Transcranial Direct Current Stimulation (tDCS) as a Treatment for Acute Fear

NCT02410954 | Terminated Results DMC

• 1 other identifier: Pro00059590
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

Locus coeruleus (LC) norepinephrine (NE) neuron activity has been convincingly linked to regulation of acute fear. This study will address whether LC NE activity examined through pupil measures will reflect carbon dioxide (CO2) induced fear-responses in humans and if transcranial direct current stimulation (tDCS) can mitigate these effects. A 2 year R21 phase establishing feasibility, tolerability, safety, and proof-of-concept (POC) in terms of capacity to engage LC NE neurons with tDCS, followed by a 3 year R33 parallel-group, double-blind, randomized, controlled trial will determine the degree to which engaging LC NE neurons with tDCS improves clinical symptoms.

Conditions

Fear

Outcome Measures

Primary Outcomes (1)

• Change in VAS-A Rating

  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.

  Every 10 min (for approximately 20 minutes) at the end of tDCS/CO2 inhalation following one week post stimulation optimization.

Study Arms (2)

tDCS electrode configuration

EXPERIMENTAL

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)

Device: NeuroConn Direct Current stimulator Multiple Channel -4

Using tDCS to reduce acute fear

PLACEBO COMPARATOR

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.

Device: NeuroConn Direct Current stimulator Multiple Channel -4

Interventions

NeuroConn Direct Current stimulator Multiple Channel -4 DEVICE

(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.

Using tDCS to reduce acute fear; tDCS electrode configuration

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (11)

• 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.

  PMID: 24687194 BACKGROUND

• 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.

  PMID: 23672542 BACKGROUND

• 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.

  PMID: 120478 BACKGROUND

• 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.

  PMID: 2536539 BACKGROUND

• 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.

  PMID: 8782535 BACKGROUND

• 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.

  PMID: 20498349 BACKGROUND

• 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.

  PMID: 16060800 BACKGROUND

• 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.

  PMID: 16254995 BACKGROUND

• 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.

  PMID: 15782425 BACKGROUND

• 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.

  PMID: 17851683 BACKGROUND

• 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.

  PMID: 9070748 BACKGROUND

Limitations and Caveats

Study terminated prematurely without generating any outcome data due to delays due to the study being moved from one institution to another and due to technical problems with the pupil measurements that required a long period of trouble-shooting/problem-solving and ultimately the replacement of the pupillometry device.

Results Point of Contact

• Title: Andrew Krystal, MD
• Organization: University of California, San Francisco

andrew.krystal@ucsf.edu

(415) 476-7702

Study Officials

• Andrew Krystal, MD, MS

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2015
• First Posted: April 8, 2015
• Study Start: December 1, 2015
• Primary Completion: January 31, 2019
• Study Completion: January 31, 2019
• Last Updated: May 18, 2021
• Results First Posted: May 18, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)