Using Transcranial Magnetic Stimulation (TMS) to Understand 'Negative' Symptoms of Schizophrenia
Primary Purpose
Schizophrenia, Negative Type; Schizophrenic, Schizo Affective Disorder
Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
repetitive Transcranial Magnetic Stimulation (rTMS)
Sponsored by
About this trial
This is an interventional basic science trial for Schizophrenia focused on measuring brain, networks, schizophrenia
Eligibility Criteria
Inclusion Criteria:
- Age between 18-55 years
- At pre-visit screening (see attached phone screening questionnaire): participants must report that they have been given a diagnosis of schizophrenia or schizoaffective disorder by a mental health professional
- Must be able to read, speak, and understand English
- Must be judged by study staff to be capable of completing the study procedures
- Diagnosis of schizophrenia or schizoaffective disorder according to DSM-V criteria and confirmed by SCID
- Participants will be in stable outpatient treatment with no recent (within the past 30 days) hospitalizations or changes in their mediation regimens
Exclusion Criteria:
- DSM-V intellectual disability
- substance use disorder within the past three months
- Ambidexterity (the EEfRT task assumes participants are not ambidextrous)
- Any history of progressive or genetic neurological disorder (e.g. Parkinson's disease, multiple sclerosis, tubular sclerosis, Alzheimer's Disease) or acquired neurological disease (e.g. stroke, traumatic brain injury, tumor), including intracranial lesions
- History of head trauma resulting in any loss of consciousness (>15 minutes) or neurological sequelae
- Current history of poorly controlled headaches including chronic medication for migraine prevention
- History of fainting spells of unknown or undetermined etiology that might constitute seizures
- History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist
- Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
- Any metal in the brain or skull (excluding dental fillings) or elsewhere in the body unless cleared by the responsible covering MD (e.g. MRI compatible joint replacement)
- Any devices such as pacemaker, medication pump, nerve stimulator, TENS unit, ventriculo-peritoneal shunt unless cleared by the responsible covering MD
- All female participants of child bearing age will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study
- Medications will be reviewed by the responsible covering physician and a decision about inclusion will be made based on the participant's past medical history, drug dose, history of recent medication changes or duration of treatment, and use of CNS active drugs. The published TMS guidelines review of medications to be considered with rTMS will be taken into consideration given their described effects on cortical excitability measures.
- Any changes in medications or hospitalizations within the past 30 days.
- Subjects who, in the investigator's opinion, might not be suitable for the study or would be unable to tolerate the study visit
Sites / Locations
- Beth Israel Deaconess Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Sham Comparator
Active Comparator
Sham Comparator
Arm Label
Active DLPFC rTMS
Sham DLPFC rTMS
Active cerebellum rTMS
Sham cerebellum rTMS
Arm Description
Active repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the right DLPFC at 80% of active motor threshold.
Sham repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the right DLPFC
Active repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the cerebellum at 100% of active motor threshold.
Sham repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the cerebellum
Outcomes
Primary Outcome Measures
Change in Negative Symptom Severity
We will evaluate the effect of sham vs active rTMS on negative symptom severity in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS
Secondary Outcome Measures
Change in Cerebellar - Prefrontal Functional Connectivity
We will evaluate the effect of sham vs active rTMS on cerebellar-prefrontal cortex functional connectivity in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS
Change in Auditory Hallucination Severity
We will evaluate the effect of sham vs active rTMS on the frequency and severity of auditory hallucinations in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS
Full Information
NCT ID
NCT03648268
First Posted
August 21, 2018
Last Updated
February 6, 2023
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Mclean Hospital, Harvard University
1. Study Identification
Unique Protocol Identification Number
NCT03648268
Brief Title
Using Transcranial Magnetic Stimulation (TMS) to Understand 'Negative' Symptoms of Schizophrenia
Official Title
Network Mediation of Experiential and Expressive Deficits in Psychotic Disorders
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 2, 2019 (Actual)
Primary Completion Date
November 30, 2023 (Anticipated)
Study Completion Date
November 30, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Mclean Hospital, Harvard University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The main purpose of this study is to learn how transcranial magnetic stimulation (TMS) helps improve negative symptoms of schizophrenia. These 'negative symptoms' include anhedonia (the inability to enjoy things), low motivation, and decreased facial expression.
TMS is a noninvasive way of stimulating the brain. TMS uses a magnetic field to cause changes in activity in the brain. The magnetic field is produced by a coil that is held next to the scalp. In this study we will be stimulating the brain to learn more about how TMS may improve these symptoms from schizophrenia.
Detailed Description
This study proposes to test the hypothesis that the medication refractory experiential (anhedonia and amotivation) and expressive deficits named 'negative symptoms' are mediated by network pathophysiology and the functional connectivity of a cerebellar-prefrontal cortical network mediates the severity of these deficits. To accomplish this participants will be recruited who are diagnosed with schizophrenia or schizoaffective disorder who demonstrate negative symptoms despite stable outpatient treatment.
Participants will undergo an initial screening session to complete informed consent and undergo baseline assessments of negative symptom severity. These assessments include reporter-based measures such as the Positive And Negative Syndrome Scale (PANSS) as well as quantitative tests of amotivation/anhedonia and diminished expressivity.
Participants will then undergo an MRI scan that includes structural and resting state functional magnetic resonance imaging (rsfMRI). These rsfMRI images will be used to isolate individual resting-state networks for targeting of rTMS modulation.
Participants will then undergo five days of twice daily rTMS sessions in one of the four arms of this study.
One week after the last rTMS session, Participants will undergo follow-up MRI imaging and the same assessments described above.
Aims:
Aim 1: To determine if network dysconnectivity is causally linked to negative symptom severity and if amelioration of this dysconnectivity results in reduced symptom severity. Symptom severity will be measured via both reporter-based and quantitative measures.
Aim 2: To determine if the relationship between functional connectivity and symptom severity arises from interactions between specific nodes of the default mode network (DMN): the cerebellum and DLPFC, or is the result of interactions between multiple nodes in the DMN (both cerebral and cerebellar).
Exploratory Aim: As an exploratory aim, additional genetic data will be collected which may be related to TMS efficacy. Hypothesis: Brain-derived neurotrophic factor (BDNF) homozygous val-allele carriers of the val66met BDNF gene will show greater response than met-carriers.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia, Negative Type; Schizophrenic, Schizo Affective Disorder
Keywords
brain, networks, schizophrenia
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
There will be four groups: an active DLPFC TMS group, an active TMS cerebellum group, a sham DLPFC group, and a sham cerebellum group. Participants will be randomized to one of these group groups, and they will receive that type of stimulation for the entire study.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The subjects, care providers, investigators and outcome assessors will all be blinded as to the randomization sequence, and thus will be blinded as to sham vs active TMS status. Blinding codes are used to determine which side of an active/passive Magpro coil (cool B65 A/P, Magventure A/S, Denmark) is used for stimulation.
Allocation
Randomized
Enrollment
68 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Active DLPFC rTMS
Arm Type
Active Comparator
Arm Description
Active repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the right DLPFC at 80% of active motor threshold.
Arm Title
Sham DLPFC rTMS
Arm Type
Sham Comparator
Arm Description
Sham repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the right DLPFC
Arm Title
Active cerebellum rTMS
Arm Type
Active Comparator
Arm Description
Active repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the cerebellum at 100% of active motor threshold.
Arm Title
Sham cerebellum rTMS
Arm Type
Sham Comparator
Arm Description
Sham repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the cerebellum
Intervention Type
Device
Intervention Name(s)
repetitive Transcranial Magnetic Stimulation (rTMS)
Other Intervention Name(s)
iTBS
Intervention Description
rTMS is a technique of TMS that allows the selective external manipulation of neural activity in a non-invasive manner. During TMS, a rapidly changing current is passed through an insulated coil placed against the scalp. This generates a temporary magnetic field that in turn induces electrical current in neurons and allows the modulation of neural circuitry. The combination of TMS with fMRI allows the selective targeting and modulation of brain networks. The repeated application of rTMS can cause long term changes in behavior and task performance that is reflected in altered brain network connectivity.
The pattern of rTMS will consist of either:
intermittent Theta Burst Stimulation (iTBS) pattern consisting of 2 s trains of 3 pulses at 50 Hz, repeated at 5 Hz, every 10s for a total of 600 pulses.
OR
sham stimulation
Primary Outcome Measure Information:
Title
Change in Negative Symptom Severity
Description
We will evaluate the effect of sham vs active rTMS on negative symptom severity in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS
Time Frame
Before treatment (Baseline) and 1 week post treatment
Secondary Outcome Measure Information:
Title
Change in Cerebellar - Prefrontal Functional Connectivity
Description
We will evaluate the effect of sham vs active rTMS on cerebellar-prefrontal cortex functional connectivity in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS
Time Frame
Before treatment (Baseline) and 1 week post treatment
Title
Change in Auditory Hallucination Severity
Description
We will evaluate the effect of sham vs active rTMS on the frequency and severity of auditory hallucinations in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS
Time Frame
Before treatment (Baseline) and 1 week post treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age between 18-55 years
At pre-visit screening (see attached phone screening questionnaire): participants must report that they have been given a diagnosis of schizophrenia or schizoaffective disorder by a mental health professional
Must be able to read, speak, and understand English
Must be judged by study staff to be capable of completing the study procedures
Diagnosis of schizophrenia or schizoaffective disorder according to DSM-V criteria and confirmed by SCID
Participants will be in stable outpatient treatment with no recent (within the past 30 days) hospitalizations or changes in their mediation regimens
Exclusion Criteria:
DSM-V intellectual disability
substance use disorder within the past three months
Ambidexterity (the EEfRT task assumes participants are not ambidextrous)
Any history of progressive or genetic neurological disorder (e.g. Parkinson's disease, multiple sclerosis, tubular sclerosis, Alzheimer's Disease) or acquired neurological disease (e.g. stroke, traumatic brain injury, tumor), including intracranial lesions
History of head trauma resulting in any loss of consciousness (>15 minutes) or neurological sequelae
Current history of poorly controlled headaches including chronic medication for migraine prevention
History of fainting spells of unknown or undetermined etiology that might constitute seizures
History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist
Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
Any metal in the brain or skull (excluding dental fillings) or elsewhere in the body unless cleared by the responsible covering MD (e.g. MRI compatible joint replacement)
Any devices such as pacemaker, medication pump, nerve stimulator, TENS unit, ventriculo-peritoneal shunt unless cleared by the responsible covering MD
All female participants of child bearing age will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study
Medications will be reviewed by the responsible covering physician and a decision about inclusion will be made based on the participant's past medical history, drug dose, history of recent medication changes or duration of treatment, and use of CNS active drugs. The published TMS guidelines review of medications to be considered with rTMS will be taken into consideration given their described effects on cortical excitability measures.
Any changes in medications or hospitalizations within the past 30 days.
Subjects who, in the investigator's opinion, might not be suitable for the study or would be unable to tolerate the study visit
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Roscoe Brady, MD, PhD
Phone
(617) 632-7933
Email
robrady@bidmc.harvard.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Adam Beermann, MA
Phone
(617) 632-7956
Email
abeerman@bidmc.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roscoe Brady, MD, PhD
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roscoe Brady, MD, PhD
Email
robrady@bidmc.harvard.edu
First Name & Middle Initial & Last Name & Degree
Adam Beermann, MA
Phone
(617) 632-7956
Email
abeerman@bidmc.harvard.edu
First Name & Middle Initial & Last Name & Degree
Jing Xie, BS
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
This study will adhere to the published Data Sharing Expectations for NIMH-funded Clinical Trials outlined in NOT-MH-14-015. We will share data collected in these experiments with the National Database for Clinical Trials related to Mental Illness using its GUID and Data Dictionary technology.
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Using Transcranial Magnetic Stimulation (TMS) to Understand 'Negative' Symptoms of Schizophrenia
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