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Interactions of Fronto-Parietal High Frequency rTMS on Anterior Cingulate Cortex Activation in Schizophrenia (rTMS-FPCC)

Primary Purpose

Schizophrenia

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

20 Hz rTMS

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
Mini-International Neuropsychiatric interview (MINI)37-40 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 Type

Experimental

Arm Label

20 Hz rTMS targeting the LDLPFC first, then 20 Hz rTMS targeting the LSPC

20 Hz rTMS Targeting the LSPC first, then 20 Hz rTMS Targeting the LDLPFC

Arm Description

Outcomes

Primary Outcome Measures

Change in BOLD Signal in Anterior Cingulate Cortex

Effects of rTMS on anterior cingulate cortex functional activation as measured by blood oxygen level dependent (BOLD) signal change scores during cognitive control Mismatch trials vs. Match trials (i.e., Mismatch - Match). The BOLD signal is measured during a functional magnetic resonance imaging (fMRI) scan and reflects the level of brain activity in the region. Change is calculated as difference between the Mismatch-Match signal at baseline and 30-60 minutes following the intervention. Higher scores indicate a larger increase in brain activity following the intervention.

Change in Cognitive Control Network Functional Connectivity

The outcome reflects changes in blood oxygen level dependent (BOLD) functional connectivity with anterior cingulate cortex (ACC) and the left dorsolateral prefrontal cortex (LDLPFC) and left superior parietal cortex (LSPC). Functional connectivity is calculated as the Fisher's transformation of the correlation coefficient of the BOLD time series in the ACC with the time series in each target region. Therefore, functional connectivity reflects how similar brain activity is between the target regions (LDLPFC and LSPC) and the ACC, with higher scores indicating greater connectivity. Outcome scores are changes in this connectivity between baseline and 30-60 minutes following the rTMS intervention targeting LDLPFC or LSPC. Positive scores indicate stronger connectivity following rTMS in the cognitive control network.

Secondary Outcome Measures

Full Information

NCT ID

NCT04309370

First Posted

December 20, 2019

Last Updated

July 17, 2023

Sponsor

Indiana University

1. Study Identification

Unique Protocol Identification Number

NCT04309370

Brief Title

Interactions of Fronto-Parietal High Frequency rTMS on Anterior Cingulate Cortex Activation in Schizophrenia

Acronym

rTMS-FPCC

Official Title

Interactions of Fronto-Parietal High Frequency Repetitive Transcranial Magnetic Stimulation on Anterior Cingulate Cortex Activation in Schizophrenia

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

March 12, 2020 (Actual)

Primary Completion Date

April 15, 2022 (Actual)

Study Completion Date

April 15, 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. 20 subjects with EPP (Early Phase Psychosis), defined as medical record documentation of the onset of clinically significant psychotic symptoms within the past 10 years, will be enrolled. Prior to randomization subjects will undergo fMRI (Functional Magnetic Resonance Imaging) during CC (Cognitive Control) task (Stroop Color-Word paradigm) and resting-state paradigms. This baseline scan will also include a high-resolution structural sequence for neuronavigation purposes. Then, on two separate days, each occurring one-week apart, subjects will receive one session of excitatory (20 Hz) (Hertz) rTMS (Repetitive Transcranial Magnetic Stimulation) targeting the LDLPFC (Left Dorsolateral Prefrontal Cortex) and one session targeting the LSPC (Left Superior Parietal Cortex). The order of stimulation sites will be randomized and counter-balanced. Immediately following each session, subjects will undergo repeat fMRI during CC and RS (Resting State) paradigms. Investigators will also examine the effect of rTMS on CC 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 rTMS targeting superficial CCN (Cognitive Control Network) structures (LDLPFC and LSPC) on ACC (Anterior Cingulate Cortex) activity or CCN connectivity 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. 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 CC in the illness, rTMS modulating the ACC, and potentially CCN circuitry, represents an unexplored and novel potential treatment option. The goal of this project is to utilize HF (20 Hz) rTMS, in conjunction with functional magnetic resonance imaging (fMRI), to provide evidence that rTMS targeting superficial CCN structures (LDLPFC and LSPC) modulates: 1) activation in the ACC during in-scanner CC task performance and 2) functional connectivity between the CCN structures during in-scanner CC task performance. This study will provide vital preliminary data on target engagement informing future clinical trials seeking to investigate rTMS as a novel treatment for CC impairment in schizophrenia. This study will also seek to refine the understanding of the brain circuitry that mediates the potential pro-CC 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

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

20 Hz rTMS targeting the LDLPFC first, then 20 Hz rTMS targeting the LSPC

Arm Type

Experimental

Arm Title

20 Hz rTMS Targeting the LSPC first, then 20 Hz rTMS Targeting the LDLPFC

Arm Type

Experimental

Intervention Type

Device

Intervention Name(s)

20 Hz rTMS

Intervention Description

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that received FDA clearance for use in treatment resistant major depressive disorder in 2008. rTMS utilizes the application of a repetitively pulsed magnetic field over the scalp to induce an electric field within a discrete area of the cerebral cortex. This electric field results in altered ion flow across the neuronal cellular membrane and ultimately changes in neuronal polarization. rTMS modulates cortical activation depending on the stimulation parameters used. Physiological studies have provided evidence that suggests that high-frequency (HF) rTMS produces an increase in local cortical excitability. Studies have also demonstrated that rTMS may increase or decrease functional connectivity between separate but related cortical structures, utilizing high and low frequency stimulation, respectively.

Primary Outcome Measure Information:

Title

Change in BOLD Signal in Anterior Cingulate Cortex

Description

Time Frame

1 day

Title

Change in Cognitive Control Network Functional Connectivity

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 Mini-International Neuropsychiatric interview (MINI)37-40 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 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tom Hummer, PhD

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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Interactions of Fronto-Parietal High Frequency rTMS on Anterior Cingulate Cortex Activation in Schizophrenia

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