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

Primary Purpose

Schizophrenia

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

1 Hz rTMS Stimulation

Sham rTMS Stimulation

About this trial

This is an interventional treatment trial for Schizophrenia focused on measuring schizophrenia, psychosis, early phase psychosis, rTMS

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesDoes not accept healthy volunteers

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:
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:

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 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, TENS unit, ventriculoperitoneal shunt, or cochlear implants
Contraindications to 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

Sites / Locations

IU Center for Neuroimaging
Prevention and Recovery Center for Early Psychosis

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

1 Hz rTMS Stimulation first, then 20 Hz rTMS Stimulation, then sham rTMS

1 Hz rTMS Stimulation first, then sham rTMS, then 20 Hz rTMS Stimulation

20 Hz rTMS Stimulation first, then 1 Hz rTMS Stimulation, then sham rTMS

20 Hz rTMS Stimulation first, then sham rTMS, then 1 Hz rTMS Stimulation

sham rTMS first, then 1 Hz rTMS Stimulation, then 20 Hz rTMS Stimulation

sham rTMS first, then 20 Hz rTMS Stimulation, then 1 Hz rTMS Stimulation

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT04182113

First Posted

October 28, 2019

Last Updated

July 10, 2023

Sponsor

Indiana University

1. Study Identification

Unique Protocol Identification Number

NCT04182113

Brief Title

rTMS as a Probe of Episodic Memory Neurocircuitry in Schizophrenia

Acronym

rTMS-EM

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

November 8, 2019 (Actual)

Primary Completion Date

June 30, 2022 (Actual)

Study Completion Date

June 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Indiana University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia

Keywords

schizophrenia, psychosis, early phase psychosis, rTMS

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Model Description

All patients will receive 1 Hz rTMS, 20 Hz rTMS, and Sham rTMS, in a randomized order.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

1 Hz rTMS Stimulation first, then 20 Hz rTMS Stimulation, then sham rTMS

Arm Type

Experimental

Arm Description

Arm Title

1 Hz rTMS Stimulation first, then sham rTMS, then 20 Hz rTMS Stimulation

Arm Type

Experimental

Arm Description

Arm Title

20 Hz rTMS Stimulation first, then 1 Hz rTMS Stimulation, then sham rTMS

Arm Type

Experimental

Arm Description

Arm Title

20 Hz rTMS Stimulation first, then sham rTMS, then 1 Hz rTMS Stimulation

Arm Type

Experimental

Arm Description

Arm Title

sham rTMS first, then 1 Hz rTMS Stimulation, then 20 Hz rTMS Stimulation

Arm Type

Experimental

Arm Description

Arm Title

sham rTMS first, then 20 Hz rTMS Stimulation, then 1 Hz rTMS Stimulation

Arm Type

Experimental

Arm Description

Intervention Type

Device

Intervention Name(s)

1 Hz rTMS Stimulation

Other Intervention Name(s)

rTMS

Intervention Description

rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.

Intervention Type

Device

Intervention Name(s)

Sham rTMS Stimulation

Intervention Description

rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation.

Primary Outcome Measure Information:

Title

Change in Precuneus Functional Activation

Description

Time Frame

1 day

Title

Precuneus Functional Connectivity

Description

Time Frame

1 day

Title

Performance During In-scanner Episodic Memory Task

Description

Time Frame

1 day

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tom Hummer

Organizational Affiliation

Indiana University

Official's Role

Principal Investigator

Facility Information:

Facility Name

IU Center for Neuroimaging

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

Prevention and Recovery Center for Early Psychosis

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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rTMS as a Probe of Episodic Memory Neurocircuitry in Schizophrenia

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