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Effect of Repetitive Transcranial Magnetic Stimulation on Resting State Brain Activity in Schizophrenia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Arkansas
ClinicalTrials.gov Identifier:
NCT01620086
First received: June 4, 2012
Last updated: October 28, 2016
Last verified: October 2016
  Purpose
This study compares the efficacy of low and high frequency repetitive transcranial magnetic stimulation (rTMS) as a means of treating subjects with schizophrenia. Magnetic pulses delivered over the scalp cause brain activity. This activity has been shown to help decrease the intensity and frequency of auditory hallucinations (AH) in schizophrenia. The investigators will compare whether low or high frequencies work best. The investigators will also examine what changes occur in the brain that are related to improvement.

Condition Intervention
Schizophrenia
Device: Active Repetitive Transcranial Magnetic Stimulation 1 Hz
Device: Active Repetitive Transcranial Magnetic Stimulation 10 Hz
Device: Active control site Repetitive Transcranial Magnetic Stimulation at 1Hz
Device: Sham control site Repetitive Transcranial Magnetic Stimulation
Device: Active control site Repetitive Transcranial Magnetic Stimulation at 10 Hz

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Effect of Repetitive Transcranial Magnetic Stimulation (RTMS) on Resting State Brain Activity in Schizophrenia

Resource links provided by NLM:


Further study details as provided by University of Arkansas:

Primary Outcome Measures:
  • Changes in Auditory Hallucinations Questionnaire (AHQ). [ Time Frame: change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls)" ] [ Designated as safety issue: No ]
    The Auditory Hallucinations Questionnaire (AHQ) will be used to determine the patient's perceptions of change in auditory hallucinations(s). Normal controls do not fill out this measure because they do not have auditory hallucinations. Change in the average results of this test between the baseline and active treatment weeks (1 and 10 Hz) will be measured. The range of scores is 0-70, higher scores mean more symptoms.


Secondary Outcome Measures:
  • Overall Change in the Percent Habituation of the P50 Evoked Response Potential at 250 Inter Stimulus Interval (ISI) Between the Control and Active Treatments (1 and 10 Hz). [ Time Frame: change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls)" ] [ Designated as safety issue: No ]
    Percent habituation refers to change in the amplitude of the P50 evoked response potential following a 250 ms inter stimulus interval. Change in the average results of this test between the baseline and active treatment weeks (1 and 10 Hz) will be measured.

  • Depression Level Changes as Measured by the Hamilton Depression Inventory (HAMD). [ Time Frame: change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls)" ] [ Designated as safety issue: No ]
    HAM-D is a multiple choice questionnaire that clinicians administer to rate the severity of a subject's depression. There are 17 questions; each question has between 3-5 possible responses which increase in severity (range 0 to 52). The clinician chooses the correct response by interviewing the subject and by observing the symptoms. A score of 0-7 is considered to be normal, scores of 20 or higher indicate moderately severe depression. Change in the average results of this test between the baseline and active treatment weeks (1 and 10 Hz) will be measured.


Enrollment: 26
Study Start Date: June 2012
Study Completion Date: August 2015
Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Patients
Patients with Schizophrenia who meet entry criteria for the study and first receive active repetitive transcranial magnetic stimulation for four days over a control site located at the vertex and then are randomized to receive repetitive Transcranial Magnetic Stimulation for four days over the temporal cortex at both 1 Hz and 10 Hz.
Device: Active Repetitive Transcranial Magnetic Stimulation 1 Hz
active rTMS delivered at 1Hz frequency over temporal cortex
Other Name: rTMS
Device: Active Repetitive Transcranial Magnetic Stimulation 10 Hz
active rTMS delivered at 10 Hz frequency over temporal cortex
Other Name: rTMS
Device: Active control site Repetitive Transcranial Magnetic Stimulation at 1Hz
active rTMS delivered at either 1 Hz frequency over the vertex
Device: Active control site Repetitive Transcranial Magnetic Stimulation at 10 Hz
Active 10 Hz rTMS delivered over the vertex
Experimental: Controls
These subjects are normal controls without schizophrenia who receive sham, repetitive transcranial magnetic stimulation at 1 Hz for two days and then receive active, repetitive Transcranial Magnetic stimulation for two days. All stimulation is delivered at the control site located over the vertex.
Device: Active control site Repetitive Transcranial Magnetic Stimulation at 1Hz
active rTMS delivered at either 1 Hz frequency over the vertex
Device: Sham control site Repetitive Transcranial Magnetic Stimulation
sham rTMS delivered at 1Hz frequency over the vertex

Detailed Description:

Background. The sub-Investigator Dr. Mennemeier has been using repetitive transcranial magnetic stimulation (rTMS) to treat phantom sound perception in subjects with tinnitus. The Principal Investigator (PI), Dr. Messias, now aims to team up with Drs. Mennemeier and James, to learn how rTMS influences phantom sound perception in schizophrenia. rTMS has already been shown to be an effective treatment for both tinnitus and schizophrenia. rTMS is a non-invasive method of regional brain stimulation that can significantly reduce phantom sound perception temporarily in 50% of subjects with tinnitus and schizophrenia. This study will go further than previous investigations by analyzing how different frequencies of rTMS influence not only auditory hallucinations (AH) in schizophrenia but also brain connectivity in schizophrenia. The investigators want to learn if rTMS decreases AH by normalizing brain connectivity. Whereas this study focuses on schizophrenic subjects with AH, the design is very similar to ongoing work on tinnitus so the findings will be comparable.

Tinnitus and AH in schizophrenia are prevalent and disabling disorders of sound perception. The investigators understanding of the precise mechanisms of these disorders is lacking. Interestingly, the symptoms of both disorders respond positively to rTMS of the temporal cortex in ways that defy contemporary understanding of the nature of these symptoms and of how rTMS should work to improve them. For example, phantom sound perception in both tinnitus and schizophrenia are linked to maladaptive, hyperactivity of auditory processing regions of temporal cortex; however, it is increasingly clear that these pathological changes alone are insufficient to explain the pronounced intrusiveness and negative emotional valance of symptoms in each disorder. Therefore, a barrier to understanding these disorders lies in understanding how changes in auditory cortex are synchronized with changes in other cortical regions that regulate perception and emotion. Additionally, at present, the decision of which rTMS frequency to apply as a treatment for phantom sound perception has no firm theoretical or empirical basis. Whereas, low frequency rTMS has traditionally been used, based upon contemporary models, to "inhibit" hyperactivity in auditory cortex; high frequency rTMS, which should induce an opposite effect on neuronal processing, not only works to improve symptoms but may be more effective for some subjects than low frequency rTMS. Therefore, contemporary models designed to explain how the frequency of rTMS influences neuronal activity immediate following stimulation are insufficient to explain how low and high frequencies of rTMS can mitigate phantom sound perception for days, weeks and months following a single course of treatment.

Hypothesis. The investigators propose that phantom sound perception in schizophrenia result from an imbalance of excitatory and inhibitory neural process in auditory networks and from synchronized, maladaptive changes in linked brain regions that regulate perception and emotion. Treating auditory cortex with repetitive, external magnetic stimulation can decrease phantom sound perception and distress by reversing the maladaptive brain reorganization that is set in motion by these underlying neural imbalances.

  Eligibility

Ages Eligible for Study:   21 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Inclusion Criteria for schizophrenic subjects.

    • Male and female patients, 21-65 years of age, of all races and ethnicities
    • Diagnosis of auditory hallucinations (AH) associated with schizophrenia (verified at screening)
    • Must report experiencing the presence of their phantom auditory perception for at least 6 months
    • Female Subjects of childbearing age must take a pregnancy test to rule out pregnancy prior to participating in this study and during the study.
    • Willing to provide informed consent to participate in all study interventions and assessments
    • Subjects must have the capacity to sign and informed consent or a legal authorized representative (LAR) must sign in addition to the subject.
  • Inclusion Criteria for control subjects.

    • Male and female patients, 21-65 years of age, of all races and ethnicities
    • Willing to provide informed consent to participate in all study interventions and assessments

Exclusion Criteria:

  • Exclusion Criteria for schizophrenic subjects:

    • Subjects with significant neurological disease, acoustic neuromas or glomus tumors, or other contraindicated neuropathology.
    • Claustrophobia, or the inability to lie still in a confined space
    • Additional exclusion criteria for repetitive Transcranial Magnetic Stimulation (rTMS) include the following:

      • a personal or family history of epilepsy;
      • a personal history of head injury, aneurysm, stroke, previous cranial neurosurgery, neurological or psychiatric disorders other than schizophrenia, or migraines
      • recent use of cocaine or alcohol
      • metal implants in the head or neck
      • a pacemaker
      • pregnancy (or the possibility of pregnancy)
      • medications that lower seizure threshold (tricyclic antidepressants or bupropion) or reduce cortical excitation (anticonvulsants or benzodiazepines).
    • Persons under 21 years of age (children) are excluded because the effect of rTMS on children is unknown, in contrast to adults, who have been well studied.
    • Exclusion items specific to Functional Magnetic Resonance Imaging (fMRI):

      • magnetic metallic implants
      • electronic or magnetic implants, such as pacemakers, as these may stop working
      • nonremovable dental implants
      • permanent makeup or tattoos with metallic dyes
      • a positive pregnancy test (for females)
      • a self-reported history of loss of consciousness greater than 10 minutes
      • physical disabilities that prohibit task performance
    • Any other condition that the investigator believes might put the participant at risk
  • Exclusion Criteria for control subjects:

    • Subjects with significant neurological disease, acoustic neuromas or glomus tumors, or other contraindicated neuropathology.
    • Claustrophobia, or the inability to lie still in a confined space
    • Magnetic metallic implants
    • Electronic or magnetic implants, such as pacemakers, as these may stop working
    • Nonremovable dental implants
    • Permanent makeup or tattoos with metallic dyes
    • A positive pregnancy test (for females)
    • A self-reported history of loss of consciousness greater than 10 minutes
    • Physical disabilities that prohibit task performance
    • Any other condition that the investigator believes might put the participant at risk
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01620086

Locations
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
Sponsors and Collaborators
University of Arkansas
Investigators
Principal Investigator: Erick Messias, MD, MPH, PhD University of Arkansas
  More Information

Responsible Party: University of Arkansas
ClinicalTrials.gov Identifier: NCT01620086     History of Changes
Other Study ID Numbers: 134662 
Study First Received: June 4, 2012
Results First Received: July 25, 2016
Last Updated: October 28, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by University of Arkansas:
Schizophrenia
Auditory hallucinations (AH)
Phantom sound perception
repetitive transcranial magnetic stimulation (rTMS)
Percent habituation in the P50 amplitude with 250 ms ISI

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders

ClinicalTrials.gov processed this record on December 02, 2016