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

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.

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