- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02410954
Transcranial Direct Current Stimulation (tDCS) as a Treatment for Acute Fear (tDCS)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The National Institutes of Mental Health (NIMH) has recently identified that a major limitation to the understanding of neuropsychiatric disorders and the development of treatments for these conditions has been the inability to identify key dimensions of observable behavior that are central to these disorders and linked to underlying neurobiology by measurable biomarkers. This project is intended to address this problem by establishing that pupillary measures of norepinephrine (NE) neuronal activity are biomarkers of fear dimension of observable behavior, alterations of which are believed to be core features of neuropsychiatric conditions such as anxiety disorders. The investigators will establish this biomarker-clinical dimension link by comparing pupillary indices in humans to a carbon dioxide (CO2) fear provocation test, as well as in these subjects undergoing transcranial Direct Current Stimulation (tDCS) prior to and after CO2 administration.
Participants will be recruited in Dr. Krystal's laboratory at Duke University which has proven infrastructure for clinical trials. The study team plans to enroll a total of 240 subjects healthy volunteers (age range: 21-65 years) in order to complete 100. This takes into account the expected rate of failure to: have a pupillary response in the auditory oddball task (AOT) (25%); have a sufficient fear response to CO2 challenge (50% - relevant for last 10 R21 and all R33 subjects); and to meet other screening criteria.
R21 Phase: First 30 Subjects will undergo two sessions separated by 1 week in which a promising electrode configuration (three promising configuration will each be tested in a cohort of 10 subjects) will be used with tDCS stimulation at increasing electrical dosage during which pupillometry will be carried out to determine the auditory oddball test (AOT) response. A maximum of 5 total tDCS dosages and sham will be tested. Last 10 Subjects. These subjects will take part in a double-blind, controlled, randomized, cross-over study over 3 sessions. At session 1 subjects will undergo electrical dose titration with the tDCS electrode configuration resulting from the 3 rounds of optimization using the same procedure as in the first 30 subjects to determine the lowest well-tolerated dose that suppresses the AOT pupil response, except that a maximum of 5 tDCS dosages will be tested at this session. At the third and fourth sessions (1 week apart) subjects will receive dose-optimized tDCS and the control treatment with order randomized along with 7.5% CO2 (to evoke an LC response) for 20 minutes. The 7.5% CO2 will be delivered to us pre-mixed provided by Airgas. At these sessions, the VAS-A and State Trait Anxiety-Inventory (STA-I) will be administered 5 minutes prior to and just after the 20 minute session and Visual Analog Scale-Anxiety (VAS-A) will also be obtained at 5, 10, 15, and 20 minute points of the CO2 inhalation. tDCS will be administered during the last 5 minutes of the 20 minute CO2 inhalation period. Subjects will be monitored for an hour post-session for safety and will undergo study physician assessment to determine suitability to leave. Following the 2nd treatment session participation will end except that subjects will be called the next day to assess for adverse effects and appropriate care will be given if found. R33 Phase: 60 subjects will participate in a double-blind, randomized, controlled, parallel-group trial. They will be randomized to either active or control treatment and at the first post-screening visit they will undergo electrical dose titration as described above for the treatment they are randomized to. For all titrations, during the 5 minutes between tDCS treatments an unblinded member of the study team not having contact with the subjects will compute their AOT pupil response and convey to the tDCS treatment physician whether to continue or stop titration. Subjects randomized to the control treatment will undergo a sham titration where the stop level will be randomly selected from the distribution of titration outcomes occurring in the R21 phase. Subjects will then return in 1 week and undergo optimal dose tDCS or control treatment for a single treatment session as described in the prior paragraph. Primary outcome will be the VAS-A "fearful" rating obtained at the end of tDCS/CO2 inhalation. AOT pupil response will be obtained every 10 minutes after the end of the tDCS/CO2 inhalation period to map the duration of persistent effects on LC. At the end of this session participation will end except that subjects will be called the next day to assess for adverse effects and care given if necessary. Preliminary data from the R21 phase will be used to provide justification for the larger R33 study, and prior to commencing the R33 investigation phase that an addendum to the Institutional Review Board (IRB) protocol with approval will be obtained.
Pupillometry Procedure. The team will employ fully mobile SensoMotoric Instruments (SMI) Eye-tracking Glasses to carry out pupillometry. Pupil diameter will be recorded continuously from the each eye at a sampling rate of 60 Hz via glasses on the subject's face. The investigators will capture pupil size at baseline and in response to the AOT and administration of 7.5% CO2. Data will be segmented into epochs from 0 to 12 s relative to the acquisition onset of each stimuli or experimental condition. An average pupil diameter measure will then be calculated for the corresponding volume by taking the mean across the remaining non-artifactual samples in that epoch. For 7.5% CO2 response the pupil diameter will be averaged over 1 minute periods while subjects are staring at a dark screen in a dark room. This will be computed at baseline, and at 5, 10, 15, and 20 minutes after the start of CO2 inhalation and 5 minutes and 30 minutes postinhalation.
Administration of 7.5% CO2. Inhalation of 7.5% CO2 for 20 min will be carried out. Subjects will be instructed to avoid alcohol for 36 hours and caffeine for 12 hour prior to testing and to eat a light lunch at least one hour prior to testing. A urine pregnancy test will be administered to women of childbearing potential on both days of gas exposure with a negative result needed in order to continue in study participation. Gas will be delivered via a nasal-oral face mask connected via tubing to a 500 L reservoir bag filled with 7.5% CO2/21% Oxygen (O2) 71.5% Nitrogen (N2). Subjects will receive air through the mask in the 10 min prior to CO2 administration during which baseline measures will be obtained.
Transcranial Direct Current Stimulation (tDCS) will be administered with a multichannel direct current stimulation device that can be programmed so that the operator doesn't know the combination of electrodes being used for stimulation, and, thereby allow double-blinding. The active tDCS electrode configuration to be used will be determined with the 3 round iterative procedure described above; based on electric field modeling and personalized electrical dose titration to find the lowest dose that is well-tolerated and engages the target in terms of inhibiting the AOT pupillary response. Electrical dosage will be personalized for each subject by titrating dosage (gradually increasing) until the dosage is found that is both well-tolerated (no more than mild discomfort on a 5-point Likert scale) and suppresses the AOT pupillary response. If the 5-point Likert tolerability rating is greater than "mild discomfort" or if maximum amperage is reached without effect on AOT then subject participation will terminate.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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California
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San Francisco, California, United States, 94143
- University of California, San Francisco
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Use of effective method of birth control for women of childbearing capacity
- Willing and able to provide informed consent
- Have a significant difference between the mean pupil diameter in response to odd and common tones in the AOT during screening
- The10 subjects in the R21 cross-over study and all of the R33 subjects must have a 26% increase in VAS-A "fearful" response to 7.5% CO2 at the first CO2 challenge session
- Able to follow study procedures.
Exclusion Criteria:
- Current or past Axis I Diagnostic and Statistical Manual (DSM-IV) disorder based on the MINI
- Current or past history of substance abuse or dependence (excluding nicotine) based on history or positive urine toxicology
- Current unstable medical condition
- Any current neurological condition or medical condition that is known to affect pupillary function, mood/anxiety, or neurologic function generally
- Pregnancy based on Urine Pregnancy Test
- Women who are breast-feeding
- Use of medications known to affect Central Nervous System (CNS) function within 5 half-lives screening
- Use of a pacemaker
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: tDCS electrode configuration
Three rounds of tDCS using NeuroConn Direct Current stimulator Multiple Channel -4, Rogue Resolutions treatment optimization where each round includes identifying a promising electrode configuration based on electric field modeling using a realistic head model and capitalizing on the experience with the prior round (for rounds 2 and 3) and testing that electrode placement by administering a series of electrical doses of tDCS with that tDCS electrode configuration (carrying out a dose titration) in a cohort of 10 healthy control subjects to see if we can find an electrical dose which is well-tolerated, safe, suppresses the AOT pupil response and is below recommended current density safety limits (the safety limit in terms of Amperage varies depending on the electrode configuration)
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(tDCS) will be administered with a multichannel tDCS device that can be programmed so that the operator doesn't know the combination of electrodes being used for stimulation, and, thereby allow double-blinding.
The active tDCS electrode configuration to be used will be determined with the 3 round iterative procedure described above; based on electric field modeling and personalized electrical dose titration to find the lowest dose that is well-tolerated and engages the target in terms of inhibiting the AOT pupillary response.
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Placebo Comparator: Using tDCS to reduce acute fear
Administration of 7.5% CO2 to see if this elicits symptoms of Acute Fear and activates LC and whether tDCS safely inhibits the LC response to 7.5% CO2 compared with sham in a pilot cross-over trial (N=10).
A 3-year double-blind, randomized, controlled trial where clinical symptoms of Acute Fear, the primary outcome are elicited with 7.5% CO2 in healthy volunteers is the final study component.
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(tDCS) will be administered with a multichannel tDCS device that can be programmed so that the operator doesn't know the combination of electrodes being used for stimulation, and, thereby allow double-blinding.
The active tDCS electrode configuration to be used will be determined with the 3 round iterative procedure described above; based on electric field modeling and personalized electrical dose titration to find the lowest dose that is well-tolerated and engages the target in terms of inhibiting the AOT pupillary response.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in VAS-A Rating
Time Frame: Every 10 min (for approximately 20 minutes) at the end of tDCS/CO2 inhalation following one week post stimulation optimization.
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Primary outcome will be the VAS-A "fearful" rating obtained at the end of tDCS/CO2 inhalation.
AOT pupil response will be obtained every 10 minutes after the end of the tDCS/CO2 inhalation period to map the duration of persistent effects on LC.
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Every 10 min (for approximately 20 minutes) at the end of tDCS/CO2 inhalation following one week post stimulation optimization.
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Collaborators and Investigators
Investigators
- Principal Investigator: Andrew Krystal, MD, MS, University of California, San Francisco
Publications and helpful links
General Publications
- Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry. 2014 Apr;171(4):395-7. doi: 10.1176/appi.ajp.2014.14020138. No abstract available.
- Cuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 2013 May 14;11:126. doi: 10.1186/1741-7015-11-126.
- Redmond DE Jr, Huang YH. Current concepts. II. New evidence for a locus coeruleus-norepinephrine connection with anxiety. Life Sci. 1979 Dec 24;25(26):2149-62. doi: 10.1016/0024-3205(79)90087-0. No abstract available.
- Nutt DJ. Altered central alpha 2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry. 1989 Feb;46(2):165-9. doi: 10.1001/archpsyc.1989.01810020067011.
- LeDoux J. Emotional networks and motor control: a fearful view. Prog Brain Res. 1996;107:437-46. doi: 10.1016/s0079-6123(08)61880-4. No abstract available.
- Gilzenrat MS, Nieuwenhuis S, Jepma M, Cohen JD. Pupil diameter tracks changes in control state predicted by the adaptive gain theory of locus coeruleus function. Cogn Affect Behav Neurosci. 2010 May;10(2):252-69. doi: 10.3758/CABN.10.2.252.
- Nieuwenhuis S, Aston-Jones G, Cohen JD. Decision making, the P3, and the locus coeruleus-norepinephrine system. Psychol Bull. 2005 Jul;131(4):510-32. doi: 10.1037/0033-2909.131.4.510.
- Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 2005 Dec 5;493(1):99-110. doi: 10.1002/cne.20723.
- Bailey JE, Argyropoulos SV, Kendrick AH, Nutt DJ. Behavioral and cardiovascular effects of 7.5% CO2 in human volunteers. Depress Anxiety. 2005;21(1):18-25. doi: 10.1002/da.20048.
- Biancardi V, Bicego KC, Almeida MC, Gargaglioni LH. Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflugers Arch. 2008 Mar;455(6):1119-28. doi: 10.1007/s00424-007-0338-8. Epub 2007 Sep 13.
- Pineda J, Aghajanian GK. Carbon dioxide regulates the tonic activity of locus coeruleus neurons by modulating a proton- and polyamine-sensitive inward rectifier potassium current. Neuroscience. 1997 Apr;77(3):723-43. doi: 10.1016/s0306-4522(96)00485-x.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- Pro00059590
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
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