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

NCT04273880 | Recruiting Phase 1

• 2 other identifiers: H13-002865R01DA037285-05
• Study Type: interventional
• Target: 146
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Stress

Outcome Measures

Primary Outcomes (8)

• Selective attention as assessed by the Flanker/Reverse Flanker task: 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

  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

  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

  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

  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

  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

  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

  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

Study Arms (2)

10 mg Psychostimulant

EXPERIMENTAL

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

90 mg Vitamin C

PLACEBO COMPARATOR

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

Interventions

Methylphenidate DRUG

10mg of MPH taken an hour and a half before one of the testing sessions.

Also known as: 02249324

10 mg Psychostimulant

Vitamin C DRUG

90 mg of Vitamin C taken an hour and a half before the other testing session

Also known as: Ascorbic Acid

90 mg Vitamin C

Eligibility Criteria

• Age: 20 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between the ages of 20 and 35 years old

You may not qualify if:

• 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

Sponsors & Collaborators

• University of British Columbia: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Developmental Cognitive Neuroscience Lab, Department of Psychiatry, University of British Columbia

Vancouver, British Columbia, V6T 2A1, Canada

RECRUITING

Related Publications (15)

• Arnsten AF, Goldman-Rakic PS. Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry. 1998 Apr;55(4):362-8. doi: 10.1001/archpsyc.55.4.362.

  PMID: 9554432 BACKGROUND

• Barkley, R. A. (2001). The inattentive type of ADHD as a distinct disorder: What remains to be done. Clinical Psychology: Science and Practice, 8, 489-493.

  BACKGROUND

• Barkley RA, DuPaul GJ, McMurray MB. Attention deficit disorder with and without hyperactivity: clinical response to three dose levels of methylphenidate. Pediatrics. 1991 Apr;87(4):519-31.

  PMID: 2011430 BACKGROUND

• Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, Hamilton C, Spencer RC. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006 Nov 15;60(10):1111-20. doi: 10.1016/j.biopsych.2006.04.022. Epub 2006 Jun 23.

  PMID: 16806100 BACKGROUND

• Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci. 2007 Mar 14;27(11):2781-7. doi: 10.1523/JNEUROSCI.4372-06.2007.

  PMID: 17360899 BACKGROUND

• Devilbiss DM, Berridge CW. Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry. 2008 Oct 1;64(7):626-35. doi: 10.1016/j.biopsych.2008.04.037. Epub 2008 Jun 30.

  PMID: 18585681 BACKGROUND

• Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull. 2004 May;130(3):355-91. doi: 10.1037/0033-2909.130.3.355.

  PMID: 15122924 BACKGROUND

• Elliott R, Sahakian BJ, Matthews K, Bannerjea A, Rimmer J, Robbins TW. Effects of methylphenidate on spatial working memory and planning in healthy young adults. Psychopharmacology (Berl). 1997 May;131(2):196-206. doi: 10.1007/s002130050284.

  PMID: 9201809 BACKGROUND

• Lataster J, Collip D, Ceccarini J, Haas D, Booij L, van Os J, Pruessner J, Van Laere K, Myin-Germeys I. Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [(1)(8)F]fallypride. Neuroimage. 2011 Oct 15;58(4):1081-9. doi: 10.1016/j.neuroimage.2011.07.030. Epub 2011 Jul 23.

  PMID: 21801840 BACKGROUND

• Milich, R., Balentine, A. C., & Lynam, D. R. (2001). ADHD combined type and ADHD predominantly inattentive type are distinct and unrelated disorders. Clinical Psychology: Science and Practice, 8, 463-488.

  BACKGROUND

• Morrow BA, Roth RH, Elsworth JD. TMT, a predator odor, elevates mesoprefrontal dopamine metabolic activity and disrupts short-term working memory in the rat. Brain Res Bull. 2000 Aug;52(6):519-23. doi: 10.1016/s0361-9230(00)00290-2.

  PMID: 10974491 BACKGROUND

• Roth RH, Tam SY, Ida Y, Yang JX, Deutch AY. Stress and the mesocorticolimbic dopamine systems. Ann N Y Acad Sci. 1988;537:138-47. doi: 10.1111/j.1749-6632.1988.tb42102.x. No abstract available.

  PMID: 3059920 BACKGROUND

• Schmeichel BE, Zemlan FP, Berridge CW. A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder. Neuropharmacology. 2013 Jan;64(1):321-8. doi: 10.1016/j.neuropharm.2012.07.005. Epub 2012 Jul 11.

  PMID: 22796428 BACKGROUND

• Spencer RC, Klein RM, Berridge CW. Psychostimulants act within the prefrontal cortex to improve cognitive function. Biol Psychiatry. 2012 Aug 1;72(3):221-7. doi: 10.1016/j.biopsych.2011.12.002. Epub 2011 Dec 29.

  PMID: 22209638 BACKGROUND

• Weiss M, Worling D, Wasdell M. A chart review study of the inattentive and combined types of ADHD. J Atten Disord. 2003 Sep;7(1):1-9. doi: 10.1177/108705470300700101.

  PMID: 14738177 BACKGROUND

MeSH Terms

Interventions

Methylphenidate; Ascorbic Acid

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sugar Acids; Acids, Acyclic; Hydroxy Acids; Carbohydrates

Study Officials

• Adele Diamond, PhD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Daphne Ling, BSc

CONTACT

6048273074; daphne.ling@ubc.ca

David Abbott, BSc

CONTACT

6048273074; david.abbott@ubc.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Tier 1 Canada Research Chair

Study Record Dates

• First Submitted: May 27, 2019
• First Posted: February 18, 2020
• Study Start: April 28, 2018
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: May 8, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)