Schizophrenia
Conditions
Keywords
Schizophrenia, Auditory hallucinations (AH), Phantom sound perception, repetitive transcranial magnetic stimulation (rTMS), Percent habituation in the P50 amplitude with 250 ms ISI
Brief summary
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.
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.
Interventions
DEVICEActive Repetitive Transcranial Magnetic Stimulation 1 Hz
active rTMS delivered at 1Hz frequency over temporal cortex
DEVICEActive Repetitive Transcranial Magnetic Stimulation 10 Hz
active rTMS delivered at 10 Hz frequency over temporal cortex
DEVICEActive control site Repetitive Transcranial Magnetic Stimulation at 1Hz
active rTMS delivered at either 1 Hz frequency over the vertex
DEVICESham control site Repetitive Transcranial Magnetic Stimulation
sham rTMS delivered at 1Hz frequency over the vertex
DEVICEActive control site Repetitive Transcranial Magnetic Stimulation at 10 Hz
Active 10 Hz rTMS delivered over the vertex
Sponsors
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
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
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Auditory Hallucinations Questionnaire (AHQ). | change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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). | change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls) | 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). | change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients Patients with Schizophrenia who meet entry criteria for the study and get stimulation over temporal cortex. | 6 |
| Controls These subjects are normal controls without schizophrenia who get stimulation over the vertex. | 8 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | failed study criteria | 1 | 4 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 0 |
Baseline characteristics
| Characteristic | Controls | Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 6 Participants | 14 Participants |
| Age, Continuous | 29 years STANDARD_DEVIATION 9.72 | 49.5 years STANDARD_DEVIATION 8.22 | 35.2 years STANDARD_DEVIATION 8.75 |
| Gender Female | 4 Participants | 4 Participants | 8 Participants |
| Gender Male | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | 8 participants | 6 participants | 14 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Changes in Auditory Hallucinations Questionnaire (AHQ).
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.
Time frame: change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls)
Population: Data are not collected on this outcome measure for controls. Data was missing for one patient in the active 1 Hz treatment condition.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients: Control Site-baseline | Changes in Auditory Hallucinations Questionnaire (AHQ). | -2.67 units on a scale | Standard Deviation 2.66 |
| Patients: Active 1Hz Treatment Site - Baseline | Changes in Auditory Hallucinations Questionnaire (AHQ). | -1.80 units on a scale | Standard Deviation 2.86 |
| Patients: Active 10 Hz Treatment Site-baseline | Changes in Auditory Hallucinations Questionnaire (AHQ). | -2.50 units on a scale | Standard Deviation 1.97 |
Secondary
Depression Level Changes as Measured by the Hamilton Depression Inventory (HAMD).
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.
Time frame: change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls)
Population: Data are not collected on this outcome measure for controls. Data was missing for one patient in the active 1 Hz treatment condition.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients: Control Site-baseline | Depression Level Changes as Measured by the Hamilton Depression Inventory (HAMD). | -.083 units on a scale | Standard Deviation 4.02 |
| Patients: Active 1Hz Treatment Site - Baseline | Depression Level Changes as Measured by the Hamilton Depression Inventory (HAMD). | -4.60 units on a scale | Standard Deviation 4.88 |
| Patients: Active 10 Hz Treatment Site-baseline | Depression Level Changes as Measured by the Hamilton Depression Inventory (HAMD). | -3.67 units on a scale | Standard Deviation 6.41 |
Secondary
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).
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.
Time frame: change between the baseline time point and 4 days of active treatment (patients) or 2 days of sham or active treatment (controls)
Population: Three patients had missing data for the control site - baseline condition and the active 1 Hz treatment site -baseline conditions. One patient had missing data for the active 10 Hz treatment site - baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Controls: 1Hz Control Site Active-Baseline | 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). | -17.55 percent of change in wave amplitude | Standard Deviation 39.17 |
| Controls: Sham Contorl Site rTMS - Baseline | 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). | -6.52 percent of change in wave amplitude | Standard Deviation 51.65 |
| Patients: Control Site-baseline | 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). | 21 percent of change in wave amplitude | Standard Deviation 47.63 |
| Patients: Active 1Hz Treatment Site - Baseline | 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). | -23.05 percent of change in wave amplitude | Standard Deviation 89.74 |
| Patients: Active 10 Hz Treatment Site-baseline | 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). | -7.65 percent of change in wave amplitude | Standard Deviation 68.3 |