Exercise Facilitation of Adolescent Fear Extinction, Frontolimbic Circuitry, and Endocannabinoids (BRAINS)

Anxiety disorders commonly begin during adolescence, and are characterized by deficits in the ability to inhibit or extinguish pathological fear. Recent research has provided new understanding of how fear is learned and can be regulated in the adolescent brain, and how the endocannabinoid system shapes these processes; however, these advances have not yet translated into improved therapeutic outcomes for adolescents with anxiety. This study will test whether a behavioral intervention, acute exercise, can help to improve fear regulation by enhancing brain activity and endocannabinoid signaling. This line of research may ultimately lead to more effect treatments for adolescent anxiety, and to new preventive strategies for at-risk youth.

Study Overview

• Status: Recruiting
• Conditions: Adolescence
• Intervention / Treatment: Behavioral: Moderate Intensity Exercise

• Study Type: Interventional
• Enrollment (Estimated): 174
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Tolan Park Medical Building
      • Contact: MacKenna Shampine; Phone Number: 313-242-7464‬; Email: mackenna.shampine@wayne.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and available for the duration of the study
3. 14-17 years of age upon enrollment
4. Right-handed
5. In good general health as evidenced by medical history
6. Adolescent and parent/guardian are English-speaking, as study assessments are in English
7. Availability of a parent or legal guardian who is willing to provide consent and attend all study visits

Exclusion Criteria:

1. Traumatic brain injury with ongoing symptoms
2. Sensory (e.g., hearing) or physical (e.g., motor, balance) impairment or significant developmental delay
3. MRI participants: MRI contraindication (e.g., braces, implants, claustrophobia)
4. Any condition that would contraindicate blood draws (e.g., hemophilia, sickle cell)
5. Past or current diagnosis or presence of likely neurological disorder (e.g., epilepsy), psychotic disorder (e.g., schizophrenia, schizoaffective disorder), or bipolar disorder
6. Severe/unstable medical condition (e.g., diabetes, rheumatoid arthritis)
7. Current (past 1-month) use of cannabis or cannabinoid products including CBD unless willing to stop for at least 4 weeks prior to entering the study
8. Currently pregnant, lactating, or positive pregnancy test at screening visit
9. Current homicidal thoughts or suicide attempt in the past year
10. Current suicidal thoughts requiring immediate intervention
11. Concurrent use (past 6 weeks) of oral contraceptives
12. Diagnosed or probable substance use disorder (past 1-month)
13. Positive drug test at baseline visit (e.g., THC, cocaine)
14. Moderate/severe drug or alcohol use in the past 8 weeks
15. Current or recent (past 1-month) COVID-19 diagnosis or febrile illness
16. Treatment with investigational drug or intervention (past 1-month)
17. Current smoker, vaper, or tobacco or nicotine use (past 1-month)
18. Ongoing exposure to abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate Intensity Exercise	Behavioral: Moderate Intensity Exercise; Participants randomized to the active (moderate intensity) exercise condition will complete a 3-minute warm-up at low speed on a treadmill. Speed and incline will be increased in 3-minute increments until moderate-intensity exercise, defined as participants staying within a zone of 60-80% AAMHR with the target being to attain and maintain 70-75% AAMHR while briskly walking and/or jogging depending on current fitness status, is reached for a total of 30 min.
No Intervention: Control (Coloring)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Unconditioned Stimulus (US) Expectancy Ratings	US Expectancy Ratings will be measured during fear learning, extinction, and recall tasks	Throughout study completion (3 days)
Endocannabinoid (eCB) Concentrations	Plasma and saliva samples will be collected immediately before and after exercise or sedentary control condition. Samples will be analyzed using liquid chromatography-mass spectrometry to quantify concentrations of eCBs.	eCB concentrations will be measured in plasma and saliva immediately before and after the exercise or control condition on Day 2
Skin Conductance Responding (SCR)	To compare the effects of acute moderate-intensity exercise (vs. sedentary control) on extinction recall, the investigators will place three electrodes on participant's left hand to acquire SCR data using a BIOPAC MP160 Data Acquisition System (BIOPAC Systems, Inc.).	Throughout study completion (3 days)
Fear extinction neural circuitry: Functional activation and coupling	MRI eligible only: fMRI blood-oxygen-level-dependent (BOLD) response will be measured across the entire brain during a test of extinction recall. The investigators will focus on response in the hippocampus and ventromedial prefrontal cortex activation and coupling (gPPI) during recall (CS+E>CS+U).	Neuroimaging will occur during the fear extinction recall phase on Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fear Ratings	Fear ratings to each CS will be captured at the beginning, middle, and end of each phase, using a response pad and a 1-5 visual analog scale (1 = not scary at all, 5 = very scary).	Throughout study completion (3 days)
Amygdala response during extinction recall	MRI Eligible Only: fMRI blood-oxygen-level-dependent (BOLD) response will be measured across the entire brain during a test of extinction recall. A secondary region of interest is amygdala response during recall (CS+E>CS+U).	Neuroimaging will occur during the fear extinction recall phase on Day 3
Approach/Avoidance Behavior	The investigators will quantify forward-to-backward response pad distance in virtual meters from the conditioned stimulus.	Throughout study completion (3 days)

Collaborators and Investigators

• Sponsor: Wayne State University
• Collaborators: National Institute of Mental Health (NIMH)

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: February 15, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 7, 2024

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: exercise; anxiety; fear
• Other Study ID Numbers: IRB-23-01-5444; R01MH132830 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No