Auditory Control Enhancement (ACE) in Schizophrenia

NCT06155695 | Completed FDA Device

• 2 other identifiers: STUDY22070009R21MH128823
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this clinical trial is to investigate neural markers of target engagement to further develop auditory control enhancement (ACE) as a novel, inexpensive, and noninvasive intervention to address treatment-refractory auditory hallucinations. Here, we will address questions about the feasibility and acceptability of ACE, as well as the degree to which ACE results in measurable engagement of biophysical and neurophysiological targets. Participants will complete:

• Auditory Control Enhancement (ACE): Participants will be assigned by chance (such as a coin flip) into one of two groups to receive a different dosage or level of transcranial direct current stimulation (tDCS) during three sessions of cognitive training. tDCS is used to stimulate the brain for a short period of time. For tDCS one or two thin wet sponges are placed on the head and/or upper arm. The sponges will be connected to electrodes which will deliver a very weak electrical current. The Neuroelectrics Starstim 32 will be used to deliver tDCS.
• Interviews: Before and after ACE, in two separate sessions, participants will be asked questions about a) background; b) functioning in daily life and across different phases of your life and past, present and future medical records.
• Cognitive Tests: During the interview sessions, participants will also perform cognitive tests. Participants will be asked to complete computerized and pen-and-paper tests of attention, concentration, reading, and problem-solving ability.
• EEG scan: Participants will be asked to complete EEG (electroencephalography) studies before and after ACE training. EEG will be measured using the same Neuroelectrics Starstim 32 system used for tDCS. EEG measures the natural activity of the brain using small sensors placed on the scalp. These sensors use conductive gel to provide a connection suitable for recording brain activity. During EEG, participants will watch a silent video while sounds are played over headphones, or sometimes count the sounds. In addition to these auditory tasks, participants will also be asked to perform visual attention tasks, such pressing a button for a letter or image.
• Magnetic Resonance Imaging (MRI) Scan: Participants will also be asked to complete MRI studies before and after ACE training. An MRI is a type of brain scan that takes pictures of the brain that will later be used to create a 3D model of the brain. The MRI does not use radiation, but rather radio waves, a large magnet and a computer to create the images. Researchers will compare individuals receiving ACE to those receiving sham tDCS during cognitive training to determine effects of ACE.

Conditions

Auditory Hallucinations

Outcome Measures

Primary Outcomes (10)

• Magnetic field modulation with tDCS current

  We will use General Linear Model (GLM) in SPM12 to assess the parametric modulation of 2nd-echo phase data with the applied tDCS current as a regressor. Magnetic field modulation of target areas will be quantified as the ratio of mean beta values within target areas in rVLPFC and left TPJ over the mean beta value over cortical voxels beyond these regions of interest.

  Week 1

• Blood-Oxygen Level Dependent (BOLD) response modulation with tDCS current

  We will use General Linear Model (GLM) in Statistical Parametric Modeling (SPM12) to assess the parametric modulation of 2nd-echo magnitude data with the applied tDCS current as a regressor. BOLD modulation within target areas will be quantified as the ratio of mean beta values within target areas in right ventrolateral prefrontal cortex (rVLPFC) and left temporoparietal junction (TPJ) over the mean beta value over cortical voxels beyond these regions of interest.

  Week 1

• Change from baseline in oscillatory measure of cognitive control during stimulus evaluation in AX-CPT

  Mean event-related spectral power will be calculated between 300-500 ms after "A" and "B" stimuli in the gamma band (30-60 Hz), across frontocentral EEG electrodes (Fz, FC1, FCz, FC2). Cognitive control during stimulus evaluation will be quantified as the mean over "A" and "B" responses.

  Week 3 minus Week 1

• Change in oscillatory measure of cognitive control during response preparation in A-X version of the continuous performance test (AX-CPT)

  Mean event-related spectral power will be calculated between 600-1200 ms after "A" and "B" stimuli in the gamma band (30-60 Hz), across frontocentral EEG electrodes. Cognitive control during response preparation will be quantified as the difference between "A" and "B" responses (B minus A)).

  Week 3 minus Week 1

• Change in Auditory Steady-State Response (ASSR) Modulation with Attention

  Mean evoked event-related spectral power will be calculated between 100-500 ms after stimulus onset and 35-45 Hz in frontocentral electrodes (Fz, FC1, FCz, FC2). Attention modulation will be quantified as the difference between signal power measures in attend and ignore conditions (attend minus ignore).

  Week 3 minus Week 1

• Change in Auditory Steady-State Response (ASSR) amplitude.

  Mean evoked event-related spectral power will be calculated between 100-500 ms after stimulus onset and 35-45 Hz in frontocentral electrodes (Fz, FC1, FCz, FC2), from data recorded while participants ignore auditory stimuli.

  Week 3 minus Week 1

• Change in cerebral blood flow in auditory control regions

  Cerebral blood flow (CBF) measured by pseudo-continuous arterial spin labeling (pcASL) will be assessed in right vlPFC and left TPJ target regions

  Week 3 minus Week 1

• Retention

  Percentage of enrolled participants who did not complete the study

  Through study completion, an average of 3 weeks

• Blinding

  Subjective forced-choice impression of treatment condition assessed by a single item on study completion questionnaire - "Which treatment condition do you think you received? ACE or sham(placebo)?"

  Week 3

• Acceptability

  Acceptability rating on a visual analogue scale (0-100; greater = more acceptable) obtained via post-study survey.

  Week 3

Secondary Outcomes (2)

• Change in MCCB Attention Scale Score

  Week 3 minus Week 1

• Change in MCCB Processing Speed Scale Score

  Week 3 minus Week 1

Other Outcomes (1)

• Change in Auditory Hallucination Severity

  Week 3 minus Week 1

Study Arms (2)

Auditory Control Enhancement (ACE)

EXPERIMENTAL

tDCS + ACCT

Device: Transcranial Direct Current Stimulation (tDCS); Behavioral: Auditory Cognitive Control Training (ACCT)

Sham tDCS + ACCT

SHAM COMPARATOR

Sham tDCS + ACCT

Device: Transcranial Direct Current Stimulation (tDCS); Behavioral: Auditory Cognitive Control Training (ACCT)

Interventions

Transcranial Direct Current Stimulation (tDCS) DEVICE

tDCS will be administered using the Starstim system. We will use the freely available Simulation of Non-Invasive Brain Stimulation (SimNIBS) software to optimally target the rVLPFC and left TPJ in each subject. Finite element models will be generated using T1 and T2 scans. We will generate multiple models to maximize on-target stimulation and minimize off-target stimulation, as determined by ratio of the summed current density within and beyond target regions of interest (ROIs). tDCS current in the active stimulation condition will be maintained at 2.0 milliamps (mA) for the first 45 minutes of each one-hour training session. Sham stimulation the same current, only the current will be ramped down to 0 mA after 30 seconds. Our previous research has shown this method to produce indistinguishable skin sensation. During tDCS, patients will be monitored for possible negative side effects.

Auditory Control Enhancement (ACE); Sham tDCS + ACCT

Auditory Cognitive Control Training (ACCT) BEHAVIORAL

ACCT incorporates a subset of components from Cognitive Enhancement Therapy found to have early benefits on the cognitive deficits of interest to the proposed studies and can be conducted more time-efficiently to achieve our specific goals. ACCT involves approximately 3 hours of computerized neurocognitive training using cognitive control and processing speed training software developed by Ben-Yishay and colleagues. Deficits in cognitive control are addressed with computer training exercises containing simple stimuli with little inherent emotional or motivational salience. ACCT requires individuals to be vigilant, inhibit irrelevant stimuli, and shift attention between auditory and visual modalities. Computer training exercises facilitate reaction time in a temporal mode using auditory cues (The Attention Reaction Conditioner), spatial focusing with visual cues (the Zero Accuracy Conditioner), and temporal vigilance with auditory and visual cues (Time Estimates).

Auditory Control Enhancement (ACE); Sham tDCS + ACCT

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Between the ages of 18-40
• Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder, Psychosis not otherwise specified (NOS), Affective Psychosis with mood incongruent hallucinations.
• ability to provide informed consent
• Intelligence quotient (IQ) \>= 70, as measured by the Weschler Abbreviated Scale of Intelligence (WASI)
• \<5 years since the onset of first psychotic episode
• persistent auditory hallucinations without remission despite attempting \>2 antipsychotic medications and having \> 1 month of medication compliance

You may not qualify if:

• hearing deficit as assessed by audiometry (hearing threshold \> 30 decibels (dB) nHL)
• standard MRI contraindications (e.g. cardiac pacemaker, aneurysm clip, cochlear implants, history of metal fragments in body, neurostimulators, weight of 300 lbs. or more, or claustrophobia)
• \[self report\] head injury with loss of conscious \> 10 min, medical illness affecting brain function or structure, significant neurologic disorder (e.g. seizure disorder),
• Diagnostic and Statistical Manual of Mental Disorders (DSM-5) substance use disorder - other than cannabis - and except individuals who have met at least early remission criteria (3 months without dependence symptoms) or a psychotic illness with a temporal relation to a substance use disorder
• currently pregnant or early postpartum (\<6 weeks after delivery or miscarriage)
• currently taking medications that affect alertness, other than antipsychotic medication (e.g. sedatives, tranquilizers, muscle relaxants, and sleeping aids)

Sponsors & Collaborators

• Brian A Coffman, PhD: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Western Psychiatric Hospital of UPMC

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Hallucinations

Interventions

Transcranial Direct Current Stimulation

Condition Hierarchy (Ancestors)

Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Convulsive Therapy; Psychiatric Somatic Therapies; Behavioral Disciplines and Activities; Electroshock; Psychological Techniques

Study Officials

• Brian A Coffman, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Research Assistant Professor

Study Record Dates

• First Submitted: November 14, 2023
• First Posted: December 4, 2023
• Study Start: September 5, 2023
• Primary Completion: December 18, 2024
• Study Completion: December 18, 2024
• Last Updated: February 14, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Immediately following publication, and for at least 5 years
• Access Criteria: Researchers who have access to NIH data archive will be able to access the data

Locations

US (1)