Influence of Stress on Encoding and Prediction

This study aims to assess the neural and behavioral mechanisms by which acute stress modulates episodic encoding (which involves the trisynaptic pathway: entorhinal cortex, dentate gyrus, cornu ammonis \[CA\] 3, and CA 1) and statistical learning (monosynaptic pathway: entorhinal cortex, CA1) in humans.

• Socially Evaluated Cold Pressor Test (Behavioral): The SECPT is a brief validated laboratory-based stress induction containing both physical and social elements
• Control (Behavioral): This is matched to the SECPT but with warm instead of cold water

Primary outcomes

• Changes in fMRI Signal [1-2 hours]: fMRI signal during learning will be assessed using connectivity, multivariate, and univariate approaches over 1-2 hour long learning period. Correlation between change in CA1-EC background connectivity and pair familiarity. rho represents the true correlation within the entire population, with values ranging from -1 to +1; values closer to +1 indicate a strong positive linear relationship, closer to -1 a strong negative one, and closer to 0 indicate no linear relationship.
• Statistical Learning [1-2 hours]: Online measures of statistical learning ( mean reaction time) based on item predictability during task for condition A, B or x.
• Retention of Statistical Learning [1 hour]: Offline measure of statistical learning assessed through familiarity tests the next day (comparison of accurate recognition of previously-studied pairs to chance, 50%)
• Episodic Memory [1 hour]: Memory for individual items will be assessed through performance on old/new recognition tests the next day, quantified as hit rates and A' (non-parametric normalized ratio of hits to false alarms). Data presented here is the proportion of studied items attributed to the correct condition (A, B or X) minus the proportion of nonstudied items incorrectly attributed to that same condition.

Secondary outcomes

• Cortisol Reactivity [1-2 hours]: Change in salivary cortisol levels following the SECPT/control procedure
• Alpha-amylase Reactivity [1-2 hours]: Change in salivary alpha-amylase levels following the SECPT/control procedure

Sex: All, ages: 18 Years to 45 Years, accepts healthy volunteers

Inclusion Criteria:

* 18-45 years old
* Fluent in English
* BMI 18-35

Exclusion Criteria:

* Meeting current DSM-V criteria for any substance use disorder (except caffeine)
* Having current significant medical conditions or psychiatric symptoms requiring medication
* Current use of medications/drugs that interfere with physiological stress responses
* Peri and post-menopausal women, pregnant or lactating women, and those with hysterectomies
* Metal in body (for MRI safety) history will be assessed for female participants.

Participant flow

Outcome results

• Changes in fMRI Signal (Primary), Number, Pearson's rho: Acute Stress 0.261; No Stress -0.264 (p 0.023)
• Statistical Learning (Primary), Mean, minutes: Acute Stress 0.692 +/- 0.092; No Stress 0.698 +/- 0.078 (p 0.281)
• Retention of Statistical Learning (Primary), Mean, correct pairs: Acute Stress 0.537 +/- 0.247; No Stress 0.477 +/- 0.188 (p 0.143)
• Episodic Memory (Primary), Mean, proportion of items: Acute Stress 0.067 +/- 0.076; No Stress 0.639 +/- 0.072 (p <0.0001)
• Cortisol Reactivity (Secondary), Mean, log nmol/L: Acute Stress 0.636 +/- 0.655; No Stress -0.252 +/- 0.475 (p < 0.000)
• Alpha-amylase Reactivity (Secondary), Mean, log nmol/L: Acute Stress -0.286 +/- 1.270; No Stress -0.281 +/- 1.199 (p 0.083)

Adverse events

Time frame: 2 days

• Study Protocol and Statistical Analysis Plan (PDF, 2023-12-06)
• Informed Consent Form (PDF, 2023-12-06)

• Elizabeth V Goldfarb, PhD, Principal investigator, Yale University

NIH grants: R21MH128740