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| Name | Class |
|---|---|
| Massachusetts General Hospital | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intermittent TBS (iTBS) | Experimental | Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis. |
|
| Continuous TBS (cTBS) | Active Comparator | Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis. |
|
| Sham TBS | Sham Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Excitatory TMS | Device | Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change (Δ) 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. |
| Change (Δ) 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. |
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Inclusion Criteria:
Patients
Healthy Controls:
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:
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:
Pregnant women
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| Name | Affiliation | Role |
|---|---|---|
| Ann K Shinn, MD, MPH | Mclean Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McLean Hospital | Belmont | Massachusetts | 02478 | United States | ||
| Massachusetts General Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38025437 | Derived | Shinn AK, Hurtado-Puerto AM, Roh YS, Ho V, Hwang M, Cohen BM, Ongur D, Camprodon JA. Cerebellar transcranial magnetic stimulation in psychotic disorders: intermittent, continuous, and sham theta-burst stimulation on time perception and symptom severity. Front Psychiatry. 2023 Nov 13;14:1218321. doi: 10.3389/fpsyt.2023.1218321. eCollection 2023. |
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Two participants did not undergo TBS after enrollment. N=1 participant enrolled and completed the pre-intervention clinical evaluation but withdrew prior to randomization (no specific reason given by the participant). N=1 participant had a positive urine drug screen after enrollment; as active substance use within the prior 3 months is an exclusion criterion, the participant was excluded prior to randomization.
N=28 participants were enrolled (provided informed consent to participate in the study).
(Note: when I enter the number in the "Protocol Enrollment" field, the number does not save.)
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| ID | Title | Description |
|---|---|---|
| FG000 | Sham-iTBS-cTBS | Randomized first to Sham. Then randomized to iTBS for the second study visit. Then randomized to cTBS for the third study visit. |
| FG001 | Sham-cTBS-iTBS | Randomized first to Sham. Then randomized to cTBS for the second study visit. Then randomized to iTBS for the third study visit. |
| FG002 | iTBS-sham-cTBS | Randomized first to iTBS. Then randomized to sham for the second study visit. Then randomized to cTBS for the third study visit. |
| FG003 | iTBS-cTBS-sham | Randomized first to iTBS. Then randomized to cTBS for the second study visit. Then randomized to sham TBS for the third study visit. |
| FG004 | cTBS-sham-iTBS | Randomized first to cTBS. Then randomized to sham for the second study visit. Then randomized to iTBS for the third study visit. |
| FG005 | cTBS-iTBS-sham | Randomized first to cTBS. Then randomized to iTBS for the second study visit. Then randomized to sham TBS for the third study visit. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study Visit 1 (1 Day) |
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| Washout 1 (≥ 36 Hours) |
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| Study Visit 2 (1 Day) |
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| Washout 2 (≥ 36 Hours) |
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| Study Visit 3 (1 Day) |
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All enrolled participants
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | All enrolled participants (study was designed for all participants to receive all 3 interventions- iTBS, cTBS, and sham TBS). |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change (Δ) 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). | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Mean | Standard Deviation | accuracy (proportion correct) | 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. |
Varied. Approximately one-month time frame (mean 11.6 ± 6.6, range 4-28 days). Participants were monitored for adverse events from enrollment to end of study participation.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Intermittent TBS (iTBS) | Single session of intermittent theta-burst stimulation (600 pulses in blocks of 2s, separated by 8s of pause) to cerebellar vermis. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Discomfort from TMS | Injury, poisoning and procedural complications | Non-systematic Assessment |
(1) Small sample size. (2) Statistical analyses uncorrected for multiple comparisons. (3) Sample consisted mostly of stable outpatients with low symptom severity. (4) IDT task difficulty was not adjusted to participant performance. (5) Negative symptoms were not evaluated. However, acute changes in negative symptoms (which tend to be trait-like phenomena) are more challenging to measure. (6) Study did not include any biological markers (e.g., imaging) by which to measure TBS effects.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ann Shinn, MD | McLean Hospital | 617-855-3053 | akshinn@partners.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 28, 2022 | Oct 17, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 22, 2022 | Oct 17, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D011618 | Psychotic Disorders |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| Inhibitory TMS | Device | Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis. |
|
|
| Sham TMS | Device | 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. |
|
|
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Change (Δ) 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. |
| Charlestown |
| Massachusetts |
| 02129 |
| United States |
| COMPLETED |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Diagnosis | Count of Participants | Participants |
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| Education | Count of Participants | Participants |
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| Estimated Intelligence Quotient (IQ) [(North American Adult Reading Test (NAART)] | The North American Adult Reading Test (NAART) is a quickly administered index that is widely used to estimate verbal intellectual ability (Uttl, J Clin & Exper Neuropsychology 2002). It consists of 61 irregular rare words scored for accuracy according to North American pronunciation rules. The NAART has been used to estimate Weschler Adult Intelligence Scale, Revised (WAIS-R) verbal IQ, performance IQ, and full scale IQ (Blair & Spreen, Clinical Neuropsychologist 1989). Higher values represent higher intellectual ability. Population average IQ is 100; 68% of scores fall between 85 and 115. | Mean | Standard Deviation | units on a scale |
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| Positive and Negative Syndrome Scale (PANSS) | The Positive and Negative Syndrome Scale (PANSS; Kay et al., Schizoph. Bulletin 1987) is a widely used standardized measure to assess the severity of psychotic symptoms. The scale is interviewer-rated and consists of 30 items (7 positive, 7 negative, and 16 general psychopathology symptoms). Each item is rated on a scale from 1 ("absent") to 7 ("extreme"). Items in each of the sub-scales are summed to produce the positive (range 7-49), negative (range 7-49), and general psychopathology (range 16-112) subscores. The sum of all PANSS items yields the PANSS total score (range 30-210). | Mean | Standard Deviation | units on a scale |
|
| Young Mania Rating Scale (YMRS) | The Young Mania Rating Scale (YMRS; Young et al., Br J Psychiatry 1978) is a widely used standardized measure to assess the severity of manic symptoms. The scale is interviewer-rated and consists of 11 items. Seven items (elevated mood, increased motor activity/energy, sexual interest, sleep, thought disorder, appearance, insight) are rated on a Likert scale from 0 to 4. Four items (irritability, speech, content, disruptive/aggressive behavior) are rated from 0 to 8. Item scores are summed to produce the total score (range 0 to 60). Higher scores indicate greater severity of manic symptoms. | Mean | Standard Deviation | units on a scale |
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| Montgomery-Asberg Depression Rating Scale (MADRS) | The Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery & Asberg, Br J Psychiatry 1979) is a widely used standardized measure to assess the severity of depressive symptoms. The MADRS is interviewer-rated and consists of 10 items. Each item is rated on a Likert scale from 0 to 6. Item scores are summed to produce the total score (range 0 to 60). Higher scores indicate greater severity of depressive symptoms. | Mean | Standard Deviation | units on a scale |
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| Psychotic Symptom Rating Scale (PSYRATS-AH) | The auditory hallucination (AH) sub-scale of the Psychotic Symptom Rating Scale (PSYRATS; Haddock et al., Psychol Med 1999) is an interviewer-administered AH measure that is widely used in AH research. The PSYRATS-AH assesses 11 AH characteristics of AH (e.g., frequency, duration, loudness, degree of distress, controllability), with each item rated on a Likert scale from 0-4 (total range 0-44). Higher scores on the PSYRATS-AH indicate greater severity of auditory hallucinations. | Mean | Standard Deviation | units on a scale |
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| Chlorpromazine equivalent dose (CPZ) | Mean | Standard Deviation | mg/day |
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| Taking antipsychotic medication | Count of Participants | Participants |
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| Taking mood stabilizer | Count of Participants | Participants |
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| Taking either antipsychotic or mood stabilizer | Count of Participants | Participants |
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| Not taking any psychotropic medication | Count of Participants | Participants |
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| Primary | Change (Δ) 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). | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Least Squares Mean | Standard Error | accuracy (proportion correct) | 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. |
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| Primary | Change (Δ) 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). | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Least Squares Mean | Standard Error | ms | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| Primary | Change (Δ) 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. | Cross-over design in which patients were assigned to 3 sessions of cerebellar TBS: one session each of iTBS, cTBS, and sham TBS. Analyses were conducted for all participants (patients who completed at least one study visit; n=26) as well as for completers only (patients who completed all 3 study visits; n=20; results not reported here). The fields for "overall number of participants analyzed" (above) indicate all participants who completed each of the sessions (iTBS, cTBS, sham TBS). | Posted | Median | Full Range | score on a scale | 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. |
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| 0 |
| 22 |
| 0 |
| 22 |
| 2 |
| 22 |
| EG001 | Continuous TBS (cTBS) | Single session of continuous theta-burst stimulation of 600 pulses to cerebellar vermis. | 0 | 21 | 0 | 21 | 0 | 21 |
| EG002 | 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. | 0 | 25 | 0 | 25 | 1 | 25 |
Not provided
Not provided
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| Ratio (post/pre) |
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Tested the null hypothesis of no difference between iTBS and sham TBS on N-back accuracy. |
| Conducted a generalized linear mixed model fit by maximum likelihood (Laplace Approximation) ['glmerMod' in R] with binomial (logit) distribution. N-back accuracy was the dependent variable. Time (pre vs. post), condition (iTBS vs. sham, cTBS vs. sham), and the interaction of time x condition (time x iTBS, time x cTBS) were the independent variables. P-value here is for the cTBS (vs. sham) x time interaction. | Mixed Models Analysis | 0.322 | Significance threshold was p < 0.05, two-sided. | Beta coefficient for timexcTBS interact | -0.0903 | 2-Sided | Equivalence | Tested the null hypothesis of no difference between cTBS and sham TBS on N-back accuracy. |
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| Change in RT (post-pre) |
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Tested the null hypothesis of no difference between iTBS and sham TBS on N-back accuracy. |
| Conducted a generalized linear mixed model fit by maximum likelihood (Laplace Approximation) ['glmerMod' in R] with gamma distribution. N-back reaction time (RT) was the dependent variable. Time (pre vs. post), condition (iTBS vs. sham, cTBS vs. sham), and the interaction of time x condition (time x iTBS, time x cTBS) were the independent variables. P-value here is for the cTBS (vs. sham) x time interaction. | Mixed Models Analysis | 0.00000009 | Significance threshold was p < 0.05, two-sided. | Beta coefficient for timexcTBS interact | -47.764 | 2-Sided | Equivalence | Tested the null hypothesis of no difference between cTBS and sham TBS on N-back accuracy. |
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| Change in VAS score (post-pre) |
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We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, depressed mood). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.243 |
| beta coefficient for depressed mood |
| 0.00071 |
| 2-Sided |
| 95 |
| -0.00048 |
| 0.00190 |
| Other |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
|
| Change in VAS score (post-pre) |
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|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, anxiety). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.284 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for anxiety |
| -0.00063 |
| 2-Sided |
| 95 |
| -0.00179 |
| 0.00052 |
| Other |
|
| Change in VAS score (post-pre) |
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|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, elated mood). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.317 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for elated mood |
| -0.00070 |
| 2-Sided |
| 95 |
| -0.00208 |
| 0.00067 |
| Other |
|
| Change in VAS score (post-pre) |
|
|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, auditory hallucinations). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.028 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for auditory hallucinat |
| 0.00195 |
| 2-Sided |
| 95 |
| 0.00021 |
| 0.00369 |
| Other |
|
| Change in VAS score (post-pre) |
|
|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, visual hallucinations). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.685 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for visual hallucinatio |
| -0.00039 |
| 2-Sided |
| 95 |
| -0.00230 |
| 0.00151 |
| Other |
|
| Change in VAS score (post-pre) |
|
|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, paranoid ideation). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.597 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for paranoid ideation |
| 0.00040 |
| 2-Sided |
| 95 |
| -0.00108 |
| 0.00188 |
| Other |
|
| Change in VAS score (post-pre) |
|
|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, ideas/delusions of reference). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.178 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for ideas/del of refere |
| -0.00142 |
| 2-Sided |
| 95 |
| -0.00350 |
| 0.00065 |
| Other |
|
| Change in VAS score (post-pre) |
|
|
We explored the association between interval discrimination task (IDT) performance (accuracy) and each symptom self-rating (here, delusions of control). We conducted a mixed effects regression analysis to test the null hypothesis of no association. Model included time (pre, post) and condition (iTBS vs. sham, cTBS vs. sham) in addition to symptom rating as independent variables, and IDT performance accuracy as the dependent variable. |
| Mixed Models Analysis |
| 0.777 |
Given the exploratory nature of this pilot study, we set the significance threshold at p <0.05, two-sided, without correcting for eight comparisons. |
| beta coefficient for delusions of contro |
| -0.00038 |
| 2-Sided |
| 95 |
| -0.00305 |
| 0.00228 |
| Other |