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

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03648268
• Collaborator: Mclean Hospital (Other), Harvard University (Other)
• Enrollment: 68
• Location: 1
• Arms: 4
• Anticipated Duration (Months): 55
• Patients Per Site Per Month: 1.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Negative Type; Schizophrenic; Schizo Affective Disorder	Device: repetitive Transcranial Magnetic Stimulation (rTMS)	N/A

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.

Study Design

• Study Type: Interventional
• Anticipated 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.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: May 2, 2019
• Anticipated Primary Completion Date: Nov 30, 2023
• Anticipated Study Completion Date: Nov 30, 2023

Arms and Interventions

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 Names: 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 Names: 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 Names: 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 Names: iTBS

Outcome Measures

Primary Outcome Measures

1. Change in Negative Symptom Severity [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 [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 [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• Mclean Hospital
• Harvard University

Investigators

• Principal Investigator: Roscoe Brady, MD, PhD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Andreasen NC, Paradiso S, O'Leary DS. "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull. 1998;24(2):203-18. Review.
• Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, Seidman LJ, Schmahmann JD, Pascual-Leone A. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010 Dec;124(1-3):91-100. doi: 10.1016/j.schres.2010.08.015.
• Eldaief MC, Halko MA, Buckner RL, Pascual-Leone A. Transcranial magnetic stimulation modulates the brain's intrinsic activity in a frequency-dependent manner. Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21229-34. doi: 10.1073/pnas.1113103109. Epub 2011 Dec 12.
• Garg S, Sinha VK, Tikka SK, Mishra P, Goyal N. The efficacy of cerebellar vermal deep high frequency (theta range) repetitive transcranial magnetic stimulation (rTMS) in schizophrenia: A randomized rater blind-sham controlled study. Psychiatry Res. 2016 Sep 30;243:413-20. doi: 10.1016/j.psychres.2016.07.023. Epub 2016 Jul 16.
• Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6.
• Parker KL, Narayanan NS, Andreasen NC. The therapeutic potential of the cerebellum in schizophrenia. Front Syst Neurosci. 2014 Sep 15;8:163. doi: 10.3389/fnsys.2014.00163. eCollection 2014.
• Power JD, Cohen AL, Nelson SM, Wig GS, Barnes KA, Church JA, Vogel AC, Laumann TO, Miezin FM, Schlaggar BL, Petersen SE. Functional network organization of the human brain. Neuron. 2011 Nov 17;72(4):665-78. doi: 10.1016/j.neuron.2011.09.006.
• Rabinowitz J, Levine SZ, Garibaldi G, Bugarski-Kirola D, Berardo CG, Kapur S. Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data. Schizophr Res. 2012 May;137(1-3):147-50. doi: 10.1016/j.schres.2012.01.015. Epub 2012 Feb 6.
• Robertson BR, Prestia D, Twamley EW, Patterson TL, Bowie CR, Harvey PD. Social competence versus negative symptoms as predictors of real world social functioning in schizophrenia. Schizophr Res. 2014 Dec;160(1-3):136-41. doi: 10.1016/j.schres.2014.10.037. Epub 2014 Nov 7.
• Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14. Review.
• Roth BJ, Cohen LG, Hallett M. The electric field induced during magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl. 1991;43:268-78.
• Roth BJ, Saypol JM, Hallett M, Cohen LG. A theoretical calculation of the electric field induced in the cortex during magnetic stimulation. Electroencephalogr Clin Neurophysiol. 1991 Feb;81(1):47-56.
• Schmahmann JD. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991 Nov;48(11):1178-87. Review.
• Schmahmann JD. Dysmetria of thought: clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn Sci. 1998 Sep 1;2(9):362-71.
• Walsh V, Cowey A. Transcranial magnetic stimulation and cognitive neuroscience. Nat Rev Neurosci. 2000 Oct;1(1):73-9. Review.
• Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, Roffman JL, Smoller JW, Zöllei L, Polimeni JR, Fischl B, Liu H, Buckner RL. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011 Sep;106(3):1125-65. doi: 10.1152/jn.00338.2011. Epub 2011 Jun 8.

• Responsible Party: Roscoe Brady, Assistant Professor of Psychiatry, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT03648268
• Other Study ID Numbers: 2018P000321
• First Posted: Aug 27, 2018
• Last Update Posted: Nov 1, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by Roscoe Brady, Assistant Professor of Psychiatry, Beth Israel Deaconess Medical Center: brain; networks; schizophrenia
• Additional relevant MeSH terms: Schizophrenia; Mood Disorders; Psychotic Disorders

Study Results

No Results Posted as of Nov 1, 2021