Auditory Control Enhancement (ACE) in Schizophrenia

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.

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). Our pilot data demonstrate the effectiveness of the behavioral training program and synergistic effects with tDCS of the auditory control network for treating treatment-refractory auditory hallucinations in schizophrenia. 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. Pilot data show feasibility of our aims and provide preliminary evidence that ACE has strong and lasting effects on auditory hallucinations assessed with the psychotic symptoms rating scale (PSYRATS), and that changes in cognitive factors associated with auditory hallucinations strongly correlate with changes in neural oscillatory measures of cognitive control. 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.

Eligibility Criteria:
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)