Frontal Stimulation to Modulate Threat Sensitivity in Anxious Depression

November 10, 2023 updated by: Laureate Institute for Brain Research, Inc.
Over 50% of patients with major depressive disorder (MDD) do not respond to initial treatment and relapse is common. In particular, comorbid depression and anxiety disorders are associated with more treatment resistance. Thus, there is a great need for novel, more targeted treatments. Transcranial direct current stimulation (tDCS) is a novel intervention that can be used to causally target neural excitability and plasticity in brain regions/circuits implicated in regulating mood and anxiety and emerging evidence suggests that it reduces threat sensitivity. Here the investigators propose to use tDCS to target threat sensitivity as a core symptom of anxious depression to determine if the investigators can engage the neural circuits that are treatment targets. Following the administration of a single dose of anxiolytic or antidepressant treatment, early changes in emotional processing have been observed in healthy people and clinical groups. Among patients, acute cognitive effects - such as a reduction in threat sensitivity - have been shown to predict response to drug and behavioral treatments. Functional magnetic resonance imaging (fMRI) studies have confirmed hyperactive amygdala and/or hypoactive prefrontal activity in patients, indicating an imbalance of activity within this cortico-limbic circuit that sub-serves threat identification (amygdala) and top-down control (prefrontal). Specifically, treatments aiming to remediate prefrontal/ amygdala dysfunction could be a critical target in patients exhibiting these deficits. Several clinical trials have shown that administration of frontal cortex tDCS is a potentially effective treatment for MDD. However, underlying mechanisms of action are unclear. To meet this gap, the investigators propose an experimental medicine study (target identification and initial target engagement paths) where 141 volunteers with anxious MDD will be randomized to receive a single session of active or sham tDCS in a parallel design. Threat sensitivity will be measured using task and resting state fMRI and potentiated startle electrophysiology. Preliminary data suggest reductions in behavioral threat sensitivity from a single session of frontal tDCS. This was followed up with an fMRI study which found that a single session of active vs sham frontal tDCS reduced amygdala response to fearful faces whilst simultaneously increasing frontal attentional control signals. This provides evidence that modulating activity in the frontal cortex inhibits amygdala response to threat, highlighting a potential neural mechanism for the behavioral reduction in threat sensitivity. In addition, this offers initial mechanistic insights into the efficacy of tDCS in clinical trials for the treatment of MDD and anxiety disorders, suggesting that threat sensitivity may be a suitable cognitive target. The current proposal builds on this to establish acute effects of frontal tDCS on amygdala response to threat (primary aim), frontoparietal response to threat (secondary aim), startle response under threat (secondary aim) and approach-avoidance-conflict (exploratory aim). The ultimate aim is to apply these multi-level acute findings to mechanistic clinical trials of tDCS, to test their prediction of treatment response (full model path) and improve patient outcomes.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

141 participants with anxious MDD were recruited from the community. Participants will undergo screening and baseline assessments using self-report and clinical assessments. Eligible participants will be invited for an additional screening session where they will allocated to either active or sham stimulation arms (50% in each arm). Participants in the active arm will receive 30 minutes tDCS over bilateral prefrontal cortex using an optimized lateral electrode (OLE) placement montage. This montage is selected as it is commonly used in clinical trials of tDCS for MDD and is designed to target the lateral DLPFC. Moreover, hypoactive frontal activation and related impaired top-down control is associated with MDD and anxiety disorders. Resting state (rs) fMRI data will be collected immediately before, during and after active or sham tDCS. After tDCS, task-based fMRI data (attentional control task with fearful distractors) and behavioral data (approach avoidance task) will be acquired. Mood will be assessed with a single item 0-100 visual analogue scale (VAS) question and Positive and Negative Affective schedule (PANAS) at multiple time points before and after imaging and tDCS. Subjective and neural responses to fearful faces in prefrontal cortical areas and subcortical-limbic areas (fearful>neutral) and their connectivity during resting state will be assessed with contrasts made between active and sham stimulation. Anxiety (unpredictable shock > neutral) and fear (predictable shock > neutral) potentiated startle will be measured using EMG. For additional exploratory analyses relating to blood based markers of neuroplasticity (Kynurenine), a blood sample will be taken.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
141

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • Oklahoma
      • Tulsa, Oklahoma, United States, 74136
        • Laureate Institute for Brain Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion criteria:

  1. Current major depressive episode assessed by clinician administered MINI;
  2. Minimum score of 8 on OASIS anxiety scale;
  3. Normal or corrected to normal vision/hearing, as protocol elements may not be valid otherwise;
  4. Fluent English speaker, capable of providing written informed consent

Exclusion criteria:

  1. Has uncontrolled, clinically significant neurologic (including seizure disorders): cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results;
  2. History of moderate or severe traumatic brain injury, as assessed by the Tulsa Head Injury Screen (THIS) questionnaire;
  3. Family history of psychotic or bipolar disorder;
  4. Current diagnosis of eating disorder or obsessive-compulsive disorder;
  5. Current use of medications with major effects on the fMRI hemodynamic response (e.g., methylphenidate, acetazolamide, excessive caffeine intake > 1000 mg/day);
  6. Moderate or severe current substance use disorder according to DSM 5 criteria, assessed via MINI;
  7. Drug or alcohol intoxication (based on positive urine test or breathalyzer test at screen or baseline) or reported acute alcohol or drug withdrawal;
  8. Has a risk of suicide according to the Investigator's clinical judgment or per Columbia-Suicide Severity Rating Scale (C-SSRS), the subject scores "yes" on items 4 or 5 in the Suicidal Ideation section with referent to a 30-day period prior to Screening/Baseline or the subject has had one or more suicidal attempts with reference to a 2-year period prior to Screening/Baseline;
  9. MRI or tDCS contraindications;
  10. Is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during this time-period;
  11. History of highly irritable skin and/or contact dermatitis that affects skin integrity of the scalp;
  12. Any participant judged by the Investigator to be inappropriate for the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: active transcranial direct current stimulation
The investigators use Soterix mini-CT Stimulator to deliver 30 minutes 2mAmp tDCS to the bilateral DLPFC (optimized lateral electrode placement montage), with the the anode on the left hemisphere and the cathode on the right hemisphere. The electrodes are rubber and are placed in an MRI compatible holder and affixed with conductive paste. The investigators will use a bespoke headstrap to place the electrodes, which are held in place by the conductive paste.
Device: transcranial direct current stimulation
the tDCS stimulator delivers very low (2mAmp) current with surface electrodes to the skull
Sham Comparator: sham transcranial direct current stimulation
In the sham stimulation mode, the device shows pseudorandom numbers on the screen that look like real stimulation is being delivered. The device gives a low level of stimulation at the very beginning and at the very end of the stimulation session (30 seconds ramp up and 30 seconds ramp down) in order to recreate the feeling of tingling that subjects perceive at the beginning and end of real stimulation.
Device: transcranial direct current stimulation
the tDCS stimulator delivers very low (2mAmp) current with surface electrodes to the skull

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
The difference between amygdala Blood-Oxygen-Level-Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) activation to fearful faces compared to neutral faces
Time Frame: immediately after intervention
Preliminary findings show that frontal tDCS can reduce amygdala threat reactivity in high trait anxious females. The investigators seek to replicate this effect in a larger, clinical sample which also includes males. Specifically, the investigators expect that, compared to sham tDCS, the active tDCS group will show changed amygdala BOLD fMRI activation to fearful faces (difference between fearful and neutral faces), following acute tDCS administration.
immediately after intervention

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
The difference between frontoparietal Blood-Oxygen-Level-Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) activation to fearful faces compared to neutral faces
Time Frame: immediately after intervention
Preliminary findings show that frontal tDCS can increase frontoparietal activation to threat in high trait anxious females. The investigators seek to replicate this effect in a larger, clinical sample which also includes males. Specifically, the investigators expect that, compared to sham tDCS, the active tDCS group will show changed frontoparietal BOLD activation to fearful faces (difference between fearful and neutral faces), following acute tDCS administration.
immediately after intervention
The difference between startle reflex measured by electromyography (EMG) under threat of unpredictable shock compared to no threat of shock
Time Frame: immediately after intervention
The significant acute reduction in behavioral threat sensitivity from a single session of tDCS is similar that seen with anxiolytic treatments. Anxiolytic treatments also reliably reduce startle response to unpredictable threat. The investigators hypothesize that compared to sham tDCS, the active tDCS group will show changed anxiety potentiated startle EMG (unpredictable shock minus no shock condition) following acute tDCS administration.
immediately after intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Laureate Institute for Brain Research, Inc.

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of General Medical Sciences (NIGMS)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Maria Ironside, DPhil, Laureate Institute for Brain Research

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 13, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 19, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 26, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 12, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 24, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 2, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 14, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 10, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • LIBR#2021-005
  • P20GM121312 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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