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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 Hz rTMS Stimulation first, then 20 Hz rTMS Stimulation, then sham rTMS | Experimental | 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. |
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| 1 Hz rTMS Stimulation first, then sham rTMS, then 20 Hz rTMS Stimulation | Experimental | 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. |
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| 20 Hz rTMS Stimulation first, then 1 Hz rTMS Stimulation, then sham rTMS | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 1 Hz rTMS Stimulation | Device | rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation. |
| 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 |
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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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tom Hummer | Indiana University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IU Center for Neuroimaging | Indianapolis | Indiana | 46202 | United States | ||
| Prevention and Recovery Center for Early Psychosis |
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| ID | Title | Description |
|---|---|---|
| FG000 | rTMS Order 1 | 1 Hz rTMS Stimulation First, Then 20 Hz rTMS Stimulation, Then Sham rTMS |
| FG001 | rTMS Order 2 | 1 Hz rTMS Stimulation first, then sham rTMS, then 20 Hz rTMS Stimulation |
| FG002 | rTMS Order 3 | 20 Hz rTMS Stimulation First, Then 1 Hz rTMS Stimulation, Then Sham rTMS |
| FG003 | rTMS Order 4 | 20 Hz rTMS Stimulation First, Then Sham rTMS, Then 1 Hz rTMS Stimulation |
| FG004 | rTMS Order 5 | Sham rTMS First, Then 1 Hz rTMS Stimulation, Then 20 Hz rTMS Stimulation |
| FG005 | rTMS Order 6 | Sham rTMS first, then 20 Hz rTMS stimulation, then 1 Hz rTMS stimulation |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (Week 1) |
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| Second Intervention (Week 2) |
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| Third Intervention (Week 3) |
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| ID | Title | Description |
|---|---|---|
| BG000 | rTMS Order 1 | 1 Hz rTMS stimulation first, then 20 Hz rTMS stimulation, then sham rTMS rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | Beta coefficient change (Target vs Foil) | 1 day |
|
1 month
Investigator evaluated for adverse events at every visit
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 1 Hz rTMS Stimulation | rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Numbness of fingers | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Research Manager | Indiana University | 3178808495 | iupdp@iupui.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 15, 2022 | Feb 7, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D011618 | Psychotic Disorders |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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All patients will receive 1 Hz rTMS, 20 Hz rTMS, and Sham rTMS, in a randomized order.
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| 20 Hz rTMS Stimulation first, then sham rTMS, then 1 Hz rTMS Stimulation | Experimental | 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. |
|
| sham rTMS first, then 1 Hz rTMS Stimulation, then 20 Hz rTMS Stimulation | Experimental | 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. |
|
| sham rTMS first, then 20 Hz rTMS Stimulation, then 1 Hz rTMS Stimulation | Experimental | 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. |
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| Sham rTMS Stimulation | Device | rTMS is an electromagnetic device that provides non-invasive stimulation to the cortex or a sham placebo stimulation that mimics properties without stimulation. |
|
| Indianapolis |
| Indiana |
| 46202 |
| United States |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | rTMS Order 2 | 1 Hz rTMS stimulation first, then sham rTMS, then 20 Hz rTMS stimulation rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
| BG002 | rTMS Order 3 | 20 Hz rTMS stimulation first, then 1 Hz rTMS stimulation, then sham rTMS rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
| BG003 | rTMS Order 4 | 20 Hz rTMS stimulation first, then sham rTMS, then 1 Hz rTMS stimulation rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
| BG004 | rTMS Order 5 | Sham rTMS first, then 1 Hz rTMS stimulation, then 20 Hz rTMS stimulation rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
| BG005 | rTMS Order 6 | Sham rTMS first, then 20 Hz rTMS stimulation, then 1 Hz rTMS stimulation rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
| BG006 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 |
| 20 Hz rTMS |
Subjects will receive one session of 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 minutes. |
| OG002 | Sham | Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. |
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| Primary | 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. | Posted | Mean | Standard Deviation | Transformed correlation coefficient | 1 day |
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| Primary | 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. | Posted | Mean | Standard Deviation | Percentage correct | 1 day |
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| 0 |
| 24 |
| 0 |
| 24 |
| 1 |
| 24 |
| EG001 | 20 Hz rTMS Stimulation | rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. | 0 | 24 | 0 | 24 | 1 | 24 |
| EG002 | Sham rTMS Stimulation | rTMS: Subjects will receive one session of low frequency rTMS within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 pulses. Subjects will receive one session of 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 minutes. Sham: Sham stimulation session targeting the precuneus. The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding. | 0 | 24 | 0 | 24 | 1 | 24 |
| Application site discomfort | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
|
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Paired t-test comparing precuneus connectivity following 1Hz rTMS to precuneus connectivity following 20 Hz rTMS stimulation. |
| t-test, 2 sided |
| 0.44 |
| Mean Difference (Net) |
| 0.009 |
| 2-Sided |
| 95 |
| -0.015 |
| 0.033 |
| Superiority |
| Paired t-test comparing precuneus connectivity following 20Hz rTMS to precuneus connectivity following sham stimulation. | t-test, 2 sided | 0.25 | Mean Difference (Net) | -0.012 | 2-Sided | 95 | -0.032 | 0.009 | Superiority |
Paired t-test of scene recognition performance accuracy following 1Hz rTMS to accuracy following sham rTMS.
| t-test, 2 sided |
| 0.17 |
Not corrected for multiple comparisons. |
| Mean Difference (Net) |
| 4.0 |
| 2-Sided |
| 95 |
| -1.9 |
| 9.9 |
| Superiority |
| Paired t-test of scene recognition performance accuracy following 20Hz rTMS to accuracy following 20 Hz rTMS. | t-test, 2 sided | 0.77 | Not adjusted for multiple comparisons. | Mean Difference (Net) | -1.3 | 2-Sided | 95 | -10.8 | 8.2 | Superiority |