Effect of Transcranial Magnetic Stimulation to the Frontoparietal Attention Network on Anxiety Potentiated Startle

• Sponsor: National Institute of Mental Health (NIMH) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT03027414
• Collaborator: (none)
• Enrollment: 61
• Location: 1
• Arms: 3
• Actual Duration (Months): 41.2
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

Background:

Researchers want to better understand brain processes related to fear and anxiety. They want to find out if transcranial magnetic stimulation (TMS), a type of brain stimulation, can reduce anxiety.

Objective:

To see how TMS affects fear and anxiety through memory and attention tasks.

Eligibility:

Healthy people ages 18-50 who are right-handed

Design:

Participants will be screened through another protocol.

Participants in the pilot study will have 1 visit. This includes:

Urine tests

Questionnaires about mood and thinking

Shock and startle workup: Electrodes are taped to the wrists or fingers. Participants will be shocked to find out what level of shock is uncomfortable but tolerable. They will hear loud, sudden noises through headphones.

TMS: A coil is held on the scalp. A magnetic field stimulates the brain. Sometimes they might receive fake TMS. This feels the same as real TMS. They will perform simple tasks. Participants in the main study will have 2 visits within 2 weeks.

The first visit includes:

Urine tests

Questionnaires about mood and thinking

MRI: Participants lie on a table that slides into a scanner. They will be in the scanner about 1 hour. A computer screen in the scanner will tell them to perform simple tasks.

The second visit includes:

Shock and startle workup

TMS

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Transcranial Magnetic Stimulation Sham; Device: Transcranial Magnetic Stimulation	N/A

Detailed Description

Objective: To determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Toward this aim we will test the effect of transcranial magnetic stimulation (TMS) on two outcome measures: 1) Fear and anxiety during the threat of predictable and unpredictable shock (NPU threat test; Substudies 1 and 3), and 2) Working memory (WM) related anxiety downregulation while performing the Sternberg WM task under threat of shock (Substudy 2).

Study population: The study population will consist of up to 184 healthy volunteers between the ages of 18-50.

Design: This study will consists of two (sub-studies 1 and 2) or three (sub-study 3) outpatient visits (1 MRI, 1 or 2 TMS visits [2 for sub-study 3]). In this protocol we will explore the effect of TMS in three sub-studies in the TMS study visit. The sub-studies will contain either the NPU or the Sternberg task during the TMS visits. The first visit (MRI) will consist of the same procedures for all sub-studies. Each subject will be assigned to only one of the sub-studies.

Sternberg Task: Expose subjects to active or sham TMS to a region of the frontoparietal attention network during the Sternberg WM task. Subjects will have to maintain a series of letters in WM for a brief interval during blocks of safety and threat of shock.

NPU Task: Expose subjects to active or sham TMS to a region of the frontoparietal attention network during the NPU threat test. Subjects will be exposed to blocks in which they are either 1) safe from shock (neutral), 2) at risk of shock delivered only during a cue (predictable), or 3) at risk of shock presented randomly (unpredictable).

Outcome measures: In both studies the primary outcome measure will be anxiety-potentiated startle (APS), which is the increase in startle magnitude during periods of threat compared to periods of safety. We expect active, but not sham TMS to increase activity in the dlPFC, and therefore reduce APS in both studies

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: The Effect of Transcranial Magnetic Stimulation to the Frontoparietal Attention Network on Anxiety Potentiated Startle
• Actual Study Start Date: Jan 23, 2017
• Actual Primary Completion Date: Jul 19, 2019
• Actual Study Completion Date: Jun 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Substudy 1 Active and Sham HVs that receive TMS over the right dlPFC	Drug: Transcranial Magnetic Stimulation Sham; TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.; Device: Transcranial Magnetic Stimulation; TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.
Experimental: Substudy 2 Active and Sham HVs that receive TMS over the right dlFPC	Drug: Transcranial Magnetic Stimulation Sham; TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.; Device: Transcranial Magnetic Stimulation; TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.
Experimental: Substudy 3 Active and Sham HVs will receive offline TMS to the lest IPS (FPN)	Drug: Transcranial Magnetic Stimulation Sham; TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.; Device: Transcranial Magnetic Stimulation; TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.

Outcome Measures

Primary Outcome Measures

1. Anxiety-potentiated Startle [Pre and post stimulation]

   Electromyography Facial electromyography (EMG) startle responses were recorded from the left orbicularis oculi muscle at 2000 Hz using a Biopac MP160 unit (Biopac; Goleta, CA) via 15 × 20 mm hydrogel coated vinyl electrodes (Rhythmlink #DECUS10026; Columbia, SC). Startle EMG was bandpass filtered from 30 to 300 Hz, rectified, and smoothed using a 20-ms sliding window. Startle responses were scored as the peak (max during the 20 ms to 120 ms post-noise window) - the baseline (50 ms pre-noise window), and converted to t-scores with a mean of 50 and a standard deviation of 10 (tx = [Zx × 10] + 50). Greater t-scores mean larger blinks, which could be associated with greater anxiety, however there is no clinically relevent threshold. Noisy trials (baseline SD > 2x run SD) were excluded, and "no blink" (peak < baseline range) trials were coded as 0. To calculate APS, we subtracted the response during the neutral ITI from the response during the unpredictable ITI.

2. Working Memory (WM) Related Anxiety Downregulation While Performing the Sternberg WM Task Under Threat of Shock. [Pre and post stimulation]

   Sternberg Task: Expose subjects to active or sham TMS to a region of the frontoparietal attention network during the Sternberg WM task. Subjects will have to maintain a series of letters in WM for a brief interval during blocks of safety and threat of shock. Electromyography Facial electromyography (EMG) startle responses are recorded from the left orbicularis oculi muscle at 2000 Hz. Startle EMG is bandpass filtered from 30 to 300 Hz, rectified, and smoothed using a 20-ms sliding window. Startle responses are scored as the peak (max during the 20 ms to 120 ms post-noise window) - the baseline (50 ms pre-noise window), and converted to t-scores (tx = [Zx × 10] + 50). Noisy trials (baseline SD > 2x run SD) are excluded, and "no blink" (peak < baseline range) trials are coded as 0. These t scores are then averaged across trials within each condition, and threat-safe contrasts are calculated independently for each level of load (low vs. high) and timing (maintenance vs. ITI).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

• Ages 18-50

• Subjects able to give their consent

• Right handed

EXCLUSION CRITERIA:

• Non-English speaking individual

• Any significant medical or neurological problems (e.g. cardiovascular illness, respiratory illness, neurological illness, seizure, etc.)

• Current or past Axis I psychiatric disorder(s) as identified with the Structured Clinical Interview for DSM-IV, non-patient edition (SCID-np)

• Active or history of active suicidal ideation.

• Evidence of a first-degree relative with history of psychosis or bipolar disorder; specifically, participant will know diagnosis or treatment in order to confirm presence of disorder.

• Alcohol/drug problems in the past year or lifetime alcohol or drug dependence according to the Structured Clinical Interview for DSM-IV.

• Current use of medications that act on histamine (i.e. diphenhydramine), dopamine (methylphenidate), norepinephrine (buproprion), serotonin (sertraline), or acetylcholine (amitryptiline) receptors. Subjects will be excluded on this basis if they either 1) take these medications on a chronic basis, or 2) if they have taken the drug within 5 half-lives of the drug metabolism, determined by the medical professional at the time of screening.

• History of seizure (childhood febrile seizures are acceptable and these subjects may be included in the study),

• History of epilepsy in self or first degree relatives, stroke, brain surgery, head injury, cranial metal implants, known structural brain lesion.

• Increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure (such as after large infarctions or trauma), or currently taking medication that lowers the seizure threshold (table below).

• Pregnancy, or positive pregnancy test.

• Neurological syndrome of the arm (e.g., carpal tunnel syndrome, cubital tunnel syndrome, etc.)

• Positive urine toxicology screen during the screening visit.

• IQ <80

• Employee or staff of NIMH or are an immediate family member of a NIMH employee, staff, or NIMH contractors.

• Allergy to lidocaine or topical anesthetics (participants in sub-study 3 only).

• Any medical condition that increases risk for fMRI or TMS:

• Any metal in their body which would make having an MRI scan unsafe, such as pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial heart valves, cochlear implants or shrapnel fragments, or if you were a welder or metal worker, since you may small metal fragments in the eye.

• Participants who are uncomfortable in small closed spaces (have claustrophobia) and would feel uncomfortable in the MRI machine

• Patients who have difficulty lying flat on their back for up to 60 min in the scanner

• History of hearing loss

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Christian Grillon, Ph.D., National Institute of Mental Health (NIMH)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 21, 2018
• Informed Consent Form - Dec 21, 2018

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Balderston NL, Quispe-Escudero D, Hale E, Davis A, O'Connell K, Ernst M, Grillon C. Working memory maintenance is sufficient to reduce state anxiety. Psychophysiology. 2016 Nov;53(11):1660-1668. doi: 10.1111/psyp.12726. Epub 2016 Jul 19.
• Schmitz A, Grillon C. Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test). Nat Protoc. 2012 Feb 23;7(3):527-32. doi: 10.1038/nprot.2012.001.
• Slotema CW, Blom JD, Hoek HW, Sommer IE. Should we expand the toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010 Jul;71(7):873-84. doi: 10.4088/JCP.08m04872gre. Epub 2010 Mar 9.

• Responsible Party: National Institute of Mental Health (NIMH)
• ClinicalTrials.gov Identifier: NCT03027414
• Other Study ID Numbers: 170042; 17-M-0042
• First Posted: Jan 23, 2017
• Last Update Posted: May 17, 2022
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by National Institute of Mental Health (NIMH): Anxiety; Startle; Dorsolateral Prefrontal Cortex; Transcranial Magnetic Stimulation (TMS); Working Memory
• Additional relevant MeSH terms: Anxiety Disorders

Study Results

Participant Flow

Arm/Group Title	Substudy 1 Active and Sham	Substudy 2 Active and Sham	Substudy 3 Active and Sham
Arm/Group Description	HVs that receive active and sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.	HVs that receive active and sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.	HVs will receive offline TMS to the lest IPS (FPN) Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.
Period Title: Overall Study
STARTED	28	0	26
COMPLETED	19	0	20
NOT COMPLETED	9	0	6

Baseline Characteristics

Arm/Group Title	Substudy 1 Active and Sham	Substudy 2 Active and Sham	Substudy 3 Active and Sham	Total
Arm/Group Description	HVs that receive active and Sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.	HVs that receive active and Sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.	HVs will receive offline TMS to the lest IPS (FPN) Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.	Total of all reporting groups
Overall Participants	28	0	26	54
Age (Count of Participants)
<=18 years	0 0%	0 NaN	0 0%
Between 18 and 65 years	28 100%	26 Infinity	54 207.7%
>=65 years	0 0%	0 NaN	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.25 (7.414392375)	30.46153846 (8.52701936)	28.7962963 (8.129460894)
Sex: Female, Male (Count of Participants)
Female	15 53.6%	16 Infinity	31 119.2%
Male	13 46.4%	10 Infinity	23 88.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 14.3%	3 Infinity	7 26.9%
Not Hispanic or Latino	24 85.7%	23 Infinity	47 180.8%
Unknown or Not Reported	0 0%	0 NaN	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN	0 0%
Asian	5 17.9%	8 Infinity	13 50%
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN	0 0%
Black or African American	4 14.3%	5 Infinity	9 34.6%
White	16 57.1%	12 Infinity	28 107.7%
More than one race	3 10.7%	1 Infinity	4 15.4%
Unknown or Not Reported	0 0%	0 NaN	0 0%
Region of Enrollment (participants) [Number]
United States	28 100%	26 Infinity	54 207.7%

Outcome Measures

1. Primary Outcome

Title	Anxiety-potentiated Startle
Description	Electromyography Facial electromyography (EMG) startle responses were recorded from the left orbicularis oculi muscle at 2000 Hz using a Biopac MP160 unit (Biopac; Goleta, CA) via 15 × 20 mm hydrogel coated vinyl electrodes (Rhythmlink #DECUS10026; Columbia, SC). Startle EMG was bandpass filtered from 30 to 300 Hz, rectified, and smoothed using a 20-ms sliding window. Startle responses were scored as the peak (max during the 20 ms to 120 ms post-noise window) - the baseline (50 ms pre-noise window), and converted to t-scores with a mean of 50 and a standard deviation of 10 (tx = [Zx × 10] + 50). Greater t-scores mean larger blinks, which could be associated with greater anxiety, however there is no clinically relevent threshold. Noisy trials (baseline SD > 2x run SD) were excluded, and "no blink" (peak < baseline range) trials were coded as 0. To calculate APS, we subtracted the response during the neutral ITI from the response during the unpredictable ITI.
Time Frame	Pre and post stimulation

Outcome Measure Data

Analysis Population Description

Healthy Volunteers

Arm/Group Title	Substudy 1 Active and Sham	Substudy 3 Active and Sham
Arm/Group Description	HVs that receive active and sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.	HVs will receive offline TMS to the lest IPS (FPN) Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.
Measure Participants	19	19
Active	6.032164105 (1.31706568)	2.420193836 (1.174992336)
Sham	3.412441384 (1.02011584)	4.467812115 (0.966471881)
No TMS / Pre-stimulation	2.832028871 (0.989278736)	4.960918182 (1.111076546)

2. Primary Outcome

Title	Working Memory (WM) Related Anxiety Downregulation While Performing the Sternberg WM Task Under Threat of Shock.
Description	Sternberg Task: Expose subjects to active or sham TMS to a region of the frontoparietal attention network during the Sternberg WM task. Subjects will have to maintain a series of letters in WM for a brief interval during blocks of safety and threat of shock. Electromyography Facial electromyography (EMG) startle responses are recorded from the left orbicularis oculi muscle at 2000 Hz. Startle EMG is bandpass filtered from 30 to 300 Hz, rectified, and smoothed using a 20-ms sliding window. Startle responses are scored as the peak (max during the 20 ms to 120 ms post-noise window) - the baseline (50 ms pre-noise window), and converted to t-scores (tx = [Zx × 10] + 50). Noisy trials (baseline SD > 2x run SD) are excluded, and "no blink" (peak < baseline range) trials are coded as 0. These t scores are then averaged across trials within each condition, and threat-safe contrasts are calculated independently for each level of load (low vs. high) and timing (maintenance vs. ITI).
Time Frame	Pre and post stimulation

Outcome Measure Data

Analysis Population Description

No participants were recruited in Substudy 2. Study was stopped because lead investigator (Dr. Balderston) changed position prior to the initiation of Study 2

Arm/Group Title	Substudy 2
Arm/Group Description	HVs that receive TMS over the right dlFPC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.
Measure Participants	0

Adverse Events

Time Frame	During study participation, which typically lasted less than 1 month.
Adverse Event Reporting Description	The Principal Investigator was responsible for detecting, documenting, and reporting unanticipated problems, adverse events (AEs), including serious adverse events (SAEs), and deviations in accordance with NIH policy, IRB requirements, and federal regulations. Relatedness to the research of all serious adverse events will be determined by the PI in consultation with the CD.
Arm/Group Title	Substudy 1 Active and Sham		Substudy 2 Active and Sham		Substudy 3
Arm/Group Description	HVs that receive active and Sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.		HVs that receive active and Sham TMS over the right dlPFC Transcranial Magnetic Stimulation Sham: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects. Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.		HVs will receive offline TMS to the lest IPS (FPN) Transcranial Magnetic Stimulation: TMS device is used to determine the effect of non-invasive brain stimulation on anxiety and anxiety-cognition interactions in healthy subjects.
All Cause Mortality
	Substudy 1 Active and Sham		Substudy 2 Active and Sham		Substudy 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/0 (NaN)		0/26 (0%)
Serious Adverse Events
	Substudy 1 Active and Sham		Substudy 2 Active and Sham		Substudy 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/28 (3.6%)		0/0 (NaN)		0/26 (0%)
Product Issues
Possible vasovagal syncope	1/28 (3.6%)	1	0/0 (NaN)	0	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	Substudy 1 Active and Sham		Substudy 2 Active and Sham		Substudy 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/28 (28.6%)		0/0 (NaN)		3/26 (11.5%)
Product Issues
mild headache	4/28 (14.3%)	5	0/0 (NaN)	0	3/26 (11.5%)	3
scalp or face discomfort	3/28 (10.7%)	3	0/0 (NaN)	0	0/26 (0%)	0
non-medical device malfunction	1/28 (3.6%)	1	0/0 (NaN)	0	0/26 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.