Targeting the Auditory Control Network With Auditory Control Enhancement (ACE) in Schizophrenia
Phase: NA
Conditions: Auditory Hallucinations
Sponsor: Brian A Coffman, PhD

 
 
Unique Protocol ID: STUDY22070009 
Brief Title: 
Auditory Control Enhancement (ACE) in Schizophrenia (ACES)   
Official Title: 
Targeting the Auditory Control Network With Auditory Control 
Enhancement (ACE) in Schizophrenia   
Secondary IDs: 
R21MH128823   [U.S. NIH Grant/Contract Award Number] 
 
Date: 02/06/2023 
 
 

Study Protocol 
Objectives 
Although Auditory Control Enhancement (ACE) shows promise for treating AH, evidence for 
neural target engagement is needed to move forward with efficacy trials. In alignment with 
NIMH priorities, we plan to incorporate objective measures that test the delivered dosage 
and the proposed mechanism of action of the intervention and determine if the 
intervention target has been modulated. MRI and EEG afford parametric tests of 
biophysical and neurophysiological target engagement. In the proposed research, we will 
investigate biological target engagement in two sham-controlled experiments. In this study, 
we will determine whether tDCS of the auditory control network (rVLPFC anode and left TPJ 
cathode) leads to alterations in electric field and blood oxygenation level dependent 
(BOLD) response in the auditory control network during stimulation using Dual-Echo Echo 
Planar Imaging. Additionally, we will examine the degree to which ACE modifies behavioral 
and neurophysiological markers of cognitive control.  
Design 
Participants were randomly assigned to either active/verum or sham/placebo tDCS in a 
parallel-arm, 2x2 between-subjects repeated-measures design. 
Methods 
Prior to obtaining informed consent, participants underwent a telephone screening using a 
standardized script, which took approximately 15 minutes. After consent was obtained, a 
hearing test using the method of ascending limits (Grayson-Stadler GSI 17 Audiometer) 
was administered by Dr. Coffman or trained research staff to rule out hearing loss, as this 
was essential for the auditory sensation experiment. This test was conducted in the 
research offices at Western Psychiatric Hospital and lasted about 15 to 30 minutes during 
the first session. Participants who did not pass the hearing test were advised to contact 
their primary care provider. Additionally, participants completed the Society of Magnetic 
Resonance Imaging’s standardized MRI screening protocol prior to each MRI visit, which 
took about 10 minutes. 
Demographic and medical history information was collected using a standard form during 
the first visit. Clinical and diagnostic assessments included the Structured Clinical 
Interview for DSM Disorders (SCID), which lasted approximately 1.5 to 2 hours. Additional 
assessments included the Positive and Negative Syndrome Scale (PANSS), Psychotic 
Symptoms Rating Scales (PSYRATS), and Global Functioning: Social and Role Scales. 

These assessments collectively took about two hours, with PSYRATS administered both 
before and after ACE. 
Neuropsychological testing involved the full MATRICS battery, targeting six cognitive 
domains affected in schizophrenia, and subtests from the WASI to assess general 
intelligence. The MATRICS battery took about one hour, and the WASI took approximately 
30 minutes. Both were administered before and after ACE. 
During the Auditory Control Enhancement (ACE) procedure, participants received 
transcranial direct current stimulation (tDCS) while performing a simple cognitive task. 
They were randomly assigned to receive either full-duration tDCS or a 30-second version 
(sham). Dr. Coffman randomized participants based on their order of entry into the study. 
The study was single-blind, with participants unaware of their group assignment. 
Electrodes were placed over the right ventrolateral prefrontal cortex (anode; F8) and the left 
temporoparietal junction (cathode; CP5). tDCS sessions, conducted at WPH (Thomas 
Detre Hall and Oxford), were administered by Dr. Coffman or trained staff. The current 
strength was set to 2.0 mA and was delivered for 30 minutes per session using saline-
soaked sponge electrodes (10 cm² in size). Stimulation began two minutes before the task 
to assess discomfort, and skin sensation was checked verbally at least twice during 
stimulation. Participants were reminded they could withdraw at any time, and electrodes 
were never placed over the heart, eyes, or ears. 
During tDCS, participants performed a cognitive task designed to train attention, working 
memory, and processing speed, lasting about one hour. The first ACE session involved a 
circular image with a single radius line, resembling a clock hand. Participants held a button 
to start each trial and released it when the line reached a target point. The task increased in 
difficulty by removing visual cues. ACE sessions 2 and 3 utilized simple button-response 
tasks and assessed reaction time and time estimation, respectively, using only basic 
shapes and lines. 
EEG testing was led by Dr. Coffman with support staff utilizing a 32-channel Starstim 
system. EEG amplifier bandpass was open (DC) to 166 Hz (24 dB/octave rolloff) digitized at 
500 Hz. ASSR and AX-CPT stimuli were be presented using Presentation software 
(NeuroBehavioral Systems). Timings of stimuli were confirmed by oscilloscope, and 
loudness confirmed with a sound meter and artificial ear canal. Sounds were created with 
NCH Tone Generator and edited in NCH Wavepad (NCH, Australia) and were presented 
over Etymotic 3A insert earphones. We measured differential 40Hz ASSR gamma power 
between attend/ignore conditions and beta-band oscillatory power in the AX-CPT as 
neurophysiological measures of auditory control network function. ASSR. Biphasic click 
trains were presented at 40 Hz (80 db, 500 ms duration, 1000 ms ±200 ms ISI). Subjects 

once ignored the click trains and watch a silent video, and once listened to the clicks, 
pressing a button to click train presented at reduced intensity (75 db, 10% of trials) . We 
recorded 360 trials each under attend/ignore conditions. We assessed 35-45 Hz gamma 
power in frontocentral electrodes in attend and ignore conditions, as well as the difference 
between attend/ignore measurements. AX-CPT uses a combination of Latin letters as cues 
and probes following the established A-then-X rule. More specifically, the rule for the AX- is 
that ‘X’’ is the target when directly preceded by the letter ‘‘A’’ trials, whereas a letter in any 
other sequence is a nontarget (e.g., AY, BX, and BY trials, where a B is any non-A cue, and a 
Y is any non-X probe). The AX and BX trials both require the representation and 
maintenance of the cue, or the goal of the task, to respond appropriately. BX trials tend to 
be the most sensitive to impairments in the ability to maintain the goal representation. That 
is, maintenance of the B cue is required to overcome the prepotent target response to the X 
on the trials when it does not follow an A. The most difficult trial is AY, given that goal 
focused maintenance of the A cue should produce a high expectancy of a subsequent X 
probe and preparation of a target response, resulting in increased errors or slowing on AY 
trials. 450 trials were presented in 6 blocks of 75 trials. The cue was presented for 500 ms 
with ISI of 1000 ms. Cognitive control was indexed by prefrontal beta-band activity 
following attention-alerting “B” trials. EEG was conducted both before and after ACE. 
MRI data were collected using a 3T Siemens Prisma MRI system. Each participant 
underwent two 13-minute DE-EPI scans to map current flow during tDCS, along with T1 and 
T2-weighted structural imaging. MRI sessions lasted about one hour and were conducted 
before and after ACE. Participants completed pre- and post-scan questionnaires to 
evaluate their scanning experience. Those who reported smoking or consuming coffee 
within two hours of testing were asked to reschedule if the session could not be delayed. 
Participants were asked to rate acceptability on a visual analogue scale, and to guess 
whether they received active or sham stimulation, using a forced choice questionnaire.