Inflammation's Impact on Reward Response in Aging and Anxiety

(ARIA Trial)

Overseen By Michael R Irwin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Los Angeles

Must not be taking: Steroids, NSAIDs, Antidepressants, others

Disqualifiers: Chronic illness, Cardiovascular, Neurological, others

Compensation: Varies

Number of Visits: 4

40 Participants Needed

Trial Summary

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. ^{1 2 3 4 5}

Is 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. ^{1 2 4 5 6}

How 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. ^{1 2 3 5 7}

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.

Research Team

Chloe C Boyle, PHD

Principal Investigator

University of California, Los Angeles

Eligibility 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.

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.

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

Treatment Details

Interventions

• N/A

Trial Overview 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.

Participant Groups

Group I: Endotoxin Experimental Treatment 1 Intervention

Endotoxin 0.8 ng/kg body weight

Group II: Placebo Placebo Group 1 Intervention

same volume of 0.9% saline

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

In a study involving 12 participants (5 with remitted major depressive disorder and 7 healthy controls), an inflammatory stimulus from a typhoid vaccine reduced motivation for effort-based tasks in those with a history of depression, indicating ongoing challenges in reward processing even after clinical remission.

The results showed that while healthy controls were more likely to choose harder tasks for rewards after a placebo, this difference disappeared after the inflammatory stimulus, suggesting that inflammation can diminish motivation in individuals with remitted depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of an experimentally induced inflammatory stimulus on motivational behavior in remitted depressed patients. Suchting, R., Razouq, D., Jose, L., et al.[2023]

In a study with 27 male mice, inflammation induced by lipopolysaccharide (LPS) reduced their motivation to perform tasks for food rewards, indicating that inflammation can affect incentive motivation rather than just appetite.

The mice showed a significant decrease in low-effort food-seeking behavior while still earning more high-effort rewards, suggesting that inflammation alters their willingness to exert effort for rewards rather than their sensitivity to the rewards themselves.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. Vichaya, EG., Hunt, SC., Dantzer, R.[2021]

Chronic low-grade inflammation can lead to reduced levels of dopamine in the brain's reward system, which may make individuals less willing to put in effort to achieve rewards.

This reduction in dopamine is linked to a steeper effort-discounting curve, suggesting that inflammation affects not just motivation but also how people perceive their ability to achieve rewards, which could have implications for various psychiatric and medical disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive. Treadway, MT., Cooper, JA., Miller, AH.[2021]

Inflammation can lead to motivational deficits and anhedonia, a key symptom of depression, by affecting neurotransmitter systems like dopamine and glutamate in brain regions involved in reward processing, such as the ventral striatum.

There is a significant opportunity to develop new or repurposed medications targeting inflammation and its effects on the brain, but current clinical trials have not effectively utilized this knowledge, highlighting the need for innovative trial designs that focus on motivation-related outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications. Lucido, MJ., Bekhbat, M., Goldsmith, DR., et al.[2022]

In a study of 64 adolescents with psychiatric symptoms, C-Reactive Protein (CRP), an inflammation biomarker, did not correlate with the severity of clinical symptoms like anxiety or depression.

However, higher CRP levels were linked to increased brain activation during reward-related tasks, suggesting that inflammation may influence brain function in the context of psychiatric conditions, even if it doesn't directly relate to symptom severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms. Liu, Q., Ely, B., Simkovic, S., et al.[2023]

In a study of 46 youth with psychiatric symptoms, specific inflammatory markers were found to negatively impact brain activity during reward anticipation and attainment, suggesting inflammation may disrupt reward processing in young people.

Certain cytokines were linked to reduced activation in key brain areas involved in reward processing, such as the basal ganglia and anterior cingulate cortex, highlighting the potential role of inflammation in psychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms. Bradley, KA., Stern, ER., Alonso, CM., et al.[2023]

In a study involving 15 healthy volunteers, the inflammatory agent lipopolysaccharide (LPS) was shown to significantly impair sensitivity to rewards compared to punishments, indicating that inflammation can negatively affect motivation and mood.

Minocycline, an antibiotic with anti-inflammatory properties, was effective in attenuating the negative effects of LPS on reward versus punishment sensitivity, suggesting a potential role for microglia in the motivational changes associated with inflammation and implications for treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by minocycline. De Marco, R., Barritt, AW., Cercignani, M., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Effects of an experimentally induced inflammatory stimulus on motivational behavior in remitted depressed patients. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by minocycline. [2023]