Targeting Cerebellum to Treat Psychosis: a Transcranial Magnetic Stimulation (TMS) Study

The cerebellum plays a major role in integrative processing of higher order cognitive and
affective functions, but it has not been considered a major treatment target for psychotic
disorders. The goal of this study is to administer three different conditions of transcranial
magnetic stimulation (TMS)-- excitatory, inhibitory, and sham TMS-- in a cross-over design in
psychosis patients (i.e., schizophrenia, schizoaffective disorder, and bipolar disorder with
psychotic features) and healthy control participants to investigate with causal explanatory
power the role of the cerebellum as a treatment target for psychotic disorders. More
specifically, the investigators will measure the effects of cerebellar excitation and
inhibition on time perception, executive function, and symptomatology. TMS will be
administered using a theta-burst stimulation (TBS) protocol applied to the posterior
cerebellar vermis. Participants will undergo three study sessions, one for each of the three
TMS conditions. During each session, the investigators will administer validated cognitive
paradigms and clinical measures immediately before and after TMS.

The specific aims are to:

1: Investigate the role of the cerebellum in abnormalities of time perception, executive
function, and mood and psychotic symptoms by evaluating these functions before and
immediately after excitatory, inhibitory, or sham TMS applied to the cerebellar vermis in
patients with psychosis and in healthy control participants.

(1a) Time perception hypothesis: Compared with controls, patients with psychotic disorders
will have impaired timing perception, i.e., higher number of errors and/or greater
inter-trial variability in an interval discrimination task (Protocol A) +/- a repetitive
tapping task (optional Protocol B) both at baseline and after sham TMS. The investigators
predict that the abnormalities in patients will improve after excitatory but not inhibitory
TMS.

(1b) Executive function hypothesis: Patients will show a higher number of errors and longer
reaction times on the N-back working memory task (Protocol A) +/- the multi-source
interference task (optional Protocol B), both at baseline and after sham TMS. The
investigators predict that these deficits in patients will improve after excitatory but not
inhibitory TMS.

(1c) Symptom hypothesis: Symptom ratings using visual analog scales will improve in the
period immediately after excitatory but not inhibitory TMS, and show no significant change
after sham TMS.

2: Investigate the relationship between time perception and (a) executive function and (b)
symptomatology in patients with psychotic disorders. Hypothesis: The investigators predict
that performance on the time perception task will correlate with performance on a working
memory task as well as with mood and psychotic symptoms.

This study may improve understanding about the role of the cerebellum in the pathophysiology
of psychotic disorders. Such knowledge can potentially guide the development of cerebellar
TMS as a therapeutic intervention for psychosis.

Inclusion Criteria:

- Patients

- Men and women

- Ages 18-50 years

- Patients diagnosed with schizophrenia (SZ), schizoaffective disorder (SZA), or
psychotic bipolar disorder (BP).

- On a stable psychiatric medication regimen for at least a month prior to and
during study participation

- Healthy Controls:

- Men and women

- Ages 18-50 years

- Without major psychiatric illness

Exclusion Criteria:

- Patients

- Any change in psychiatric medications within a month prior to and during study
participation

- Legal or mental incompetency

- Intellectual disability

- Substance use disorder (abuse or dependence) with active use within the last 3
months

- Significant medical or neurological illness

- Prior neurosurgical procedure

- History of seizures

- History of ECT treatment or clinical TMS within the past three months

- History of participation in a cerebellar TMS study

- Implanted cardiac pacemakers

- Patients who have conductive, ferromagnetic or other magnetic-sensitive metals
implanted in their head or neck, or are non-removable and within 30 cm of the
treatment coil. These include:

- Aneurysm clips or coils

- Carotid or cerebral stents

- Metallic devices implanted in the head (e.g. Implanted pacemaker, medication
pump, vagal stimulator, deep brain stimulator, TENS unit, or
ventriculo-peritoneal shunt)

- Magnetically active dental implants

- Cochlear/otologic implants

- CSF shunts

- Ferromagnetic ocular implants

- Pellets, bullets, fragments less than 30 cm from the coil

- Facial tattoos with metallic ink, permanent makeup less than 30 cm from the
coil

- Pregnant women

- Healthy Controls:

- History of major psychiatric illness, including psychosis

- Has a first-degree relative with psychosis

- Active use of neuropsychoactive medications

- Legal or mental incompetency

- Intellectual disability

- Substance use disorder (abuse or dependence) with active use within the last 3
months

- Significant medical or neurological illness

- Prior neurosurgical procedure

- History of seizures

- History of ECT treatment or clinical TMS within the past three months

- History of participation in a cerebellar TMS study

- Implanted cardiac pacemakers

- Individuals who have conductive, ferromagnetic or other magnetic-sensitive metals
implanted in their head or neck, or are non-removable and within 30 cm of the
treatment coil. These include:

- Aneurysm clips or coils

- Carotid or cerebral stents

- Metallic devices implanted in the head (e.g. Implanted pacemaker, medication
pump, vagal stimulator, deep brain stimulator, TENS unit, or
ventriculo-peritoneal shunt)

- Magnetically active dental implants

- Cochlear/otologic implants

- CSF shunts

- Ferromagnetic ocular implants

- Pellets, bullets, fragments less than 30 cm from the coil

- Facial tattoos with metallic ink, permanent makeup less than 30 cm from the
coil

- Pregnant women