Measurement and Modification of Threat Interpretation Bias in Neurodegenerative Movement Disorders (Aims 2 & 3)
Phase: NA
Conditions: Huntington Disease, Parkinson Disease
Sponsor: University of Virginia

 
 
Title: Protocol: Measurement and Modification of Threat Interpretation Bias in 
Neurodegenerative Movement Disorders (Aims 2 & 3) 
 
NCT#: NCT05126862 
 
Document date: Protocol version 3/26/24, uploaded 7/1/24 
 
 

Measurement and Modification of Threat Interpretation Bias in Neurodegenerative Movement 
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PROTOCOL 
Background 
1. Provide the scientific background, rationale and relevance of this project.   
Answer/Response: [REDACTED]  Anxiety symptoms are experienced by up to 71% of persons 
with Huntington’s disease (PwHD), causing significant burden for patients and caregivers 2, 3. 
[REDACTED] Further, there have been no randomized controlled trials (RCTs) to evaluate 
efficacy of a specific psychological intervention for anxiety symptoms in PwHD. [REDACTED]  
Our long-term goal is to develop effective, accessible non-pharmacological interventions to 
reduce neuropsychiatric symptoms in patients with neurodegenerative movement disorders 
(e.g., HD, Parkinson’s disease [PD]). With this overarching purpose in mind, our next step is to 
evaluate a cognitive bias modification for interpretation bias (CBM-I) intervention for reducing 
anxiety symptoms in PwHD. [REDACTED] For the current proposal, we will [REDACTED] pilot an 
existing web-based CBM-I intervention (MindTrails) in PwHD. MindTrails (PI: Teachman) is a 
free, multi-session, internet-delivered CBM-I training intervention to reduce anxious thinking. 
Participants complete five, weekly 20-minute modules designed to encourage cognitive 
flexibility through repeated practice assigning benign resolutions to ambiguous, anxiety-
provoking situations. Launched in 2016, it has been completed by thousands of individuals and 
has been found to reduce interpretation bias and anxiety symptoms in a community sample 
with high trait anxiety 13. 
PD sub-study: 
As in HD, anxiety is very common in people with Parkinson’s disease (PD). In keeping with our 
long-term goal to develop effective, accessible non-pharmacological interventions to reduce 
neuropsychiatric symptoms in patients with neurodegenerative movement disorders (e.g., HD, 
PD), we will [REDACTED] pilot an existing web-based CBM-I intervention (MindTrails) in PwPD.  
 
[REDACTED] Objectives/Hypothesis  
Answer/Response:  
Main study: 
[REDACTED] Aim 2: To assess feasibility and preliminary efficacy of a web-based CBM-I 
intervention (MindTrails) for reducing interpretation bias and anxiety symptoms in PwHD 
Hypothesis 2: MindTrails will be feasible and will demonstrate preliminary efficacy for reducing 
interpretation bias and anxiety symptoms in PwHD. 
N=20 PwHD will enroll in a pilot open trial of the existing MindTrails protocol. Mixed effects 
models will be used to evaluate preliminary effects of the intervention on interpretation bias 
and anxiety symptom change.  
Aim 3: To conduct a qualitative evaluation of the MindTrails program in HD 
Hypothesis 3: Qualitative data will reveal overall satisfaction with MindTrails and 
recommendations for future trials. 
Participants in the Aim 2 open trial will be invited to complete qualitative interviews regarding 
their experiences with the MindTrails intervention (invite n=20 to obtain a minimum of n=10 

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interviews). Data will be used to develop a subsequent RCT of MindTrails specifically adapted 
for PwHD.  
 
PD sub-study: 
[REDACTED] Aim 2: To assess feasibility and preliminary efficacy of a web-based CBM-I 
intervention (MindTrails) for reducing interpretation bias and anxiety symptoms in PwPD 
Hypothesis 2: MindTrails will be feasible and will demonstrate preliminary efficacy for reducing 
interpretation bias and anxiety symptoms in PwPD. 
N=20 PwPD will enroll in a pilot open trial of the existing MindTrails protocol. Mixed effects 
models will be used to evaluate preliminary effects of the intervention on interpretation bias 
and anxiety symptom change.  
Aim 3: To conduct a qualitative evaluation of the MindTrails program in PD 
Hypothesis 3: Qualitative data will reveal overall satisfaction with MindTrails and 
recommendations for future trials. 
Participants in the Aim 2 open trial will be invited to complete qualitative interviews regarding 
their experiences with the MindTrails intervention (invite n=20 to obtain a minimum of n=10 
interviews). Data will be used to develop a subsequent RCT of MindTrails specifically adapted 
for PwPD.  
 
[REDACTED]  
Study Design: Biomedical 
1.  Will controls be used? 
Answer/Response: No 
►IF YES, explain the kind of controls to be used. 
Answer/Response: 
 
2. What is the study design?  
Answer/Response: Other 
[REDACTED] Aim 2: Single-group feasibility open trial 
Aim 3: Cross-sectional qualitative interview 
 
PD sub-study: same as above 
 
3. [REDACTED] Does the study involve a placebo? 
Answer/Response: No 
►IF YES, provide a justification for the use of a placebo 
Answer/Response: 
Human Participants 
Ages: ≥21 years old 
Sex: 
Any 
Race: Any 

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Subjects- see below 
1.  Provide target # of subjects (at all sites) needed to complete protocol. 
Answer/Response: [REDACTED] 
Main study: [REDACTED] 20 [REDACTED] 
PD sub-study: [REDACTED] 20 [REDACTED] 
[REDACTED] 
 
2.  Describe expected rate of screen failure/ dropouts/withdrawals from all sites.   
Answer/Response:  Main study: [REDACTED] 
For Aim 2, we anticipate 40% dropout as attrition can be quite high for online mental 
health interventions and CBT-based HD studies. 
For Aim 3, we do not anticipate dropout.  
PD sub-study: [REDACTED] For Aim 2, we anticipate 40% dropout as attrition can be 
quite high for online mental health interventions and CBT-based HD studies. 
For Aim 3, we do not anticipate dropout.  
[REDACTED] 3.  How many subjects will be enrolled at all sites?    
Answer/Response: [REDACTED] 
 
4.  How many subjects will sign a consent form under this UVA protocol?     
Answer/Response: Main study: [REDACTED] 20 of these will sign an 
additional consent for Aims 2 & 3[REDACTED] PD sub-study: 
[REDACTED] 20 of these will sign an additional consent for Aims 2 & 3. 
[REDACTED] [REDACTED] Inclusion/Exclusion Criteria 
Main study: 
AIM #1 and instrument feedback 
1.  List the criteria for inclusion  
Answer/Response: 
• Diagnosis of Huntington’s disease 
• Age 21 or older  
2.  List the criteria for exclusion 
Answer/Response: 
• Unable to read and understand English 
• Previously diagnosed with dementia 
• Not located in the USA 
AIM #2 and 3 
Inclusion Criteria- 
Participated in Aim 1 

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Has anxiety symptoms (NeuroQoL-Anxiety > 12) (based on Aim 1 responses) 
Exclusion Criteria- 
 None  
 
PD substudy: 
AIM #1 and instrument feedback 
1.  List the criteria for inclusion  
Answer/Response: 
• Diagnosis of Parkinson’s disease 
• Age 21 or older  
2.  List the criteria for exclusion 
Answer/Response: 
• Unable to read and understand English 
• Previously diagnosed with dementia 
• Not located in the USA 
AIM #2 and 3 
Inclusion Criteria- 
Participated in Aim 1 
Has anxiety symptoms (NeuroQoL-Anxiety > 12) (based on Aim 1 responses) 
Exclusion Criteria- 
 None  
 
[REDACTED]  
3.  List any restrictions on use of other drugs or treatments. 
Answer/Response: None 
Statistical Considerations 
1. 
Is stratification/randomization involved? 
Answer/Response: No 
►IF YES, describe the stratification/ randomization scheme. 
►IF YES, who will generate the randomization scheme?  
_____ Sponsor 
_____ UVA Statistician.   Answer/Response: 
_____ UVA Investigational Drug Service (IDS) 
_____ Other:  Answer/Response: 
 
2.  What are the statistical considerations for the protocol?  
Answer/Response: 
Main study: 

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[REDACTED]  
Aim 2: To assess feasibility and preliminary efficacy of a web-based CBM-I intervention 
(MindTrails) for reducing interpretation bias and anxiety symptoms in PwHD 
Subjects (N=20) will complete five, 20-minute MindTrails training sessions over five weeks, 
consistent with the existing MindTrails protocol which has been found to modify negative 
interpretations and reduce anxiety 13. In addition, they will complete assessments included in 
the established MindTrails measures, which measure anxiety symptoms (Depression, Anxiety, 
Stress Scales-Short Form [DASS]: Anxiety Subscale  (DASS AS)23), depressive symptoms (DASS: 
Depression Subscale 23), interpretation bias (BBSIQ 14), a mental health history and treatment 
questionnaire, and user experience survey. These assessments will be completed at baseline, 
after training sessions in weeks 3 and 5, and 2 months following the last (week 5) training 
session to assess durability of the effects. We will also collect HD-specific demographic data  
via Demographic HD History Interpret (e.g., CAG repeat length on the HD-affected allele) at 
baseline and HD-related measures (NeuroQoL-Anxiety, NeuroQoL-Depression 20, 21, and our 
novel MDIB measure) that are not included in the established MindTrails protocol.  
 
 
Aim 3: To conduct a qualitative evaluation of the MindTrails program in HD  
Subjects will complete a semi-structured interview that about their experiences with MindTrails 
and anxiety. Dr. Gibson or study staff will also administer the Total Functional Capacity 24 scale 
to classify participants by stage of HD and the Montreal Cognitive Assessment (5 
minute/telephone). 
 
PD sub-study: 
[REDACTED] Aim 2: To assess feasibility and preliminary efficacy of a web-based CBM-I 
intervention (MindTrails) for reducing interpretation bias and anxiety symptoms in PwPD 
Subjects (N=20) will complete five, 20-minute MindTrails training sessions over five weeks, 
consistent with the existing MindTrails protocol which has been found to modify negative 
interpretations and reduce anxiety 13. In addition, they will complete assessments included in 
the established MindTrails measures, which measure anxiety symptoms (Depression, Anxiety, 
Stress Scales-Short Form [DASS]: Anxiety Subscale  (DASS AS)23), depressive symptoms (DASS: 
Depression Subscale 23), interpretation bias (BBSIQ 14), a mental health history and treatment 
questionnaire, and user experience survey. These assessments will be completed at baseline, 
after training sessions in weeks 3 and 5, and 2 months following the last (week 5) training 
session to assess durability of the effects. We will also collect PD-specific demographic data  via 
Demographic PD History Interpret (e.g., age of diagnosis) at baseline and PD-related measures 
(NeuroQoL-Anxiety, NeuroQoL-Depression 20, 21, and our novel MDIB measure) that are not 
included in the established MindTrails protocol.  
 
 
Aim 3: To conduct a qualitative evaluation of the MindTrails program in PD  
Subjects will complete a semi-structured interview that about their experiences with MindTrails 
and anxiety. Dr. Gibson or study staff will also administer the Montreal Cognitive Assessment (5 
minute/telephone). 

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[REDACTED]  
3.  Provide a justification for the sample size used in this protocol.   
Answer/Response:  
Main study: 
[REDACTED]  
Aims 2 and 3 include a feasibility study and qualitative interviews. We will include 20 
participants in the feasibility study, which will be sufficient to gather preliminary data in 
preparation for a future RCT. We will recruit all 20 participants in the feasibility study to 
complete qualitative interviews. All 20 subjects may not want to complete interviews, and we 
expect that a sample of 10 participants will be sufficient to reach data saturation on qualitative 
analysis based on Dr. Gibson’s prior experience conducting and analyzing qualitative interviews 
in HD. 
 
PD sub-study: 
[REDACTED]  
Aims 2 and 3 include a feasibility study and qualitative interviews. We will include 20 
participants in the feasibility study, which will be sufficient to gather preliminary data in 
preparation for a future RCT. We will recruit all 20 participants in the feasibility study to 
complete qualitative interviews. All 20 subjects may not want to complete interviews, and we 
expect that a sample of 10 participants will be sufficient to reach data saturation on qualitative 
analysis based on Dr. Gibson’s prior experience conducting and analyzing qualitative interviews. 
 
[REDACTED]  
 
4.  What is your plan for primary variable analysis? 
Answer/Response:  
Main study: 
[REDACTED]  
5.  What is your plan for secondary variable analysis?  
Answer/Response: 
Main Study: 
Aim 2: Descriptive statistics will be used to summarize patient demographic, health history, and 
user experience variables. Because attrition can be quite high for online mental health 
interventions and CBT-based HD studies 6, 26, we will consider the intervention feasible in PwHD 
if 50% of participants complete at least 50% of the sessions. We will also compare demographic 
and clinical variables between adherers (>50% completers) and non-adherers to provide insight 
into which patients may require targeted retention efforts in a follow-up study (this will be 
done descriptively given small sample size). To evaluate target engagement and preliminary 
efficacy of MindTrails, we will use linear mixed-effects models to assess changes in 
interpretation bias and anxiety symptoms over the course of the intervention, including age, 
gender, and CAG repeat length as fixed effects. In the case that MDIB is not a valid and reliable 

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measure of interpretation bias in HD (Aim 1), we will use only BBSIQ, and not MDIB, in our 
analysis of interpretation bias for this aim. Because prior studies have shown potential for CBM-
I to be effective in depressed samples 12, an exploratory mixed effects model will also be used 
to evaluate potential effects of the intervention on depressive symptoms, using the same fixed 
effects. (Note: Analyses for this aim are limited by the small, pilot sample, but Dr. Gibson will 
use this feasibility study to develop data analysis skills for this data as well as data for a future 
large RCT. We will focus our interpretation on effect size estimates given the small sample size 
limits power for significance testing; specifically, effect sizes will be reported as standardized β 
estimates.)  
 
Aim 3: We will perform qualitative descriptive content analysis of answers, including iterative, 
line-by-line coding by multiple coders, and organization of findings into categories or themes. 
Qualitative interviews will continue until data saturation is reached, and no new themes are 
identified. Participant responses between disease stage groups will be qualitatively compared. 
This will help us to determine whether MindTrails is best suited for early-stage (1-2) HD 
patients as compared to those in later stages (3-4). The feedback will be used to modify the 
program in an iterative fashion and inform protocol development for a follow-up RCT.  
 
PD sub-study: 
Aim 2: Descriptive statistics will be used to summarize patient demographic, health history, and 
user experience variables. Because attrition can be quite high for online mental health 
interventions and CBT-based studies in neurodegenerative populations 6, 26, we will consider the 
intervention feasible in PwPD if 50% of participants complete at least 50% of the sessions. We 
will also compare demographic and clinical variables between adherers (>50% completers) and 
non-adherers to provide insight into which patients may require targeted retention efforts in a 
follow-up study (this will be done descriptively given small sample size). To evaluate target 
engagement and preliminary efficacy of MindTrails, we will use linear mixed-effects models to 
assess changes in interpretation bias and anxiety symptoms over the course of the intervention, 
including age, gender, and CAG repeat length as fixed effects. In the case that MDIB is not a 
valid and reliable measure of interpretation bias in PD (Aim 1), we will use only BBSIQ, and not 
MDIB, in our analysis of interpretation bias for this aim. Because prior studies have shown 
potential for CBM-I to be effective in depressed samples 12, an exploratory mixed effects model 
will also be used to evaluate potential effects of the intervention on depressive symptoms, 
using the same fixed effects. (Note: Analyses for this aim are limited by the small, pilot sample, 
but Dr. Gibson will use this feasibility study to develop data analysis skills for this data as well as 
data for a future large RCT. We will focus our interpretation on effect size estimates given the 
small sample size limits power for significance testing; specifically, effect sizes will be reported 
as standardized β estimates.)  
 
Aim 3: We will perform qualitative descriptive content analysis of answers, including iterative, 
line-by-line coding by multiple coders, and organization of findings into categories or themes. 
Qualitative interviews will continue until data saturation is reached, and no new themes are 

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identified. Participant responses between disease stage groups will be qualitatively compared. 
This will help us to determine whether MindTrails is best suited for early-stage (1-2) PD patients 
as compared to those in later stages (3-4). The feedback will be used to modify the program in 
an iterative fashion and inform protocol development for a follow-up RCT.  
 
MindTrails-Movement Development substudy: n/a 
 
6. Have you been working with a statistician in designing this protocol? 
Answer/Response: Yes 
IF YES, what is their name?   
Answer/Response: [REDACTED] 
 
7.  Will data from multiple sites be combined during analysis?   
Answer/Response: No 
7(a).  Does the study involve randomization?   
Answer/Response: 
IF YES, will randomization be done at each site or among sites?   
Answer/Response: 
 
7(b).  Has the sample size calculation considered the variation among sites?  
Answer/Response: 
 
7(c).  When combining the data from multiple sites to assess the study results, is the 
effect of the treatment to be tested (or the association to be tested) assumed to be the 
same across sites or vary among sites? What is the modelling strategy? 
Answer/Response: 
 
7(d). Is there a common protocol used in all sites?  
Answer/Response: 
IF NO, how will differences among sites, such as those related to the 
implementation, inclusion criteria, patient characteristics, or other sites 
characteristics, be considered to assess the study results? 
Answer/Response: 
Study Procedures-Biomedical Research 
1.  What will be done in this protocol?    
Answer/Response:  
Main study: 
[REDACTED]  
Aim 2: We will conduct a pilot open trial of MindTrails in 20 PwHD. MindTrails 
(https://mindtrails.virginia.edu/calm/public/researchSupport ) is based on Mathews and 

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Mackintosh’s Ambiguous Scenario Training design, a CBM-I protocol with established 
efficacy in trait anxious samples, which trains participants to assign more benign 
interpretations to ambiguous, anxiety-relevant situations 7, 9. 
 
 In each session, participants will read and resolve a series of 40 ambiguous scenarios 
(from a pool of 200 scenarios, see Figure 1 and demo training session: 
http://mt.sartography.com/demo/#/training/1 ). Participants will be asked to imagine 
themselves in each scenario, as previous work has highlighted the strengthening effect 
of imagery on interpretation training 27. Ninety percent of scenarios will end with a word 
fragment that resolves the ambiguity of the scenario in a benign (anxiety-incongruent) 
manner. Once participants correctly complete a word fragment, they will answer a 
comprehension question, which ensures that they read the scenario and reinforces the 
positive interpretation of the scenario. They will then move on to the next scenario. 
Later sessions will make the task slightly more challenging by having word fragments 
missing 2 letters, rather than only 1 16.   
 
Figure 1. Sample MindTrails Scenario 
 
 
Subjects will complete five, 20-minute MindTrails training sessions over five weeks 
consistent with the existing MindTrails protocol which has been found to modify 
negative interpretations and reduce anxiety 13. In addition, they will complete 
assessments (see statistical considerations section above) at baseline, after training 
sessions in weeks 3 and 5, and 2 months following the last (week 5) training session to 
assess durability of the effects. MindTrails assessments are as follows: 
• MindTrails Measures.pdf 
Additional HD-specific assessments include: 
• MDIB_samplequestion 
• MDIB_REDCap.pdf 
• NeuroQOLSF-Anxiety.pdf 
• NeuroQOLSF-Depression.pdf 
At baseline, participants will also complete ContactInfo.pdf. 
 
 
For participants whose training sessions or assessments are incomplete, a member of 
the study team will contact these participants via phone and/or email as needed to 

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request completion of training sessions and/or assessments and to answer any study-
related questions. 
 
Aim 3: We will gather feedback from MindTrails PwHD participants, using semi-
structured interviews. The 20 participants who participate in the MindTrails pilot (Aim 
2) will also complete telephone interviews. Each participant will complete a semi-
structured interview (~30 minutes) to query perceived benefits and limitations of 
MindTrails, specifically, web-based self-management interventions in general, as well as 
anxiety symptoms and social difficulties. Interview questions will be refined based on 
results of Aim 2. Sample interview questions are as follows: 
1. What was your overall impression of the MindTrails program? 
a. In what ways was the program helpful for you? 
b. In what ways could the program be improved to help people with HD, 
specifically? 
2. What barriers do you think might prevent someone with HD from completing 
the MindTrails program? 
 
Subjects will also answer questions to complete the Total Functional Capacity (TFC.docx ) 
scale and Montreal Cognitive Assessment 5 minute/telephone (MoCA 5 min-T – Version 
2.1 English test.pdf)28 during their telephone interview session.  
 
PD sub-study: 
[REDACTED]  
Aim 2: We will conduct a pilot open trial of MindTrails in 20 PwPD. MindTrails 
(https://mindtrails.virginia.edu/calm/public/researchSupport ) is based on Mathews and 
Mackintosh’s Ambiguous Scenario Training design, a CBM-I protocol with established 
efficacy in trait anxious samples, which trains participants to assign more benign 
interpretations to ambiguous, anxiety-relevant situations 7, 9. 
 
 In each session, participants will read and resolve a series of 40 ambiguous scenarios 
(from a pool of 200 scenarios, see Figure 1 and demo training session: 
http://mt.sartography.com/demo/#/training/1 ). Participants will be asked to imagine 
themselves in each scenario, as previous work has highlighted the strengthening effect 
of imagery on interpretation training 27. Ninety percent of scenarios will end with a word 
fragment that resolves the ambiguity of the scenario in a benign (anxiety-incongruent) 
manner. Once participants correctly complete a word fragment, they will answer a 
comprehension question, which ensures that they read the scenario and reinforces the 
positive interpretation of the scenario. They will then move on to the next scenario. 
Later sessions will make the task slightly more challenging by having word fragments 
missing 2 letters, rather than only 1 16.   
 
Figure 1. Sample MindTrails Scenario 

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Subjects will complete five, 20-minute MindTrails training sessions over five weeks 
consistent with the existing MindTrails protocol which has been found to modify 
negative interpretations and reduce anxiety 13. In addition, they will complete 
assessments (see statistical considerations section above) at baseline, after training 
sessions in weeks 3 and 5, and 2 months following the last (week 5) training session to 
assess durability of the effects. MindTrails assessments are as follows: 
• MindTrails Measures.pdf 
Additional PD-specific assessments include: 
• MDIB_samplequestion 
• MDIB_REDCap.pdf 
• NeuroQOLSF-Anxiety.pdf 
• NeuroQOLSF-Depression.pdf 
At baseline, participants will also complete ContactInfo.pdf. 
 
 
For participants whose training sessions or assessments are incomplete, a member of 
the study team will contact these participants via phone and/or email as needed to 
request completion of training sessions and/or assessments and to answer any study-
related questions. 
 
Aim 3: We will gather feedback from MindTrails PwPD participants, using semi-
structured interviews. The 20 participants who participate in the MindTrails pilot (Aim 
2) will also complete telephone interviews. Each participant will complete a semi-
structured interview (~30 minutes) to query perceived benefits and limitations of 
MindTrails, specifically, web-based self-management interventions in general, as well as 
anxiety symptoms and social difficulties. Interview questions will be refined based on 
results of Aim 2. Sample interview questions are as follows: 
3. What was your overall impression of the MindTrails program? 
a. In what ways was the program helpful for you? 
b. In what ways could the program be improved to help people with PD, 
specifically? 
4. What barriers do you think might prevent someone with PD from completing 
the MindTrails program? 
Subjects will also complete Montreal Cognitive Assessment 5 minute/telephone (MoCA 
5 min-T – Version 2.1 English test.pdf)28 during their telephone interview session. 

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[REDACTED]  
2. If this protocol involves study treatment, explain how a subject will be transitioned from 
study treatment when they have completed their participation in the study.   
Answer/Response: N/A 
Bibliography 
 
 
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