaz becoming aware of the event to the IRB and any appropriate funding and 
regulatory agencies (using the UPIRSO Reporting Form 710 FR 4). Serious or unexpected 
adverse events that are not life-threatening will also be reported immediately followed by a 
written report within 5 calendar days of Dr. Tinaz becoming aware of the event to the IRB and 
any appropriate funding and regulatory agencies. Expected or non-serious adverse events will 
be reported at the time of continuing review. For each adverse event, Dr. Tinaz will record the 
onset, end, intensity, required treatment, outcome, seriousness, and action taken.
Dr. Tinaz will apprise study personnel of all UPIRSOs and adverse events that occur during 
the conduct of this research project through regular study meetings.
6.3
Subject Confidentiality
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor(s) and their interventions. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
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confidence. No information concerning the study or the data will be released to any 
unauthorized third party.
All research activities will be conducted in as private a setting as possible.
The representatives of the Yale IRB or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator. 
The study participant's contact information will be securely stored for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for 
as long a period as dictated by the Yale IRB and Institutional policies.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored on username- and password-protected servers 
provided by the Yale University and managed by the Yale IT Department in Dr. Tinaz’s lab. 
This will not include the participant's contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived in Dr. 
Tinaz’s lab. 
Access 
Only the principal investigator, Dr. Tinaz, will have access to the centrally and 
electronically stored and password-protected subject identification list to decode data files. 
Principal investigator and research staff will have access to study data to perform statistical 
analyses and to monitor fidelity of the data. 
Recorded Identifiers 
The following information for research will be collected and recorded for each subject:

HIPAA identifiers: Name, date of birth, sex, phone, email, postal address. Postal 
address will be used to mail the debit card in a nondescript envelope to subjects for 
study payments.

Clinical screening information: Handedness; any history or current condition of 
alcohol/substance use, neurological or psychiatric disorders such as brain tumor, 
stroke, central nervous system infection, multiple sclerosis, movement disorder (other 
than PD), seizures, dementia, depression, bipolar disorder, schizophrenia, attention 
deficit disorder, obsessive compulsive disorder; and history of head injury with loss of 
consciousness.

The Yale MRRC MRI Safety Questionnaire will be used for MRI screening.  
Storage and Security 
Risk for potential breach of confidentiality will be minimized by the use of non-identifying 
labeling and the secure storage of electronic and paper files. All team members will use 
encrypted research computers. 
Hard copies of HIPAA identifiers, consent forms, clinical screening information, and MRI 
screening form will be kept in a locked filing cabinet in Dr. Tinaz’s lab.
De-identified paper records will be kept in binders in Dr. Tinaz’s lab. 
Data on paper records will also be entered in electronic databases and stored on secure 
Yale servers (Yale REDCap).
Imaging data will be transferred securely to workstations for analysis and stored on HIPAA-
compliant secure central storage servers (“Storage@Yale”) provided by the Yale IT 
Department for a monthly fee. 
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6.4
Deviations/Unanticipated Problems
This study is considered to pose not more than minimal risk. There will not be a DSMB. 
The principal investigator, Dr. Tinaz, will identify and report deviations within 5 working 
days of identification of the protocol deviation. All deviations will be addressed in study source 
documents and the Yale IRB per their policies.
The principal investigator will report unanticipated problems involving risks to participants 
or others including any incident, experience, or outcome that meets all of the following criteria:

Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied;

Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and

Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.
The principal investigator will report unanticipated problems (UPs) to the Yale IRB. The 
UP report will include the following information: 

Protocol identifying information: protocol title and number, PI's name, and the IRB 
project number

A detailed description of the event, incident, experience, or outcome

An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP

A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:

UPs that are serious adverse events (SAEs) will be reported immediately, followed by 
a written report within 5 calendar days of Dr. Tinaz becoming aware of the event to the 
IRB. 

Any other UPs that are not life-threatening will also be reported immediately followed 
by a written report within 5 calendar days of Dr. Tinaz becoming aware of the event to 
the IRB in accordance with policy 710.

All UPs should be reported to appropriate institutional officials (as required by an 
institution's written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within 5 business days of the 
IRB's receipt of the report of the problem from the investigator.
Inclusion or exclusion criteria may have to be modified or added safety monitoring 
practices may have to be put in place to mitigate risk newly identified by a UPIRSO. Newly 
identified risks will be outlined in the informed consent if changes do not completely address 
the problem. Past participants will also be informed of newly identified risks if applicable. If 
needed, trial enrollment will be suspended until safety measures and/or criteria modification 
can be implemented to address the risk. 
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IRB and all investigators will immediately be notified about risk newly identified by a 
UPIRSO. During the conduct of the study, there will be ongoing review and surveillance by 
the principal investigator, Dr. Tinaz, and other study investigators. Any protocol deviation 
and/or adverse event will be formally written up by and submitted to the IRB by Dr. Tinaz. 
Protocol deviations and actions to limit future deviations will be arbitrated by IRB with the help 
of study investigators. Written report of UPIRSO will include protocol title, number, PI name, 
and IRB project number. A detailed description of the event or outcome will be relayed as well 
as an explanation of the basis for determining that the event represents an UP. Finally, any 
changes to the protocol or addition of safety measures will be described to the IRB. 
6.5
Data Quality Assurance
The trial will be registered in clinicaltrials.gov within one of week of the start of enrollment. 
Dr. Tinaz has built the infrastructure for this study in her lab and will further implement and 
maintain quality assurance and quality control system with written standard operating 
procedures to ensure that the trial is conducted and data are generated, recorded, and 
reported in compliance with the protocol, good clinical practice, and applicable regulatory 
requirements. Dr. Tinaz will review the data in the databases for evidence of data entry errors 
and omissions. 
6.6
Study Records
The documents that will be considered study records are:
Recruitment

Recruitment flyers 
Health and Safety Records

Demographic Data 

Clinical screening information

The Yale MRRC MRI Safety Questionnaire
Clinical and Cognitive Evaluation Records 

Case reports forms

MDS-UPDRS and Hoehn & Yahr

MoCA test

PD Cognitive Function Rating Scale

Neuro-QoL

QMI mental imagery vividness scale 

Modified Six-Elements 

Executive Function tests (i.e., Stroop, F-A-S letter fluency, and Trail Making A-B test)

RBANS test

Structured cognitive interview forms 
Online Surveys

Geriatric Depression Form

Parkinson Anxiety Scale 

Starkstein Apathy scale 

PD Quality of Life Questionnaire-39

Parkinson Fatigue Scale 

Scales for Outcomes in Parkinson’s Disease – Sleep
 
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Online Homework

Mental imagery practice logs

Responses to psychoeducation quizzes
Imaging Data

Structural and functional MRI Data
Other

Consent form
6.7
Access to Source
Source data will be maintained per Medical Records policy in a password protected, 
secure, Health Insurance Portability and Accountability Act (HIPAA) compliant, web-based 
electronic database with a built-in audit trail.
Only Institutional Review Board (IRB) approved research team members who have current 
HIPAA and Collaborative Institutional Training Initiative (CITI) Good Clinical Practice (GCP) 
and human subjects protection training will be authorized to access records.
For detailed description of source documents, data recording, and data storage, please 
see section 5.1.1.  
The data will be collected specifically for this project. The information obtained in this study 
will be recorded in such a manner that the identity of the human subjects cannot be 
ascertained directly. The data will not contain personally identifiable information and will be 
labeled using a coding system. The data labels will contain the subject code, date and time of 
recording, and mode and condition of recording. Only the principal investigator, Sule Tinaz, 
will have access to the centrally and electronically stored and password-protected subject 
identification list to decode data files. All other study investigators will have access to the de-
identified data. All study investigators will use encrypted research computers.
The link to personal information will be kept until the end of the study, after which time the 
link will be destroyed and the data will become anonymous. The data will be kept in this 
anonymous form indefinitely. Anonymous data will be made accessible to other researchers 
on free web-based platforms such as the Neuroimaging Data Repository of the Neuroimaging 
Tools & Resources Collaboratory (NITRC) (www.nitrc.org).
6.8
Data or Specimen Storage/Security
For detailed description of data recording and storage, please see section 5.1.1.  
6.9
Retention of Records
Upon completion of the study, study binders will be stored in a locked facility for the amount 
of time required by law. After this time, the study binders will be destroyed by shredding. The 
electronic databases will stay on the password-protected research computers until the study 
closes. The link to personal information will be kept until the end of the study, after which time 
the link will be destroyed and the data will become anonymous. The data will be kept in this 
anonymous form indefinitely.
If permission is needed to move or destroy the records, Dr. Tinaz will need to be contacted. 
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6.10 Study Monitoring
This study presents minimal. There will be no DSMB. The study will be monitored by the 
internal team: 

Principal Investigator: Dr. Sule Tinaz 

Co-Investigators: Dr. Ana Vives-Rodriguez and Dr. Emily Sharp 

Research Assistant: Jared Cherry
We will hold biweekly team meetings to discuss research progress and address potential 
issues. Dr. Tinaz will be responsible for oversight of the study, immediate reporting of any 
protocol deviations, and the reporting of unanticipated problems or adverse events. 
6.11 Study Modification
Any modifications to the study will be discussed with all investigators. Amendments will be 
submitted to the IRB to allow for any protocol modifications. No protocol modifications will take 
place until approval from the IRB is received. 
6.12 Study Completion
We estimate it will take 6 years to complete the study. IRB will be notified through 
continuing reviews and finally with study closure documents.
6.13 Funding Source
The study will be funded through Dr. Tinaz’s NINDS 1R56NS129540-01A1 grant. 
Salary support for Dr. Tinaz for this study is provided by the NINDS 1R561NS129540-01A1 
grant. 
6.14 Conflict of Interest Policy
The research which will be done as part of this protocol is investigator initiated and free 
from influence from any pharmaceutical or private company. None of the investigators has a 
conflict of interest with this study (patent ownership, royalties, or financial gain greater than 
the minimum allowable by their institution). Any conflicts of interest which may arise as part of 
this research will be presented to Yale IRB and the conflict will be reviewed by the appropriate 
committee at Yale University.
6.15 Publication Plan
Abstracts will be submitted to the Movement Disorders Society, American Academy of 
Neurology, Organization Human Brain Mapping or other relevant subspecialty meetings as 
appropriate.
Manuscripts will be written and submitted to scientific journals at the intersection between 
neuroimaging and Parkinson’s disease such as Movement Disorders and NeuroImage.
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List of Tables
1.
Table 1. Study Timeline
2.
Table 2. Planned Enrollment  
List of Attachments
1.
Case report form
2.
Demographic and medical screening form
3.
MRI Safety Questionnaire 
4.
Structured cognitive interview
5.
Study Flyer 
6.
Scales for Outcomes in Parkinson’s Disease – Sleep
7.
Geriatric Depression Scale
8.
Movement Disorder Society- Unified Parkinson’s Disease Rating Scale (includes Hoehn 
and Yahr)
9.
Montreal Cognitive Assessment 
10. Neuro-Quality of Life Version 2- Cognitive Functions
11. Parkinson’s Disease Fatigue Scale
12. Parkinson’s Disease Cognitive Functional Rating Scale
13. Parkinson’s Disease Questionnaire-39
14. Questionnaire Upon Mental Imagery Vividness of Imagery Scale
15. Parkinson Anxiety Scale
16. Starkstein Apathy Scale
Please note we are not attaching copyright protected testing material. 
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