Auditory Hallucinations
Conditions
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.
Detailed description
Auditory hallucinations associated with schizophrenia (Sz) are pervasive, debilitating, and disturbing. Unfortunately, they are also difficult to treat - auditory hallucinations persist in about 25% of cases despite pharmacotherapy and treatment of cognitive symptoms (the symptoms most strongly related to global functioning) is modest at best. We propose a novel, inexpensive, and noninvasive intervention to address treatment-refractory symptoms, a critical need in Sz. Auditory hallucinations and impaired cognition in schizophrenia are not independent. Both are associated with system-level dysfunction of the fronto-temporal auditory control network, comprising auditory/verbal perceptual areas in temporoparietal junction (TPJ) and cognitive/behavioral control systems in ventrolateral prefrontal cortex (VLPFC). VLPFC traditionally inhibits and reattributes perceptual misrepresentations in most people. For those with schizophrenia, impairment of auditory cognitive control makes this impossible. Data from our lab suggest that auditory control network dysfunction may be central to the early etiology of the disorder. Auditory control enhancement (ACE) is designed to improve auditory control network function, thereby increasing inhibition of spurious auditory system activity in temporoparietal cortex and reducing auditory hallucinations. ACE combines a time-tested psychotherapeutic behavioral training program with targeted non-invasive brain stimulation using transcranial Direct Current Stimulation (tDCS). To further develop ACE for efficacy trials, we plan to investigate neural markers of target engagement in two sham-controlled experiments. Aim 1 will determine whether tDCS of right vlPFC (anode) and left TPJ (cathode) during MRI alters electric field measures and blood oxygenation level dependent (BOLD) response during stimulation to demonstrate that markers of tDCS current flow and BOLD fluctuate with induced current, and these fluctuations align spatially with computer models. Aim 2 will examine feasibility of subject retention and blinding for ACE. Aim 3 will examine the degree to which ACE modifies behavioral, neurophysiological, and hemodynamic markers of target engagement using neural oscillatory and cerebral blood flow (CBF) measures. ACE represents a novel, transformative intervention with long-lasting effects that has the potential to change the treatment of schizophrenia and vastly improve the outcome for afflicted individuals.
Interventions
DEVICETranscranial Direct Current Stimulation (tDCS)
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.
BEHAVIORALAuditory Cognitive Control Training (ACCT)
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).
Sponsors
Brian A Coffman, PhD
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Oscillatory Measure of Cognitive Control During Stimulus Evaluation in AX Version of the Continuous Performance Test (AX-CPT) | Week 3 minus Week 1 | Most trials in this task show letter A, then X, requiring response. Occasionally, stimuli other than A (generally called "B" stimuli) or other than X (generally, "Y" stimuli) are presented, requiring no response. Mean event-related spectral magnitude calculated between 200-500 ms after "A" and "B" stimuli in the beta band (15-25 Hz), across frontocentral EEG electrodes (Fz, FC1, FCz, FC2, Cz). Signals were averaged over electrodes, time, and frequency. Values reported here represent the mean of "A" and "B" responses. |
| Change From Baseline in Oscillatory Measure of Cognitive Control During Response Preparation in A-X Version of the Continuous Performance Test (AX-CPT) | Week 3 minus Week 1 | Most trials in this task show letter A, then X, requiring response. Occasionally, stimuli other than A (generally called "B" stimuli) or other than X (generally, "Y" stimuli) are presented, requiring no response. Mean event-related spectral magnitude calculated between 600-1200 ms after "A" and "B" stimuli in the gamma band (30-60 Hz), across frontocentral EEG electrodes (Fz, FC1, FCz, FC2, Cz). Signals were averaged over electrodes, time, and frequency. Values reported here represent the difference between "A" and "B" responses (B minus A)). |
| Change in Auditory Steady-State Response (ASSR) Modulation With Attention | Week 3 minus Week 1 | Mean evoked event-related spectral magnitude calculated between 100-500 ms after stimulus onset and 35-45 Hz in frontocentral electrodes (Fz, FC1, FCz, FC2, Cz). Magnitude is calculated as the average over electrodes, time, and frequency. These values represent the difference between signal magnitude measures in attend and ignore conditions (attend minus ignore). |
| Change in Auditory Steady-State Response (ASSR) Amplitude. | Week 3 minus Week 1 | Mean evoked event-related spectral magnitude calculated between 100-500 ms after stimulus onset and 35-45 Hz in frontocentral electrodes (Fz, FC1, FCz, FC2, Cz). Magnitude is calculated as the average over electrodes, time, and frequency. These values represent the response during ignore condition. |
| Retention | Through study completion, an average of 3 weeks | Percentage of enrolled participants who completed the study |
| Blinding | Week 3 | 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)?" Numbers reported indicate count of participants who selected "ACE". |
| Acceptability | Week 3 | Acceptability rating on a visual analogue scale (0-100; greater = more acceptable) obtained via post-study survey. |
| Magnetic Field Modulation With tDCS Current | Week 1 | 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. |
| Blood-Oxygen Level Dependent (BOLD) Response Modulation With tDCS Current | Week 1 | 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. |
| Change in Cerebral Blood Flow in Auditory Control Regions | Week 3 minus Week 1 | Cerebral blood flow (CBF) measured by pseudo-continuous arterial spin labeling (pcASL) will be assessed in right vlPFC and left TPJ target regions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in MCCB Attention Scale Score | Week 3 minus Week 1 | t-score (mean = 50, standard deviation= 10; greater=better) obtained on the Attention scale of the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)- Consensus Cognitive Battery (MCCB) |
| Change in MCCB Processing Speed Scale Score | Week 3 minus Week 1 | t-score (mean = 50, SD = 10; greater=better) obtained on the Processing Speed scale of the MATRICS Consensus Cognitive Battery (MCCB) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBrian A Coffman, PhD
University of Pittsburgh
Participant flow
Recruitment details
Participants were recruited between 9/5/2023 and 12/1/2024 from UPMC Western Psychiatric Hospital and outpatient services.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 30.2 years STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| General Symptoms measured by the Positive and Negative Syndrome Scale | 36 units on a scale STANDARD_DEVIATION 4 |
| IQ measured by the Weschler Abbreviated Scale of Intelligence | 108 units on a scale STANDARD_DEVIATION 22 |
| Matrix Reasoning T-Score measured by the Weschler Abbreviated Scale of Intelligence | 58 T-score STANDARD_DEVIATION 4 |
| Negative Symptoms measured by the Positive and Negative Syndrome Scale | 16 units on a scale STANDARD_DEVIATION 6 |
| Positive Symptoms measured by the Positive and Negative Syndrome Scale | 22 units on a scale STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
| Total score measured by the Positive and Negative Syndrome Scale | 69 units on a scale STANDARD_DEVIATION 14 |
| Vocabulary T-Score measured by the Weschler Abbreviated Scale of Intelligence | 45 T-score STANDARD_DEVIATION 9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 5 |
| other Total, other adverse events | 0 / 7 | 0 / 5 |
| serious Total, serious adverse events | 0 / 7 | 0 / 5 |
Outcome results
None listed