rTMS as a Probe of Episodic Memory Neurocircuitry in Schizophrenia (rTMS-EM)

Repetitive Transcranial Magnetic Stimulation (rTMS) as a Probe of Episodic Memory (EM) Neurocircuitry in Schizophrenia

This will be a single site pilot study. 30 subjects with Early Phase Psychosis (EPP), defined as medical record documentation of the onset of clinically significant psychotic symptoms within the past ten years, will be enrolled. Prior to randomization (Session 1), subjects will undergo Functional Magnetic Resonance Imaging (fMRI) during Episodic Memory (EM) and Resting State (RS) paradigms. This baseline scan will also include a high-resolution structural sequence for neuronavigation purposes. Then on three separate days each occurring one-week apart, subjects will receive one session of inhibitory (1 Hertz [Hz]) Repetitive Transcranial Magnetic Stimulation (rTMS), one session of excitatory (20 Hz) rTMS, and one sham stimulation session targeting the precuneus. The order of the three interventions will be randomized. Immediately following each rTMS or sham session, subjects will undergo repeat fMRI during EM and RS paradigms. The investigators will also examine the effect of rTMS on EM performance.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Device: 1 Hz rTMS Stimulation; Device: Sham rTMS Stimulation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Prevention and Recovery Center for Early Psychosis
    • Indianapolis, Indiana, United States, 46202
      • IU Center for Neuroimaging

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

6. Clinical stability defined by:

   1. 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
   2. Antipsychotic treatment stability for at least 4 weeks prior to randomization (no change in antipsychotic dosing or addition of new antipsychotic medication)

Exclusion Criteria:

1. Lifetime history of a seizure, excluding febrile seizures and those induced by substance withdrawal
2. First degree relative with idiopathic epilepsy or other seizure disorder
3. History of significant neurological illness
4. History of head trauma as defined by a loss of consciousness or a post-concussive syndrome
5. Pregnant or breast feeding
6. Known intelligence quotient (IQ) < 70 based on subject report
7. Current acute, serious, or unstable medical conditions
8. 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
9. Contraindications to Magnetic Resonance Imaging (MRI) or otherwise unable to tolerate MRI procedures
10. History of electroconvulsive therapy
11. Subjects taking clozapine
12. 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
13. 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
14. Current DSM-5 diagnosis of alcohol or drug use disorder (excluding nicotine or caffeine)
15. Subjects who require concomitant treatment with prohibited medication, as specified in Attachment 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1 Hz rTMS Stimulation first, then 20 Hz rTMS Stimulation, then sham rTMS; Subjects will receive one session of each: low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of motor threshold (MT), for a total of 1200 pulses, high frequency rTMS within the following stimulation parameters: 20 Hz, at 120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 15 seconds, for a total of 1200 pulses over 16 minute, Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.	Device: 1 Hz rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.; Other Names: rTMS; Device: Sham rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.
Experimental: 1 Hz rTMS Stimulation first, then sham rTMS, then 20 Hz rTMS Stimulation; Subjects will receive one session of each: low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of motor threshold (MT), for a total of 1200 pulses, high frequency rTMS within the following stimulation parameters: 20 Hz, at 120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 15 seconds, for a total of 1200 pulses over 16 minute, Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.	Device: 1 Hz rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.; Other Names: rTMS; Device: Sham rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.
Experimental: 20 Hz rTMS Stimulation first, then 1 Hz rTMS Stimulation, then sham rTMS; Subjects will receive one session of each: low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of motor threshold (MT), for a total of 1200 pulses, high frequency rTMS within the following stimulation parameters: 20 Hz, at 120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 15 seconds, for a total of 1200 pulses over 16 minute, Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.	Device: 1 Hz rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.; Other Names: rTMS; Device: Sham rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.
Experimental: 20 Hz rTMS Stimulation first, then sham rTMS, then 1 Hz rTMS Stimulation; Subjects will receive one session of each: low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of motor threshold (MT), for a total of 1200 pulses, high frequency rTMS within the following stimulation parameters: 20 Hz, at 120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 15 seconds, for a total of 1200 pulses over 16 minute, Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.	Device: 1 Hz rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.; Other Names: rTMS; Device: Sham rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.
Experimental: sham rTMS first, then 1 Hz rTMS Stimulation, then 20 Hz rTMS Stimulation; Subjects will receive one session of each: low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of motor threshold (MT), for a total of 1200 pulses, high frequency rTMS within the following stimulation parameters: 20 Hz, at 120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 15 seconds, for a total of 1200 pulses over 16 minute, Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.	Device: 1 Hz rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.; Other Names: rTMS; Device: Sham rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.
Experimental: sham rTMS first, then 20 Hz rTMS Stimulation, then 1 Hz rTMS Stimulation; Subjects will receive one session of each: low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of motor threshold (MT), for a total of 1200 pulses, high frequency rTMS within the following stimulation parameters: 20 Hz, at 120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 15 seconds, for a total of 1200 pulses over 16 minute, Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.	Device: 1 Hz rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.; Other Names: rTMS; Device: Sham rTMS Stimulation; rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Precuneus Functional Activation	Change in estimated beta coefficients for the Target vs. Foil contrast during scene recognition in the precuneus. Beta coefficients reflect the strength of the blood oxygen-level dependent (BOLD) signal during each condition.Target images are those previously shown to participants, and Foil images have not been previously shown, as participants indicate whether they have been shown images. A higher measure indicates that the intervention increased brain activity during recognition of previously shown scenes.	1 day
Precuneus Functional Connectivity	Blood oxygen level dependent (BOLD) signal functional connectivity with the precuneus in the bilateral dorsolateral prefrontal cortex, hippocampus, and anterior cingulate cortex. Value is the mean Fisher's transform of the correlation of BOLD time-series in the precuneus with the BOLD time-series in other named regions. Higher values indicate greater connectivity with the precuneus following the intervention. Value of zero indicates no relationship (no connectivity). This value has no unit of measurement.	1 day
Performance During In-scanner Episodic Memory Task	Percent accuracy (0-100%) on detecting whether an image shown during a scene recognition was among those shown during the previous five-minute session. Higher scores indicate better performance in recalling images.	1 day

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Tom Hummer, Indiana University

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2019
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): June 30, 2022

Study Registration Dates

• First Submitted: October 28, 2019
• First Submitted That Met QC Criteria: November 26, 2019
• First Posted (Actual): December 2, 2019

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: schizophrenia; psychosis; rTMS; early phase psychosis
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: 1907931487

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes