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

Schizophrenia Clinical Trial

Official title:

Network Mediation of Experiential and Expressive Deficits in Psychotic Disorders

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03648268
• Other study ID #: 2018P000321
• Status: Completed
• Phase: N/A
• Start date: May 2, 2019
• Est. completion date: December 22, 2023

Study information

• Verified date: March 2024
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 22, 2023
• Est. primary completion date: December 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Mood Disorders
• Negative Type; Schizophrenic
• Psychotic Disorders
• Schizo Affective Disorder
• Schizophrenia

Intervention

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

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Harvard University, Mclean Hospital

Country where clinical trial is conducted

United States, 

References & Publications (16)

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. doi: 10.1093/oxfordjournals.schbul.a033321. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. doi: 10.1016/j.neuron.2004.12.033. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Roth BJ, Cohen LG, Hallett M. The electric field induced during magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl. 1991;43:268-78. — View Citation

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. doi: 10.1016/0168-5597(91)90103-5. — View Citation

Schmahmann JD. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991 Nov;48(11):1178-87. doi: 10.1001/archneur.1991.00530230086029. — View Citation

Schmahmann JD. Dysmetria of thought: clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn Sci. 1998 Sep 1;2(9):362-71. doi: 10.1016/s1364-6613(98)01218-2. — View Citation

Walsh V, Cowey A. Transcranial magnetic stimulation and cognitive neuroscience. Nat Rev Neurosci. 2000 Oct;1(1):73-9. doi: 10.1038/35036239. — View Citation

Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, Roffman JL, Smoller JW, Zollei 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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Before treatment (Baseline) and 1 week post treatment
Secondary	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	Before treatment (Baseline) and 1 week post treatment
Secondary	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	Before treatment (Baseline) and 1 week post treatment