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

The goal of this study is to use transcranial magnetic stimulation (TMS) to investigate the impact of modulating cerebellar activity on time perception, executive function, and mood and psychotic symptoms in psychosis patients (i.e., schizophrenia, schizoaffective disorder, and bipolar disorder with psychotic features). The investigators hypothesize that abnormally reduced activity in the cerebellum contributes to the abnormalities in patients, that cerebellum-mediated disruptions in time perception may partially underlie executive dysfunction and symptoms, and that cerebellar stimulation will normalize disease-relevant outcome measures.

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) 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.

(1a) Time perception hypothesis: 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 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, 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 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.

Eligibility Criteria:
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 electroconvulsive therapy (ECT) 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 psychotropic 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, transcutaneous electrical nerve stimulation (TENS) unit, or ventriculo-peritoneal shunt)
    * Magnetically active dental implants
    * Cochlear/otologic implants
    * Cerebrospinal fluid (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