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

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 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.

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 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 either schizophrenia 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