Schizophrenia
Conditions
Keywords
schizophrenia, psychosis, early phase psychosis, rTMS
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.
Interventions
DEVICE20 Hz rTMS
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.
Sponsors
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
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. Mini-International Neuropsychiatric interview (MINI)37-40 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 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, TENS unit, ventriculoperitoneal shunt, or cochlear implants 9. Contraindications to 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BOLD Signal in Anterior Cingulate Cortex | 1 day | 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 | 1 day | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 20 Hz rTMS Targeting the LDLPFC First, Then 20 Hz rTMS Targeting the LSPC 20 Hz rTMS: 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. | 7 |
| 20 Hz rTMS Targeting the LSPC First, Then 20 Hz rTMS Targeting the LDLPFC 20 Hz rTMS: 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. | 7 |
| Total | 14 |
Baseline characteristics
| Characteristic | 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 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 7 Participants | 14 Participants |
| Age, Continuous | 25.9 years STANDARD_DEVIATION 2.1 | 27.2 years STANDARD_DEVIATION 5.1 | 26.5 years STANDARD_DEVIATION 3.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment United States | 7 participants | 7 participants | 14 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 1 / 14 | 2 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 20 Hz rTMS Targeting the Left DLPFC | Change in BOLD Signal in Anterior Cingulate Cortex | -0.0188 BOLD signal change (Mismatch vs. Match) |
| 20 Hz rTMS Targeting the Left Superior Parietal Cortex | Change in BOLD Signal in Anterior Cingulate Cortex | 0.0124 BOLD signal change (Mismatch vs. Match) |
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 20 Hz rTMS Targeting the Left DLPFC | Change in Cognitive Control Network Functional Connectivity | -0.006 Change in correlation |
| 20 Hz rTMS Targeting the Left Superior Parietal Cortex | Change in Cognitive Control Network Functional Connectivity | -0.01 Change in correlation |