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

Sponsor

Mclean Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT02642029

Collaborator

Massachusetts General Hospital (Other)

Enrollment

Locations

Arms

39.8

Actual Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia Schizoaffective Disorder Bipolar Disorder I	Device: Excitatory TMS Device: Inhibitory TMS Device: Sham TMS	N/A

Detailed Description

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 (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.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

Cerebellar Transcranial Magnetic Stimulation (cTMS) in Psychotic Disorders: Effect on Time Perception, Executive Function, and Mood and Psychotic Symptoms

Actual Study Start Date :

Feb 18, 2016

Actual Primary Completion Date :

Jun 14, 2019

Actual Study Completion Date :

Jun 14, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intermittent TBS (iTBS) Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis.	Device: Excitatory TMS Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis. Other Names: iTBS
Active Comparator: Continuous TBS (cTBS) Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis.	Device: Inhibitory TMS Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis. Other Names: cTBS
Sham Comparator: Sham TBS Single session, using the exact same procedures as the active arms but with a sham coil, which is designed to induce the same nonspecific sensory effects of TMS (auditory and somatosensory activation) without inducing the neuromodulatory magnetic fields.	Device: Sham TMS Single session, using the exact same procedures as the active arms but with a sham coil, which is designed to induce the same nonspecific sensory effects of TMS (auditory and somatosensory activation) without inducing the neuromodulatory magnetic fields. Other Names: shamTBS

Arm

Intervention/Treatment

Experimental: Intermittent TBS (iTBS)

Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis.

Device: Excitatory TMS

Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis.

Other Names:

iTBS

Active Comparator: Continuous TBS (cTBS)

Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis.

Device: Inhibitory TMS

Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis.

Other Names:

cTBS

Sham Comparator: Sham TBS

Single session, using the exact same procedures as the active arms but with a sham coil, which is designed to induce the same nonspecific sensory effects of TMS (auditory and somatosensory activation) without inducing the neuromodulatory magnetic fields.

Device: Sham TMS

Other Names:

shamTBS

Outcome Measures

Primary Outcome Measures

Change (Δ) in accuracy of time interval discrimination pre- and post-TMS [In each of the 3 study visits, participants will undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Thus, approximately 30-45 min will separate the pre- and post-TMS task performances.]
In each trial, participants are presented with two tones separated by 1200 ms (the standard interval), a 1s delay, then a comparison pair of tones. The time interval of the second tone pair will be either equal to (E-condition), longer than (L-condition), or shorter than (S-condition) that of the first pair. Participants are asked to indicate using a keyboard whether the second time interval is equal, longer, or shorter than the first.
Symptoms (mood and psychosis) [In each of the 3 study visits, participants will undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Thus, approximately 30-45 min will separate the pre- and post-TMS symptom ratings.]
Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS) and asked to indicate current levels of depression, anxiety, euphoria, auditory hallucinations, visual hallucinations, paranoia, referential thinking, and delusions of control. The VAS format will allow participants to self-report ratings quickly and easily with simple mouse clicks.
Change (Δ) in accuracy of N-back working memory task pre- and post-TMS [In each of the 3 study visits, participants will undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Thus, approximately 30-45 min will separate the pre- and post-TMS task performances.]
Participants are presented with a series of words or numbers and prompted to indicate whether the currently presented stimulus is the same as the one presented n-stimuli previously.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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