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

Schizophrenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02642029
• Other study ID #: 2015P001833
• Status: Completed
• Phase: N/A
• Start date: February 18, 2016
• Est. completion date: June 14, 2019

Study information

• Verified date: December 2022
• Source: Mclean Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: June 14, 2019
• Est. primary completion date: June 14, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Bipolar Disorder
• Bipolar Disorder I
• Disease
• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia

Intervention

Device:
• Excitatory TMS
Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis.
• Inhibitory TMS
Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis.
• 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.

Locations

Country	Name	City	State
United States	McLean Hospital	Belmont	Massachusetts
United States	Massachusetts General Hospital	Charlestown	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Mclean Hospital	Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change (?) in Accuracy of Time Interval Discrimination Pre- and Post-TMS	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. The tones for all conditions were 700Hz in frequency, 50ms in duration, and presented binaurally via headphones. Participants completed 15 trials during each pre- or post-TMS session for a total of up to 90 total trials across the three study visits. Prior to each IDT session, participants performed a practice run consisting of six trials. The primary outcome for this task was overall accuracy (proportion of correct responses).	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Accuracy of N-back Working Memory Task Pre- and Post-TMS	Participants are presented with a series of words or numbers and prompted to indicate as quickly as possible whether the currently presented stimulus is the same as the one presented n-stimuli previously. For example, in a 2-back task a subject would be asked to indicate whether the current stimulus was identical to that presented 2 stimuli before. To increase the likelihood of detecting change in task performance with each TMS condition (and minimize potential ceiling or floor effects), the difficulty level was individualized so that each participant performed at approximately 80% accuracy; during the "pre" session of the first study visit, a trial session established the difficulty level, i.e., how many presentations back (n-stimuli) at which the task would start. After the trial session, a session with 50 presentations was carried out and recorded whether the response was correct (accuracy) and the time from presentation to response (reaction time).	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Reaction Time (RT) of N-back Working Memory Task Pre- and Post-TMS	Participants are presented with a series of words or numbers and prompted to indicate as quickly as possible whether the currently presented stimulus is the same as the one presented n-stimuli previously. For example, in a 2-back task a subject would be asked to indicate whether the current stimulus was identical to that presented 2 stimuli before. To increase the likelihood of detecting change in task performance with each TMS condition (and minimize potential ceiling or floor effects), the difficulty level was individualized so that each participant performed at approximately 80% accuracy; during the "pre" session of the first study visit, a trial session established the difficulty level, i.e., how many presentations back (n-stimuli) at which the task would start. After the trial session, a session with 50 presentations was carried out and recorded whether the response was correct (accuracy) and the time from presentation to response (reaction time).	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Depressed Mood)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Anxiety)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Elated Mood)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent/no elation, 100=most severe) and asked to indicate current levels of depression, anxiety, euphoria, auditory hallucinations, visual hallucinations, paranoia, referential thinking, and delusions of control. Higher VAS scores for elation indicate more elation (suggestive of mania). The VAS format will allow participants to self-report ratings quickly and easily with simple mouse clicks.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Auditory Hallucinations)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Visual Hallucinations)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Paranoid Ideation)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Ideas/Delusions of Reference)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.
Primary	Change (?) in Symptoms (Delusions of Control)	Participants will take a brief computerized survey pre- and post-TMS, in which they will be presented with visual analogue scales (VAS, range 0-100, 0=absent, 100=most severe) 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.	In each of the 3 study visits (separated by at least 36h), participants undergo (a) pre-TMS assessments (15-20min), (b) TMS (15min), and (c) post-TMS assessments (15-20min). Approximately 30-45 min separate the pre- and post-TMS task performances.