Neuromodulation of Brain and Emotional Responses to Psychological Stress (NUMBER)

Investigators are conducting this study to test if temporarily and non-invasively stimulating the brain will affect the emotional response to stress in healthy participants.

Participants will perform a series of tasks while completing an MRI scan. After this, participants will be randomized to undergo transcranial magnetic stimulation (TMS) at two visits, undergoing active stimulation at one visit and undergoing 'sham' stimulation at another visit. Immediately following both stimulation sessions, participants will repeat the tasks during MRI scanning.

Study Overview

• Status: Recruiting
• Conditions: Healthy; Anxiety
• Intervention / Treatment: Device: Active continuous theta burst stimulation; Device: Sham continuous theta burst stimulation

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas E Kraynak, PhD; Phone Number: 412-246-6361; Email: tekraynak@pitt.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Jacob White; Phone Number: 412-290-1097; Email: whitej32@upmc.edu
      • Contact: Natasha Brinkley; Phone Number: 412-551-9163; Email: brinkleynd@upmc.edu
      • Principal Investigator: Thomas E Kraynak, PhD

Participation Criteria

Eligibility Criteria

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

Description

1. Medication Use

   a. The following medications can affect brain and cardiovascular measures being obtained in this study; thus, use of the following medications on one or more occasions in the past 14 days constitutes grounds for exclusion: i. Antihypertensive or cardiac medications (diuretics, beta blockers, calcium channel blockers, ACE inhibitor/ARB, cardiac glycosides, central sympatholytic HTN drugs, anti-arrhythmic drugs, vasodilator drugs, other cardiac drugs) ii. Anticonvulsant medications iii. Anti-Parkinson medications iv. Protease inhibitors or other Anti-HIV medications v. Medications for the treatment of mania, including antipsychotics vi. All other centrally active or psychotropic medications (e.g., stimulants), excluding anxiolytic and antidepressant medications (see 1.b).

   vii. Insulin viii. Chemotherapy ix. Immunosuppressants and related biological agents (Imuran, methotrexate, and cyclophosphamide) x. Prescription weight loss medications and ephedrine OTC b. Reported use of the following medications on a "regular" basis is grounds for exclusion. For this purpose, "regular use" is defined as reporting that the prescribed medication was taken 7 or more days in the past 14 days. Individuals who take these medications, but less frequently than 7 out of the past 14 days are not excluded: i. Short-lasting benzodiazepines ii. Asthma oral medications iii. Asthma/allergy inhalants iv. Glucocorticoids (e.g., oral prednisone, cortisol) v. Medical marijuana c. The following medications can affect the CNS for 24 hours following administration; thus, reported use of the following medications within 48 hours of scanning is excluded: i. Longer acting benzodiazepines ii. Sleep medications (e.g., trazodone) d. Reported use of more than 2 non-insulin medications for diabetes on a "regular" basis is grounds for exclusion. For this purpose, reported use of combination medications, involving two or more non-insulin medications for diabetes in a single pill, is counted as 2 separate medications and would be grounds for exclusion.

   e. A person who reports that he or she was once on a disallowed medication but has discontinued this medication for at least a month or longer and is otherwise eligible, is allowed to participate in the study.

2. Substance use exclusions:

   1. Anyone reporting 35 or more alcoholic drinks in the last 7 days is excluded.
   2. Anyone reporting consumption of 6 or more alcoholic drinks on 3 or more occasions in the past 7 days is excluded.
   3. Anyone reporting use of illicit drugs on 7 or more days in the past 2 weeks is excluded.

3. Medical conditions:

   1. Epilepsy or a history of seizures.
   2. Self-reported prior heart attack, stroke, bypass surgery, angioplasty, congestive heart failure, arrhythmia (cardiac rhythm problems).
   3. Severe hypertension (SBP/DBP > 160/and/or >100 mmHg)
   4. Cancer (treatment in last 12 months, allowances for non-melanoma skin cancer)
   5. Liver disease
   6. Kidney disease
   7. Type I diabetes
   8. Self-reported history of a major neurological disorder or brain injury resulting in ongoing symptoms or cognitive impairment (e.g., multiple sclerosis, cerebral palsy, major head injury)
   9. Self-reported chronic psychotic illness (schizophrenia, bipolar disorder)
   10. Lung disease requiring drug treatment (note however that asthma or allergy inhalers are not exclusionary unless they are used on a "regular basis")
4. Pregnant participants, or participants actively planning to become pregnant in the next 3 months, are excluded.
5. Those with a visual impairment that would prevent them from reading printed text or text on a computer screen, iPad, or other electronic device are excluded.
6. Those with color blindness, who may not be able to distinguish colors on some of the tasks used in this study, are excluded.
7. Those who report that they are not comfortable with undergoing MRI because of the confined space would be excluded. If individuals are interested in the study, but unsure about their comfortability with undergoing an MRI, then they would be given the option to try going into a mock MRI, which is a replica of an MRI scanner. This is meant to aid interested individuals in determining whether they are comfortable with having an MRI. If they report that they are comfortable after this experience, then they would be eligible to continue. If not, then they would be discontinued from further participation.
8. Those who use certain medical devices, implants, or other metal objects in or on the body that cannot be removed and are incompatible with use of fMRI (for example, tattooed eyeliner) are excluded. Many devices can be deemed MRI compatible with the make and model of medical device. If a participant reports a metal medical device, a letter from a medical professional with the make and model number of the device may be used to assess compatibility.
9. Those who are unable to fit into an MRI scanner (over 7ft2in tall or greater than 350lbs weight) are excluded.
10. Those who report working the night shift on a frequent basis (half or more of the hours worked in a full workday are between midnight and 8 am, and this has occurred more than 12 times during the past year) are excluded.
11. Those who report undergoing brain stimulation procedures (including transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, or transcranial ultrasound stimulation) as part of research or therapy in the past month are excluded.
12. Lifetime history of a suicide attempt, or suicidal ideation within the past year.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active then Sham; In this arm, participants will first undergo active theta burst stimulation (cTBS) at the first visit and then undergo sham cTBS in the second visit.	Device: Active continuous theta burst stimulation; This intervention involves an active form of continuous theta burst stimulation (cTBS) that will be targeted to the dorsal anterior cingulate cortex based on neural navigation software. cTBS will be delivered in one session, lasting a few minutes, before participants complete additional testing.; Device: Sham continuous theta burst stimulation; This intervention involves an sham form of continuous theta burst stimulation (cTBS) that will be targeted to the dorsal anterior cingulate cortex based on neural navigation software. cTBS will be delivered in one session, lasting a few minutes, before participants complete additional testing.
Experimental: Sham then Active; In this arm, participants will first undergo sham theta burst stimulation (cTBS) at the first visit and then undergo active cTBS in the second visit.	Device: Active continuous theta burst stimulation; This intervention involves an active form of continuous theta burst stimulation (cTBS) that will be targeted to the dorsal anterior cingulate cortex based on neural navigation software. cTBS will be delivered in one session, lasting a few minutes, before participants complete additional testing.; Device: Sham continuous theta burst stimulation; This intervention involves an sham form of continuous theta burst stimulation (cTBS) that will be targeted to the dorsal anterior cingulate cortex based on neural navigation software. cTBS will be delivered in one session, lasting a few minutes, before participants complete additional testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic blood pressure response to stress	The difference in systolic blood pressure (in mmHg) obtained during the psychological stress task compared to a resting pre-stressor period.	30-60 mins post-stimulation
Heart rate response to stress	The difference in heart rate (in beats per minute) obtained during the psychological stress task compared to a resting pre-stressor period.	30-60 mins post-stimulation
Dorsal anterior cingulate cortex activation to stress	Blood-oxygen-level-dependent (BOLD) signal in a dorsal anterior cingulate cortex (dACC) region of interest mask extracted from the incongruent (stress) vs congruent (control) contrast.	30-60 mins post-stimulation
Dorsal anterior cingulate cortex connectivity to stress	Generalized psychophysiological interaction (gPPI) estimate reflecting stressor-evoked dorsal anterior cingulate cortex (dACC) functional connectivity to the anterior insula, amygdala, and periaqueductal gray.	30-60 mins post-stimulation
Change in arousal during stress	Rating on a modified self-assessment manikin scale (SAM) measuring subjective ratings of arousal ("To what extent do you feel calm?" 1 - very calm, 9 - very aroused) following the psychological stressor task compared to a pre-stressor baseline.	30-60 mins post-stimulation
Change in valence during stress	Rating on a modified self-assessment manikin scale (SAM) measuring subjective ratings of valence ("To what extent do you feel happy vs unhappy?" 1 - very unhappy, 9 - very unhappy) following the psychological stressor task compared to a pre-stressor baseline.	30-60 mins post-stimulation
Change in perceived control during stress	Rating on a modified self-assessment manikin scale (SAM) measuring subjective ratings of perceived control ("To what extent do you feel in control?" 1 - very little control, 9 - very much control) following the psychological stressor task compared to a pre-stressor baseline.	30-60 mins post-stimulation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dorsal anterior cingulate cortex (dACC) resting cerebral blood flow (rCBF)	Cerebral blood flow (in mL/g/min) obtained at rest within a dorsal anterior cingulate cortex (dACC) region of interest.	30-60 mins post-stimulation
Positive and Negative Affect Schedule - Expanded Form (PANAS-X)		30-60 mins post-stimulation

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Thomas E Kraynak, PhD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: September 16, 2024
• First Submitted That Met QC Criteria: September 16, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: stress; fMRI; neuromodulation; emotion; TMS; cardiovascular; functional Magnetic Resonance Imaging; transcranial magnetic stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders
• Other Study ID Numbers: STUDY24020114; K01MH137517 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will comply with all National Institute of Mental Health (NIMH) guidelines regarding data sharing and make use of NIMH databases.

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