Aging and Reward System Response to Inflammation and Anxiety Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Experimental Model of Depression in Aging: Anxiety, Inflammation, and Reward Mechanisms

Conditions
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Anhedonia, Inflammation, Anxiety, Aging, Depression

Intervention / Treatment
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* Biological: Endotoxin
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Endotoxin vs. Placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Endotoxin<br>Endotoxin 0.8 ng/kg body weight | Biological: Endotoxin<br>* Endotoxin<br>|
| Placebo Comparator: Placebo<br>same volume of 0.9% saline | Biological: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neural Indices of Reward Motivation - Anticipatory Reward Response | 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. | approximately 2 hours post-injection for 7 minutes | 
| Neural Indices of Reward Motivation - Effort-Based Decision Making | 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). | approximately 2 hours post-injection for 14 minutes | 
| Neural Indices of Monetary Reward Sensitivity during Effort-Based Decision Making | 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. | approximately 2 hours post-injection for 14 minutes | 
| Neural Indices of Reward Sensitivity for Non-Monetary Reward | 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. | approximately 2 hours post-injection for 10 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting state functional connectivity | 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 hours post-injection for 7 minutes | 
| Social Incentive Delay Task - Neural Indices of Social Reward Motivation | 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. | approximately 2 hours post-injection for 7 minutes | 
| Social Incentive Delay Task - Neural Indices of Reward Motivation for Close Social Reward | 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). | approximately 2 hours post-injection for 7 minutes | 
| Behavioral Indices of Reward motivation - close other social reward | 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). | 2 hours post-injection | 
| Monetary Incentive Delay Task -Neural Indices of Monetary Reward Sensitivity | 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. | approximately 2 hours post-injection for 7 minutes | 
| Social Incentive Delay Task - Neural Indices of Social Reward Sensitivity | Sensitivity for social reward as assessed by VS and VMPFC activity during outcomes (reward vs. no-reward) on the Social Incentive Delay Task. | approximately 2 hours post-injection for 7 minutes | 
| Social Incentive Delay Task - Neural Indices of Reward Sensitivity for Close Social Reward | 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. | approximately 2 hours post-injection for 7 minutes | 
| Behavioral Indices of Reward Motivation - Effort-Based Decision Making | 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. | Pre-injection and approximately 2 hours post-injection | 
| Behavioral Indices of Reward Sensitivity and Learning - Probabilistic Reward Task | 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. | Pre-injection and approximately 2 hours post-injection | 
| Depressed Mood Subscale of the Profile of Mood States (POMS) | 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 | 10 hours | 
| Motivation for social and non-social reward (interest in activities scale). | 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. | 10 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anxiety, aging, anhedonia, inflammation