Differences by Sex and Genotype in the Effects of Stress on Executive Functions

May 16, 2022 updated by: Adele Diamond, University of British Columbia
The aim of this project is to test the effects of an environmental factor (mild stress) on prefrontal cortex (PFC) and the cognitive functions that depend on PFC (collectively called executive functions [EFs]), and to test our predictions concerning how those effects differ by biological factors (hormones and genotype). To test our hypotheses concerning mechanism, the investigators will model the effects of mild stress on EFs pharmacologically. The purpose is to pharmacologically model the effects of mild stress on the cognitive functions (collectively called "executive functions" [EFs]) dependent on the frontal lobe. The investigators would also like to investigate how gender differences and genotype mediate the effect of methylphenidate (MPH) on EFs.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The investigators propose to test each young adult twice; once on the lowest clinically relevant dose of MPH and once on a placebo (Vitamin C), with the order counterbalanced. The two testing sessions will be scheduled 4 weeks apart, once 90 minutes after taking 10mg MPH and once 90 minutes after taking a placebo (90 mg of Vitamin C). Peak plasma concentration of MPH is reached approximately 2 h after ingestion, thus to gain the maximum effect of MPH, the investigators will test subjects 90 minutes after ingestion. They will tell subjects that they are studying the effects of low-dose MPH on EFs, and that they expect it to help the EFs of some but hinder those of others, without telling them the study's predictions. Before each testing session, subjects will come to the lab 90 minutes in advance of the testing period. First, they will be given a pill they will take in front of a research assistant (MPH or placebo). The conditions will be counterbalanced across subjects within each subject group. This is a double-blind design, where neither subject nor tester will know which condition they will be in. The pills (10mg MPH, and 90mg Vitamin C) are made to be identical. They will be over-encapsulated with an opaque coloured capsule. The pills will be in kept in sealed containers that are labeled in such a way that neither the subjects, nor the testers, nor the PI, will not know which pill is which, until it is time for the data analysis. Only a pharmacist, at the compounding pharmacy, will know which container contains which pill.

At low doses the mode of action of MPH increases DA efflux specifically in PFC and preferentially enhances signal processing in PFC. Low dosages of MPH are often effective in improving EFs and specifically because of their effect on PFC. This slight increase of DA in the PFC is similar to the effects of mild stress on the brain, which is why the study uses a low dose of MPH as the pharmacological model of mild stress. Even mild stress markedly increases DA levels in PFC, impairing PFC function and EFs. The use of MPH is meant to mimic the effect of mild stress on the PFC and executive functions.

Purpose/objective: This double-blind study aims to compare performance on tasks of executive function between males, females when their estrogen levels are high, and females when their estrogen levels are low when they have undergone a pharmacological model of mild stress (low dosage of MPH) and when they have not undergone this stress. It also aims to compare the same across the three variants of the catechol-O-methyltransferase (COMT) genotype (methionine-methionine, methionine-valine, and valine-valine).

Hypotheses: MPH, like mild-stress, should raise PFC DA levels in COMT-Vals to optimal, but raise PFC DA levels in COMT-Mets past optimal (since low dose of MPH increases DA levels in PFC). While COMT-Mets generally show better EFs than COMT-Vals without MPH, on MPH that should be reversed with COMT-Vals performing better. An increase in PFC DA levels pharmacologically should mimic the sex difference in the effect of mild stress on EFs, harming females with high estrogen level's performance while enhancing males' performance on tasks of executive functions.

Study Type

Interventional

Enrollment (Anticipated)

146

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6T 2A1
        • Recruiting
        • Developmental Cognitive Neuroscience Lab, Department of Psychiatry, University of British Columbia
        • Contact:
        • Contact:
        • Principal Investigator:
          • Adele Diamond, Ph.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 33 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Between the ages of 20 and 35 years old

Exclusion Criteria:

  • a neurological impairment or disorder, learning disability, or psychological syndrome that might affect EF performance (such as ADHD)
  • inability to understand the task instructions (which are in English), or difficulty hearing the instructions, seeing the stimuli, or executing a manual response.
  • a serious adverse event during pregnancy or birth.
  • an injury (such as a head injury with loss of consciousness) that might affect EF performance.
  • a major trauma that might affect current EFs and stress responsivity
  • undue current life stress level
  • taking any medication that affects thinking, memory, mental clarity, or any other EF ability.
  • taking any medication that influences circulating gonadal hormone levels (such as oral contraceptives [birth control pill]).
  • having taken such medications within the preceding four months.
  • smokers
  • use of recreational drugs or consumption of alcohol 24 hours prior to the testing sessions
  • women without a period that occurs roughly every month (predicting the onset of the next menses in women who don't have their period monthly is difficult)
  • women who are pregnant or who are nursing.
  • having the eye problem glaucoma
  • having a heart condition
  • being anxious, tense or agitated
  • taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.
  • taking pressor agents (for hypotension treatment)
  • taking coumarin anticoagulants
  • taking anticonvulsants (phenobarbital, diphenylhydantoin, primidone)
  • taking phenylbutazone (nonsteroidal anti-inflammatory drug)
  • taking tricyclic antidepressants (imipramine, desipramine)
  • taking cold or allergy medicine that contain decongestants
  • being allergic to anything in either the MPH or Vitamin C capsules (methylphenidate HCL, ascorbic acid, lactose, gelatin, Titanium dioxide, D&C Red #28, FD&C Blue #1, FD&C Red #40)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 10 mg Psychostimulant
Drug: Methylphenidate (MPH) Participants will be tested twice, approximately one month apart. In one of the sessions, they will be given 10mg of MPH an hour and a half before the testing session is set to begin, to account for the time taken for the effects of the drug to start.
Drug: Methylphenidate
10mg of MPH taken an hour and a half before one of the testing sessions.
Other Names:
  • 02249324
Placebo Comparator: 90 mg Vitamin C
Placebo: Vitamin C Participants will be tested twice, approximately one month apart. In one of the sessions, they will be given 90mg of Vitamin an hour and a half before the testing session is set to begin, to follow the exact protocol that is used for MPH.
Drug: Vitamin C
90 mg of Vitamin C taken an hour and a half before the other testing session
Other Names:
  • Ascorbic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Selective attention as assessed by the Flanker/Reverse Flanker task: Day 1
Time Frame: Day 1
In the regular Flanker task, participants must selectively attend to the direction in which the center stimulus is pointing, ignoring the flanking stimuli. They must press the leftmost key or the rightmost key depending on the direction of the center stimulus. In the Reverse Flanker task, participants must selectively attend to the direction in which the flanking stimulus are pointing, ignoring the center stimulus. Response time and accuracy are measured.
Day 1
Selective attention as assessed by the Flanker/Reverse Flanker task: 1 Month
Time Frame: 1 Month
In the regular Flanker task, participants must selectively attend to the direction in which the center stimulus is pointing, ignoring the flanking stimuli. They must press the leftmost key or the rightmost key depending on the direction of the center stimulus. In the Reverse Flanker task, participants must selectively attend to the direction in which the flanking stimulus are pointing, ignoring the center stimulus. Response time and accuracy are measured.
1 Month
Working memory as assessed by the N-back task: Day 1
Time Frame: Day 1
In the N-back task, participants must watch a series of letters flash on screen and press the left mouse button whenever the stimulus that appeared was the same as the stimulus that appeared one stimulus prior (e.g. "A, J, A" - press at the second "A"). Response time and accuracy are measured in both tasks.
Day 1
Working memory as assessed by the N-back task: 1 Month
Time Frame: 1 Month
In the N-back task, participants must watch a series of letters flash on screen and press the left mouse button whenever the stimulus that appeared was the same as the stimulus that appeared one stimulus prior (e.g. "A, J, A" - press at the second "A"). Response time and accuracy are measured in both tasks.
1 Month
Working memory as assessed by the Forward Re-Ordering Digit Span task: Day 1
Time Frame: Day 1
In the Forward Re-Ordering Digit Span task, participants listen to a series of numbers read out by the tester and they must verbally re-order the numbers in the forward direction. Response time and accuracy are measured in both tasks.
Day 1
Working memory as assessed by the Forward Re-Ordering Digit Span task: 1 Month
Time Frame: 1 Month
In the Forward Re-Ordering Digit Span task, participants listen to a series of numbers read out by the tester and they must verbally re-order the numbers in the forward direction. Response time and accuracy are measured in both tasks.
1 Month
Inhibition as assessed by the Hearts & Flowers task: Day 1
Time Frame: Day 1
On the first block of the Hearts & Flowers task, participants must press the button on the same side as a stimulus (e.g. a heart). Then, on the second block, they must press the button on the opposite side as a stimulus (e.g. a flower). Response time and accuracy are measured.
Day 1
Inhibition as assessed by the Hearts & Flowers task: 1 Month
Time Frame: 1 Month
On the first block of the Hearts & Flowers task, participants must press the button on the same side as a stimulus (e.g. a heart). Then, on the second block, they must press the button on the opposite side as a stimulus (e.g. a flower). Response time and accuracy are measured.
1 Month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Collaborators

National Institute on Drug Abuse (NIDA)

Investigators

  • Principal Investigator: Adele Diamond, PhD, University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 28, 2018

Primary Completion (Anticipated)

December 1, 2024

Study Completion (Anticipated)

December 1, 2024

Study Registration Dates

First Submitted

May 27, 2019

First Submitted That Met QC Criteria

February 14, 2020

First Posted (Actual)

February 18, 2020

Study Record Updates

Last Update Posted (Actual)

May 18, 2022

Last Update Submitted That Met QC Criteria

May 16, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H13-00286
  • 5R01DA037285-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Data will be analyzed at the group level

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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