Inflammation's Impact on Reward Response in Aging and Anxiety
(ARIA Trial)
Recruiting in Palo Alto (17 mi)
Overseen byChloe C Boyle, PHD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of California, Los Angeles
Must not be taking: Steroids, NSAIDs, Antidepressants, others
Disqualifiers: Chronic illness, Cardiovascular, Neurological, others
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
Yes, you will need to stop taking certain medications. The trial excludes participants who currently use prescription medications like steroids, anti-inflammatory drugs, antidepressants, and several others. You must not have used these medications in the last 6 months.
What data supports the effectiveness of this treatment for inflammation's impact on reward response in aging and anxiety?
The research suggests that inflammation affects motivation and reward processing in the brain, which is linked to psychiatric symptoms like anhedonia (inability to feel pleasure). Although no specific treatment is mentioned, understanding these mechanisms could help develop therapies targeting inflammation to improve motivation and reward response.
12345Is the treatment generally safe for humans?
The research does not provide specific safety data for the treatment in humans, as it focuses on the effects of inflammation on behavior and brain function rather than safety outcomes.
12456How does this treatment differ from other treatments for inflammation's impact on reward response in aging and anxiety?
This treatment is unique because it explores the role of inflammation in altering motivation and reward sensitivity, potentially using minocycline to target microglia (immune cells in the brain) to modulate these effects. Unlike traditional treatments that may not address the inflammatory component, this approach focuses on the underlying neuroimmune mechanisms that affect reward processing.
12357Eligibility Criteria
This trial is for adults aged 60-80, with or without anxiety. Participants must be in good health and not have severe chronic diseases, autoimmune disorders, uncontrolled medical conditions, a BMI over 35, or use certain medications like steroids or anti-inflammatories. They can't have a history of serious psychiatric issues or current sleep disorders.Inclusion Criteria
I am between 60 and 80 years old.
Revised Criterion: Half of the participants (40 out of the total) will be those who have significant anxiety, which is determined by a score of 5 or higher on the GAD-7 questionnaire.
Half of the participants (40 out of the total) will be those who have very low anxiety, as indicated by a GAD-7 score of less than 5.
+1 more
Exclusion Criteria
You have used recreational drugs, as shown by a urine test.
You have tried to harm yourself or have been hospitalized for mental health reasons in the past.
You drink a lot of caffeine every day (more than 600 mg), which can affect certain substances in the body that cause inflammation.
+24 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
Up to 30 minutes
Phone screening
Visit 1
In-person evaluation including clinical interviews, questionnaires, and computer tasks to assess motivation and sensitivity to reward
4 hours
1 visit (in-person)
Visit 2
Administration of endotoxin vs. placebo, repeated blood sampling, mood and symptom questionnaires, and a brain scan
10.5 hours
1 visit (in-person)
Follow-up
Participants are monitored for physical and mood symptoms post-treatment
2 weeks
2 follow-up calls
Participant Groups
The study tests how older adults with varying levels of anxiety respond to an experimental inflammation challenge (using Endotoxin vs Placebo). It measures changes in pleasure and motivation through questionnaires, computer tasks, and brain scans.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: EndotoxinExperimental Treatment1 Intervention
Endotoxin 0.8 ng/kg body weight
Group II: PlaceboPlacebo Group1 Intervention
same volume of 0.9% saline
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Norman Cousins Center for Psychoneuroimmunology, University of California, Los AngelesLos Angeles, CA
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Who Is Running the Clinical Trial?
University of California, Los AngelesLead Sponsor
National Institute on Aging (NIA)Collaborator
References
Effects of an experimentally induced inflammatory stimulus on motivational behavior in remitted depressed patients. [2023]Acute inflammation is associated with sickness behavior characterized by reduced motivation for pleasurable activities in humans. The current study investigated the effect of an experimentally induced inflammatory stimulus on motivational reward in people who remitted from depression.
Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. [2021]Inflammation has been implicated in the development of various psychiatric disorders, including depression. However, the neurobehavioral mechanism involved in this relationship remains elusive. This gap in knowledge may best be filled by evaluating elementary neurobehavioral units affected by inflammation rather than behavioral changes in conventional animal tests of depression. To this end, the current study used a concurrent choice paradigm to evaluate inflammation-induced motivational changes. Male C57BL/6J mice (n=27) were food restricted to between 85 and 90% of their free-feeding weight and were trained to perform a concurrent choice task where they nose-poked for grain rewards on a fixed ratio (FR) 1 schedule (low effort/low reward) and chocolate-flavored rewards on a FR-10 schedule (high effort/high reward). A counterbalanced-within subjects design was used. A single intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) was used to induce peripheral inflammation. Twenty-four hours after LPS administration, mice showed a reduction in the total number of nose pokes. A proportionally greater reduction in nose pokes was observed for grain, resulting in an increase in percent chocolate pellets earned. These behavioral changes cannot be explained by reduced appetite as feeding before the test led to a similar increase in percent chocolate pellets earned but without any decrease in responding. These results indicate that inflammation modulates incentive motivation by affecting willingness to exert effort for reward and not by reducing sensitivity to reward.
Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive. [2021]Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA) that is associated with a reduced willingness to expend effort for reward. To date, however, the broader implications of this communication between inflammation and mesolimbic DA have yet to be explored. Here, we suggest that the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can't) versus preference (won't) for reward. This theoretical framework can inform how the mesolimbic DA system responds to increased immunometabolic demands during chronic inflammation, ultimately contributing to motivational impairments in psychiatric and other medical disorders.
Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications. [2022]Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.
Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms. [2023]Increased inflammation has been implicated in many psychiatric conditions across ages. We previously reported relationships between blood cytokine levels and anhedonia, the decreased capacity to experience pleasure, as well as with reward brain activation in adolescents with psychiatric symptoms. Here, we sought to extend this work in a larger cohort of adolescents with psychiatric symptoms and assess the relationships of C-Reactive Protein (CRP, inflammation biomarker) with clinical symptoms and reward-related brain activation.
Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms. [2023]Inflammation has been hypothesized to contribute to reward dysfunction across psychiatric conditions, but little is known about this relationship in youth. Therefore, the present study investigated the associations between general and specific markers of inflammation and neural activation during reward processing, including anticipation and attainment, in youth with diverse psychiatric symptoms.
Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by minocycline. [2023]Label="BACKGROUND">Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1 ng/kg) and placebo. Half (N = 8) received minocycline (100 mg bd) and half (N = 7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 h post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-α, IL-8, IL-10 responses (all condition × time interactions: p < 0.005), none were significantly modulated by minocycline (p > 0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F(1,13) = 6.10, p = 0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F(1,13) = 4.28, p = 0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression.