rTMS as a Probe of Episodic Memory Neurocircuitry in Schizophrenia

In spite of existing work studying rTMS as a treatment modality in schizophrenia, there are no studies that have examined the effects of precuneus directed rTMS on either EM deficits or the neurocircuitry subserving EM in schizophrenia. It is also important to note that the vast majority of studies using rTMS in schizophrenia have examined chronic populations where confounds associated with prolonged duration of illness may be present. Early Phase Psychosis (EPP) is a desirable population to study because these individuals tend to have fewer psychiatric and physical comorbidities and less antipsychotic drug exposure, all of which are factors that may confound investigations of new treatment interventions for this illness. In light of the significant unmet medical need associated with schizophrenia and the grave clinical effect of disrupted EM in the illness, rTMS modulating the precuneus, and potentially EM circuitry, represents an unexplored and potentially novel potential treatment option.

This study proposes to combine functional magnetic resonance imaging (fMRI) with inhibitory Low Frequency (LF) (1 Hz) and excitatory High Frequency (HF) (20 Hz) rTMS protocols to interrogate the effects of rTMS targeting the precuneus on: 1) precuneus activation during EM task performance; 2) functional connectivity between the precuneus and key EM circuitry, specifically the Dorsolateral Prefrontal Cortex (DLPFC), Anterior Cingulate Cortex (ACC), and hippocampus and 3) performance during an in-scanner scene encoding and recognition EM task. This study will provide vital preliminary data on target engagement informing future clinical trials seeking to utilize rTMS to treat EM impairment in schizophrenia. This is an important population for study because if effective, rTMS may represent a novel treatment for EM deficits in schizophrenia. This study will also seek to refine the understanding of the brain circuitry that mediates the potential pro-EM effects of rTMS through the use of fMRI at baseline and following the course of rTMS administration.

Inclusion criteria

• Between 18 and 40 years of age
• Within 10 years of illness onset as defined by entry into treatment for psychotic symptoms
• Able to give informed consent
• Willing and able to adhere to the study schedule
• Structured Clinical Interview for DSM-5 (SCID-5) diagnosis of schizophrenia
• Clinical stability defined by:

• Subjects must not have experienced an exacerbation of their illness within 4 weeks prior to randomization, leading to an intensification of psychiatric care in the opinion of the investigator. Examples of intensification of care include, but are not limited to: inpatient hospitalization, day/partial hospitalization, outpatient crisis management, or psychiatric treatment in an emergency room AND
• Antipsychotic treatment stability for at least 4 weeks prior to randomization (no change in antipsychotic dosing or addition of new antipsychotic medication)

Exclusion criteria

• Lifetime history of a seizure, excluding febrile seizures and those induced by substance withdrawal
• First degree relative with idiopathic epilepsy or other seizure disorder
• History of significant neurological illness
• History of head trauma as defined by a loss of consciousness or a post-concussive syndrome
• Pregnant or breast feeding
• Known intelligence quotient (IQ) < 70 based on subject report
• Current acute, serious, or unstable medical conditions
• Metallic objects planted in or near the head, including implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, Transcutaneous Electrical Nerve Stimulation (TENS) unit, ventriculoperitoneal shunt, or cochlear implants
• Contraindications to Magnetic Resonance Imaging (MRI) or otherwise unable to tolerate MRI procedures
• History of electroconvulsive therapy
• Subjects taking clozapine
• Subjects who have participated in a clinical trial with any pharmacological treatment intervention for which they received study-related medication in the 4 weeks prior to randomization
• Subjects considered a high risk for suicidal acts - active suicidal ideation as determined by clinical interview OR any suicide attempt in 90 days prior to screening
• Current DSM-5 diagnosis of alcohol or drug use disorder (excluding nicotine or caffeine)
• Subjects who require concomitant treatment with prohibited medication, as specified in Attachment 2