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Using Transcranial Magnetic Stimulation (TMS) to Understand 'Negative' Symptoms of Schizophrenia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03648268
Recruitment Status : Recruiting
First Posted : August 27, 2018
Last Update Posted : August 22, 2019
Sponsor:
Collaborators:
Mclean Hospital
Harvard University
Information provided by (Responsible Party):
Roscoe Brady, Beth Israel Deaconess Medical Center

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.


Condition or disease Intervention/treatment Phase
Schizophrenia Negative Type; Schizophrenic Device: repetitive Transcranial Magnetic Stimulation (rTMS) Not Applicable

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.
Primary Purpose: Basic Science
Official Title: Network Mediation of Experiential and Expressive Deficits in Psychotic Disorders
Actual Study Start Date : February 4, 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Active Comparator: Active DLPFC rTMS
Active repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the right DLPFC at 80% of active motor threshold.
Device: repetitive Transcranial Magnetic Stimulation (rTMS)

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

Other Name: iTBS

Sham Comparator: Sham DLPFC rTMS
Sham repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the right DLPFC
Device: repetitive Transcranial Magnetic Stimulation (rTMS)

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

Other Name: iTBS

Active Comparator: Active cerebellum rTMS
Active repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the cerebellum at 100% of active motor threshold.
Device: repetitive Transcranial Magnetic Stimulation (rTMS)

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

Other Name: iTBS

Sham Comparator: Sham cerebellum rTMS
Sham repetitive Transcranial Magnetic Stimulation (rTMS) with iTBS pattern to the cerebellum
Device: repetitive Transcranial Magnetic Stimulation (rTMS)

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

Other Name: iTBS




Primary Outcome Measures :
  1. Change in Negative Symptom Severity [ Time Frame: Before treatment (Baseline) and 1 week post treatment ]
    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 :
  1. Change in Cerebellar - Prefrontal Functional Connectivity [ Time Frame: Before treatment (Baseline) and 1 week post treatment ]
    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

  2. Change in Auditory Hallucination Severity [ Time Frame: Before treatment (Baseline) and 1 week post treatment ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03648268


Contacts
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Contact: Roscoe Brady, MD, PhD (617) 754-1261 robrady@bidmc.harvard.edu
Contact: Uzma Nawaz, MS (617) 754-1242 unawaz@bidmc.harvard.edu

Locations
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United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02115
Contact: Roscoe Brady, MD, PhD       robrady@bidmc.harvard.edu   
Contact: Uzma Nawaz, MS    (617) 754-1242    unawaz@bidmc.harvard.edu   
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Mclean Hospital
Harvard University
Investigators
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Principal Investigator: Roscoe Brady, MD, PhD Beth Israel Deaconess Medical Center

Publications:

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Responsible Party: Roscoe Brady, Assistant Professor of Psychiatry, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT03648268    
Other Study ID Numbers: 2018P000321
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by Roscoe Brady, Beth Israel Deaconess Medical Center:
brain
networks
schizophrenia
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders