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Aging and Reward System Response to Inflammation and Anxiety Study (ARIA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05363527
Recruitment Status : Recruiting
First Posted : May 6, 2022
Last Update Posted : August 24, 2022
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Chloe Boyle, PhD, University of California, Los Angeles

Brief Summary:
The purpose of this study is to use an experimental inflammatory challenge to examine whether older adults with symptoms of anxiety experience loss of pleasure or loss of motivation when they are exposed to inflammation. Loss of pleasure or loss of motivation will be evaluated using self-report questionnaires, computer tasks, and during a brain scan.

Condition or disease Intervention/treatment Phase
Anhedonia Inflammation Anxiety Aging Depression Biological: Endotoxin Biological: Placebo Phase 1

Detailed Description:

Participants will undergo phone screening, two in-person visits, and telephone follow-up. The first visit will last 4 hours and the second visit will last 10.5 hours. Phone screening and follow-up will take no longer than 30 minutes.

Phone Screening and Visit #1:

Following phone screening to determine potential eligibility, participants will have an in-person evaluation. Following informed consent in the first session, participants will undergo semi-structured clinical interviews and complete questionnaires to assess medical- and medication histories; current- and past history of psychiatric disorders, and evaluation of behavioral symptoms of anxiety and depression. They will also complete computer tasks that assess motivation and sensitivity to reward. As part of one of these tasks, they will be asked to provide a picture of a loved one, which they will later view during a fMRI scan.

Visit #2 and telephone follow-up:

The second session will be about two weeks later. It will begin at 7:30AM and will involve placement of two intravenous catheters (one in each arm), evaluation of heart rate and blood pressure, administration of endotoxin vs. placebo, repeated blood sampling along with questionnaires about mood and symptoms for approximately 10.5 hours. Two hours post-injection participants will complete a 1-hour brain scan that includes tasks to assess motivation and sensitivity to reward. Study staff will escort the participant to a nearby facility to complete the brain scan. 24 hrs and 2-weeks following this session, study staff will call the subject and ask about physical and mood symptoms, using the same set of items used during the experimental protocol.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Endotoxin vs. Placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Blinded infusion
Primary Purpose: Other
Official Title: Experimental Model of Depression in Aging: Anxiety, Inflammation, and Reward Mechanisms
Estimated Study Start Date : October 2022
Estimated Primary Completion Date : March 15, 2026
Estimated Study Completion Date : March 15, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Endotoxin
Endotoxin 0.8 ng/kg body weight
Biological: Endotoxin
Endotoxin

Placebo Comparator: Placebo
same volume of 0.9% saline
Biological: Placebo
Placebo




Primary Outcome Measures :
  1. Neural Indices of Reward Motivation - Anticipatory Reward Response [ Time Frame: approximately 2 hours post-injection for 7 minutes ]
    Task-based functional magnetic resonance imaging (fMRI) will be used to assess reward motivation, as operationalized by ventral striatum (VS) activity during anticipation of monetary reward cue trials vs no-reward cue trials during the Monetary Incentive Delay Task.

  2. Neural Indices of Reward Motivation - Effort-Based Decision Making [ Time Frame: approximately 2 hours post-injection for 14 minutes ]
    Task-based functional magnetic resonance imaging (fMRI) will be used to assess effort-based motivational processing, as assessed by VS, ventromedial prefrontal cortex (vmPFC), and pre-supplementary motor area (pre-SMA) activity with choice phase as event onset during an adapted version of the Effort Expenditure for Rewards Task (EEfRT).

  3. Neural Indices of Monetary Reward Sensitivity during Effort-Based Decision Making [ Time Frame: approximately 2 hours post-injection for 14 minutes ]
    Task-based functional magnetic resonance imaging (fMRI) will be used to assess sensitivity for monetary reward, as operationalized by VS and VMPFC activity during receipt of monetary reward (vs. fixation) and during choice of low vs. high reward trials during the EEfRT.

  4. Neural Indices of Reward Sensitivity for Non-Monetary Reward [ Time Frame: approximately 2 hours post-injection for 10 minutes ]
    Sensitivity for non-monetary reward as assessed by VS and VMPFC activity when viewing positive non-social vs neutral images, and when viewing positive social vs. neutral images, in a positive picture viewing task.


Secondary Outcome Measures :
  1. Resting state functional connectivity [ Time Frame: 2 hours post-injection for 7 minutes ]
    Resting-state functional connectivity will be assessed over a 7-minute period, focusing on functional connectivity between the ventromedial prefrontal cortex and ventral striatum.

  2. Social Incentive Delay Task - Neural Indices of Social Reward Motivation [ Time Frame: approximately 2 hours post-injection for 7 minutes ]
    Task-based functional magnetic resonance imaging (fMRI) will be used to assess social reward motivation, as operationalized by ventral striatum (VS) activity during anticipation of social reward cue trials vs no-reward cue trials on the Social Incentive Delay Task.

  3. Social Incentive Delay Task - Neural Indices of Reward Motivation for Close Social Reward [ Time Frame: approximately 2 hours post-injection for 7 minutes ]
    Motivational processing for a close other social reward will be assessed with the Social Incentive Delay Task as VS activity during anticipation of viewing images of a close other (vs no-reward cue).

  4. Behavioral Indices of Reward motivation - close other social reward [ Time Frame: 2 hours post-injection ]
    Motivational processing for a close other social reward will be assessed as self-reported desire to be around the close other on a scale of 1 (not at all) to 7 (a lot).

  5. Monetary Incentive Delay Task -Neural Indices of Monetary Reward Sensitivity [ Time Frame: approximately 2 hours post-injection for 7 minutes ]
    Sensitivity for monetary reward as assessed by VS and VMPFC activity during outcome (reward vs. no-reward) and anticipation (low vs. high reward cues) on the Monetary Incentive Delay task.

  6. Social Incentive Delay Task - Neural Indices of Social Reward Sensitivity [ Time Frame: approximately 2 hours post-injection for 7 minutes ]
    Sensitivity for social reward as assessed by VS and VMPFC activity during outcomes (reward vs. no-reward) on the Social Incentive Delay Task.

  7. Social Incentive Delay Task - Neural Indices of Reward Sensitivity for Close Social Reward [ Time Frame: approximately 2 hours post-injection for 7 minutes ]
    Reward sensitivity for a close other will be assessed as VS and VMPFC activity during the outcome phase (close other reward vs no-reward outcomes) and anticipation phase (general social reward vs. close other social reward cue anticipation) on the Social Incentive Delay Task.

  8. Behavioral Indices of Reward Motivation - Effort-Based Decision Making [ Time Frame: Pre-injection and approximately 2 hours post-injection ]
    Motivation for monetary reward is assessed with an Effort Expenditure for Rewards Task (EEfRT); willingness to exert physical effort for monetary reward (i.e., selection of hard vs easy tasks) is the outcome measure with higher willingness indicative of higher motivation.

  9. Behavioral Indices of Reward Sensitivity and Learning - Probabilistic Reward Task [ Time Frame: Pre-injection and approximately 2 hours post-injection ]
    Implicit reward learning and sensitivity to monetary reward is assessed with the probabilistic reward task (PRT); change in the magnitude of response bias from baseline to post-injection is the outcome measure. Higher response bias indicates higher reward sensitivity/learning.

  10. Depressed Mood Subscale of the Profile of Mood States (POMS) [ Time Frame: 10 hours ]
    The Depressed Mood Subscale of the POMS is a self-reported assessment of depressed mood in which subjects rate severity of depressed mood using a visual analog scale from 1 to 10 (10 being most severe). Each timepoint is scored and analyses examine the temporal profile of change with assessment every hour

  11. Motivation for social and non-social reward (interest in activities scale). [ Time Frame: 10 hours ]
    This task will evaluate motivation for reward by subjective reports of interest in engaging in a variety of social and non-social activities on a 1 to 5 Likert scale on an hourly basis, with higher score indicating more interest. Each timepoint is scored and analyses examine the temporal profile of change with assessment at baseline and at 1 hour intervals post-injection.


Other Outcome Measures:
  1. Behavioral Indices of Reward Motivation and Sensitivity with Incentive Delay Tasks [ Time Frame: approximately 2 hours post-injection for 14 minutes ]
    Behavioral performance on the Monetary and Social Incentive Delay Tasks is tested as reaction time for reward vs no- reward cue trials (an index of motivation) and reaction time for low vs. high reward trials (an index of sensitivity to changes in reward magnitude).

  2. Behavioral Indices of Reward Sensitivity - Positive Images Task [ Time Frame: approximately 2 hours post-injection for 10 minutes ]
    Sensitivity for non-monetary reward assessed by self-report affect when viewing positive non-social vs neutral images, and when viewing positive social vs. neutral images, on a 1(extremely negative affect) to 4(extremely positive affect) scale.

  3. Behavioral Indices of Reward Sensitivity - EEfRT [ Time Frame: Pre-injection and 2 hours post-injection ]
    Sensitivity for monetary reward assessed by the degree to which higher potential winnings predict hard task choice.

  4. Emotion Intensity Task [ Time Frame: Baseline and 3 hours post-injection for five minutes ]
    This is a short computer-based task used to test emotion detection with a face morphing task. Faces morph from neutral to expressions of emotions (happy, sad, angry, or fearful) and participants indicate when and what emotion is presented; the dependent variables are reaction time and accuracy.

  5. Attentional Bias Task [ Time Frame: Baseline and 3 hours post-injection for five minutes ]
    This is a short computer-based task used to test attentional bias towards positive and negative valenced facial expressions (low arousal happy, high arousal happy, sad, angry) relative to neutral faces. Higher attentional bias scores indicate greater bias towards emotion.

  6. Systemic marker of inflammation as indexed by interleukin-6. [ Time Frame: 10 hours ]
    Systemic inflammation as measured by circulating levels of interleukin-6 in plasma in pg/ml. Each timepoint is assayed and analyses examine the temporal profile of change with assessment every hour

  7. Genomic marker of inflammation [ Time Frame: baseline and .5, 1, and 2 hours post-injection ]
    Transcriptional profile of inflammation as measured by Conserved Translational Response to Adversity in circulating peripheral blood mononuclear cells

  8. Executive function - inhibition with the antisaccade task. [ Time Frame: Baseline and 4 hours post-injection for 10 minutes. ]
    The Antisaccade task is used to assess Inhibition. Participants are tasked with inhibiting a reflexive response towards a visual cue in order to correctly identify a target stimulus presented elsewhere. For each of 72 trials, participants view a centrally positioned fixation point (the letter X) on the computer screen for a variable amount of time (1500-3500ms). A visual cue (a black circle) is then presented on one side of the computer screen for 225ms. The target stimulus (a number from 1 to 9) is presented on the opposite side of the screen for 250, 233, or 200ms before being masked by gray cross-hatching. The participant verbally reports the target number to a trained research assistant or recording device or uses the keyboard to indicate the number. The participant does not receive feedback regarding accuracy, and there is no time limit for participant response for each trial.

  9. Executive function - updating with the spatial 2-back task [ Time Frame: Baseline and 4 hours post-injection for 10 minutes. ]
    The Spatial 2-Back task is used to assess Updating, the ability to monitor and replace information in working memory. For each of 120 trials, participants view an array of boxes, 11 white and 1 black. The location of the black box varies across trials. Participants are tasked with using one of two keys to indicate whether the black box is presented in the same location as it was two trials back. Participants do not receive feedback regarding accuracy, and trials proceed automatically if a response is not made within 2000ms. The task includes 20 practice trials

  10. Executive function - shifting with color-shape task. [ Time Frame: Baseline and 4 hours post-injection for 10 minutes. ]
    The Color-Shape task is used to assess Shifting, or the ability to switch between mental sets. For each of 104 trials, participants are presented with a circle or square that is of blue or red color. Participants are asked to use 1 of 2 keys to indicate whether the figure is red or blue (52 color trials) or square or triangle (52 shape trials). One key is paired with a color and a shape (e.g., red and square) and one key is paired with the other color and shape (e.g., blue and circle). For each trial, the letter C or S is presented above the figure to indicate color versus shape trials. The order of C/S trials is randomized, and there is no time limit for participant response for each trial. A quiet "ding" occurs following incorrect trials. The task includes 52 practice trials: 26 color followed by 26 shape trials.

  11. Depressed mood and depressive symptoms as measured by the Montgomery Asberg Depression Rating Scale (MADRS) [ Time Frame: 10 hours ]
    Depressed mood and depressive symptom severity by self-reported assessment using the Montgomery Asberg Depression Rating scale with a range from 0 to 54 with a higher score indicating more severe depressive symptoms. Each timepoint is scored and analyses examine the temporal profile of change with assessment at baseline and at 2 hour intervals post-injection.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   60 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Participants will be required to be in good general health (as evaluated during the phone and in-person baseline session)
  • Participants will be aged 60 to 80 years.
  • Half the participants (n=40) will be those with clinically significant anxiety as defined by a score of 5 or greater on the GAD-7;
  • Half the participants (n=40) will be those with low anxiety as defined by a GAD-7 score of <5.

Exclusion Criteria:

  • Presence of chronic mental or physical illness (except for anxiety)
  • History of allergies, autoimmune, liver, or other severe chronic diseases
  • Current and regular use of prescription medications such as steroids, non-steroid anti-inflammatory drugs, aspirin, immune modifying drugs, opioid analgesics, statins, antihypertensive drugs, anti-arrhythmic drugs, and antidepressant medications (none in the last 6 months)
  • Nightshift work or time zone shifts (> 3hrs) within the previous 6 weeks
  • Previous history of fainting during blood draws.
  • Claustrophobia
  • Metal in the body
  • Presence of co-morbid medical conditions not limited to but including cardiovascular (e.g., history of acute coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders;
  • Presence of comorbid inflammatory disorders such as rheumatoid arthritis or other autoimmune disorders;
  • Presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or to put the study participant at undue risk;
  • Presence of chronic infection, which may elevate pro-inflammatory cytokines;
  • Presence of an acute infectious illness in the two weeks prior to an experimental session.
  • Current Axis I psychiatric disorders other than anxiety as determined by the Research Version of the Structured Clinical Interview
  • Lifetime history of suicide attempt or inpatient psychiatric admission.
  • Sleep Disorders: Current history of sleep apnea or nocturnal myoclonus;
  • Phase-shift disorder
  • Current and/or past regular use of hormone-containing medications including steroids;
  • Current and/or past regular use of non-steroid anti-inflammatory drugs;
  • Current and/or past regular use of immune modifying drugs that target specific immune responses such as cytokine antagonists;
  • Current and/or past regular use of analgesics such as opioids;
  • Current and/or past regular use of cardiovascular medications, including antihypertensive, anti-arrhythmic, antianginal, and anticoagulant drugs;
  • Current smoking
  • Current excessive caffeine use (>600 mg/day) because of the known effects on pro-inflammatory cytokine levels;
  • Evidence of recreational drug use from urine test.
  • Body mass index > 35 because of the effects of obesity on proinflammatory cytokine activity
  • Any clinically significant abnormality on screening laboratory tests
  • Clinically significant abnormalities in electrocardiogram

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05363527


Contacts
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Contact: Chloe C Boyle, PHD 3107949383 ccboyle@mednet.ucla.edu
Contact: Michael R Irwin, MD 3108258281 mirwin1@ucla.edu

Locations
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United States, California
Norman Cousins Center for Psychoneuroimmunology, University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Chloe Boyle, PhD    310-825-8788      
Principal Investigator: Chloe C Boyle, PHD         
Sub-Investigator: Michael R Irwin, MD         
Sponsors and Collaborators
University of California, Los Angeles
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Chloe C Boyle, PHD University of California, Los Angeles
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Responsible Party: Chloe Boyle, PhD, Adjunct Assistant Professor, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT05363527    
Other Study ID Numbers: K01AG072049 ( U.S. NIH Grant/Contract )
1K01AG072049-01A1 ( U.S. NIH Grant/Contract )
First Posted: May 6, 2022    Key Record Dates
Last Update Posted: August 24, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified data will be available to users upon request, provided the investigators are working under an institution with a Federal Wide Assurance (FWA). All requests for transfer of materials for research purposes will be made through a UCLA onlineMTA. Persons requesting access will be required to complete a data-sharing agreement providing for the maintenance of the confidentiality of research participants, describing use to which the data will be put, and requiring acknowledgement of the source of the data and its underlying NIA funding. The names and institutions of persons either given or denied access to the data, and the bases for such decisions, will be summarized in annual progress reports.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data will be made available by the on-line publication date once the data has been accepted for publication. All submitted data will conform to relevant data and terminology standards. This data sharing policy is intended to allow investigators sufficient time for data verification, and for submission of primary publications based on the collected data. We will identify where the data will be available, and how to access the data (i.e., by contacting Dr. Boyle directly), in any publication or presentation by Dr. Boyle and her mentorship team. Finally, we will acknowledge the funding source in any and all publications and presentations using these data.
Access Criteria:
  • investigators must be working under an institution with a Federal Wide Assurance (FWA);
  • persons requesting access will be required to complete a data-sharing agreement providing for the maintenance of the confidentiality of research participants, describing use to which the data will be put, and requiring acknowledgement of the source of the data and its underlying NIA funding.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chloe Boyle, PhD, University of California, Los Angeles:
anxiety
aging
anhedonia
inflammation
Additional relevant MeSH terms:
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Anhedonia
Inflammation
Depression
Anxiety Disorders
Behavioral Symptoms
Mental Disorders
Pathologic Processes
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases